TUBERCULOSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Tuberculosis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83644-2 1. Tuberculosis-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on tuberculosis. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON TUBERCULOSIS .......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Tuberculosis .................................................................................. 9 E-Journals: PubMed Central ..................................................................................................... 133 The National Library of Medicine: PubMed .............................................................................. 176 CHAPTER 2. NUTRITION AND TUBERCULOSIS .............................................................................. 315 Overview.................................................................................................................................... 315 Finding Nutrition Studies on Tuberculosis............................................................................... 315 Federal Resources on Nutrition ................................................................................................. 323 Additional Web Resources ......................................................................................................... 324 CHAPTER 3. ALTERNATIVE MEDICINE AND TUBERCULOSIS ........................................................ 327 Overview.................................................................................................................................... 327 National Center for Complementary and Alternative Medicine................................................ 327 Additional Web Resources ......................................................................................................... 345 General References ..................................................................................................................... 350 CHAPTER 4. DISSERTATIONS ON TUBERCULOSIS .......................................................................... 353 Overview.................................................................................................................................... 353 Dissertations on Tuberculosis.................................................................................................... 353 Keeping Current ........................................................................................................................ 360 CHAPTER 5. CLINICAL TRIALS AND TUBERCULOSIS..................................................................... 361 Overview.................................................................................................................................... 361 Recent Trials on Tuberculosis.................................................................................................... 361 Keeping Current on Clinical Trials ........................................................................................... 377 CHAPTER 6. PATENTS ON TUBERCULOSIS ..................................................................................... 379 Overview.................................................................................................................................... 379 Patents on Tuberculosis ............................................................................................................. 379 Patent Applications on Tuberculosis ......................................................................................... 432 Keeping Current ........................................................................................................................ 465 CHAPTER 7. BOOKS ON TUBERCULOSIS ........................................................................................ 467 Overview.................................................................................................................................... 467 Book Summaries: Federal Agencies............................................................................................ 467 Book Summaries: Online Booksellers......................................................................................... 482 The National Library of Medicine Book Index ........................................................................... 496 Chapters on Tuberculosis........................................................................................................... 498 CHAPTER 8. MULTIMEDIA ON TUBERCULOSIS.............................................................................. 501 Overview.................................................................................................................................... 501 Video Recordings ....................................................................................................................... 501 Audio Recordings....................................................................................................................... 507 Bibliography: Multimedia on Tuberculosis................................................................................ 508 CHAPTER 9. PERIODICALS AND NEWS ON TUBERCULOSIS........................................................... 511 Overview.................................................................................................................................... 511 News Services and Press Releases.............................................................................................. 511 Newsletter Articles .................................................................................................................... 513 Academic Periodicals covering Tuberculosis ............................................................................. 514 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 515 Overview.................................................................................................................................... 515 U.S. Pharmacopeia..................................................................................................................... 515 Commercial Databases ............................................................................................................... 517 Researching Orphan Drugs ....................................................................................................... 517
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APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 521 Overview.................................................................................................................................... 521 NIH Guidelines.......................................................................................................................... 521 NIH Databases........................................................................................................................... 523 Other Commercial Databases..................................................................................................... 551 The Genome Project and Tuberculosis....................................................................................... 551 APPENDIX B. PATIENT RESOURCES ............................................................................................... 555 Overview.................................................................................................................................... 555 Patient Guideline Sources.......................................................................................................... 555 Associations and Tuberculosis ................................................................................................... 590 Finding Associations.................................................................................................................. 592 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 595 Overview.................................................................................................................................... 595 Preparation................................................................................................................................. 595 Finding a Local Medical Library................................................................................................ 595 Medical Libraries in the U.S. and Canada ................................................................................. 595 ONLINE GLOSSARIES................................................................................................................ 601 Online Dictionary Directories ................................................................................................... 602 TUBERCULOSIS DICTIONARY................................................................................................ 603 INDEX .............................................................................................................................................. 691
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with tuberculosis is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about tuberculosis, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to tuberculosis, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on tuberculosis. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to tuberculosis, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on tuberculosis. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON TUBERCULOSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on tuberculosis.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and tuberculosis, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “tuberculosis” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Preventing and Controlling Tuberculosis Along the US-Mexico Border : Work Group Report Source: MMWR Morbidity and Mortality Weekly Report 2001; 50(RR-1):1-28. Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, Office of the Morbidity and Mortality Weekly Report Series, 1600 Clifton Rd NE M/S C-08, Atlanta, GA, 30333, (404) 639-2100, http://www.cdc.gov/mmwr. US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report, for health professionals, organizations, and government agencies, provides recommendations for the improvement of tuberculosis (TB) infection
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control and prevention along the border between the United States (US) and Mexico. It addresses the challenges created by border-crossing populations, for example, Mexico's higher TB rate, low socioeconomic status and limited access to health care, frequent border crossing and travel to the United States, and a lack of coordinated care across health jurisdictions in Mexico and the US. Surveillance needs, case management and therapy completion, performance indicators and program evaluation, and research needs are discussed. •
Tuberculosis Treatment Source: City Health Information June 1999;18 (2):1-8. Contact: New York City Department of Health, Bureau of Tuberculosis Control, 125 Worth St Rm 216 Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This newsletter provides healthcare professionals information on tuberculosis (TB) treatment. It presents ten basics on the diagnosis, treatment, and prevention of TB and information on countries and areas with an estimated or reported high incidence of TB, a therapy timeline for previously untreated TB patients with drugsusceptible active disease, medications used in the treatment of TB, recommended antituberculosis treatment regimens for HIV-infected persons with drug-susceptible TB disease, and the use of antituberculosis medications in special situations, such as pregnancy, TB meningitis, and renal failure. The newsletter lists contact information for resources in New York City providing TB-related services.
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Testing and Treatment for Latent Tuberculosis Infection Source: City Health Information October 2000;19(3):1-8. Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This newsletter provides healthcare professionals with information on the testing and treatment of latent tuberculosis infection (LTBI). It summarizes and synthesizes the Centers for Disease Control and Prevention's and the American Thoracic Society's treatment recommendations, offers ten basic steps in testing and treatment, and provides a pullout guide on fundamental aspects of the testing and treatment of LTBI, including when and how to administer therapy, how to interpret the tuberculin skin test in BCG-vaccinated individuals, and how to treat HIV-positive individuals who are taking antiretroviral agents. The newsletter lists contact information for resources in New York City providing TB-related services.
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Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children Source: American Journal of Respiratory and Critical Care Medicine 1994 (May);149(5):1359-1374. Contact: American Lung Association of Maryland, 11720 Beltsville Drive 3rd FL, Beltsville, MD, 20705, (301) 572-3205. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://cdcnpin.org. Summary: This is an official statement of the American Thoracic Society on the treatment of tuberculosis (TB) and TB infection in adults and children. This paper discusses the following topics: treatment of TB, drugs in current use, potentially
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effective drugs, initial treatment regimens, monitoring adverse reactions, evaluation of response to treatment, management of patients whose treatment has failed or who have relapsed, management of patients who have drug-resistant disease, TB in children and adolescents, special considerations in treatment, treatment of TB infection, persons for whom preventive therapy is recommended, screening procedures, administration of isoniazid preventive therapy, monitoring preventive therapy, and alternative forms of TB prevention. •
Controlling the Resurgent Tuberculosis Epidemic: A 50 - State Survey of TB Statutes and Proposals for Reform Source: Journal of the American Medical Association; Vol. 269, No. 2. Contact: American Society of Law Medicine and Ethics, 765 Commonwealth Ave Ste 1634, Boston, MA, 02215-1401, (617) 262-4990, http://www.aslme.org. Summary: This article reports on a 50-state survey of tuberculosis (TB) laws, based on an examination of both TB-specific statutes and more general communicable disease statutes. The survey found that many statutes still in force were enacted at the turn of the century or in the early to mid-1900s, before the development of modern concepts of constitutional law and the concept of the need to protect public health. The article also recommends the development of an individualized treatment plan for all persons diagnosed with the disease, the balancing of constitutional rights against public health risk, the maintainence of confidentiality and antidiscrimination, and the bringing of communicable disease statutes into conformity with the American With Disabilities Act (ADA).
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Return of a Plague: The Perils of Tuberculosis in the 90's Source: The Exchange; Issue 21, July 1993. Contact: National Lawyers Guild AIDS Network, 558 Capp St, San Francisco, CA, 94110, (415) 824-8884. Summary: The re-emergence of the tuberculosis (TB) epidemic with its associated medical and legal problems, especially in relation to AIDS, is examined in this journal article. TB, its treatment, and the problem of incomplete treatment are described. The definition of AIDS has been expanded to include pulmonary TB. The article suggests that social reform is required to control TB, including the restructuring of the public health and social service systems. The interdependent reforms include public funding for TB education, emphasizing Directly Observed Therapy (DOT) to use in fighting incomplete treatment, funding research in diagnostics and treatments of TB, and developing guidelines for the legal issues involved. These legal concerns include civil rights with respect to state-mandated quarantine, confidentiality, and employment practices where infection control, not discrimination, prevents disease.
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Tuberculose et Infection par le VIH. [Tuberculosis and HIV Infection.] Contact: Agence Nationale de Recherches Sur le SIDA, 101 rue de Tolbiac, Paris. Summary: This factsheet explains epidemiology and treatment of tuberculosis (TB) in Persons with AIDS (PWA's). Since 1988, the number of French TB cases has risen, especially among PWA's. Active tuberculosis makes its appearance in one of two ways: a previous infection resurfaces, or a fresh infection is transmitted by another infected individual. Although PWA's experience more serious side effects, drugs are very effective against the tuberculosis bacterium. The drug-resistant strain of TB which has
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been observed in the United States is very rare in France. The factsheet also outlines the stages of TB and suggests medications for each stage. A short bibliography is appended. •
An Outbreak of Tuberculosis With Accelerated Progression Among Persons Infected With the Human Immunodeficiency Virus: An Analysis Using Restriction - Fragment - Length Polymorphisms Source: New England Journal of Medicine; Vol. 326, no. 4. Contact: San Francisco General Hospital, Department of Medicine, Chest Service, Pulmonary Complications of AIDS Study, SFGH-5K1, 1001 Potrero Ave, San Francisco, CA, 94110, (415) 821-8313. Louisiana State University Medical Center, Delta Region AIDS Education and Training Center, 136 S Roman St 3rd Fl, New Orleans, LA, 70112, (504) 568-3855, http://www.lsumc.edu. Summary: This reprint of a journal article analyzes an outbreak of tuberculosis (TB) that took place among residents of a housing facility for persons with HIV infection. As background information, the article points out that TB can develop from either a reactivation of a latent infection or from a primary infection. It then reviews the outbreak, which took place between December 1990 and April 1991, during which time 12 cases of TB were diagnosed. Two patients under treatment for TB had been admitted in the previous six months. Organisms isolated from 11 culture-positive residents had similar patterns, but isolates from the two patients treated prior to the outbreak showed different strains. The article says that this implicates the first of the 12 patients to come down with TB as the source of the outbreak. It concludes that newly acquired TB infection in HIV-positive patients can spread readily and progress rapidly to active disease. There should be heightened TB surveillance in facilities where HIV-positive persons live.
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Prevention and Control of Tuberculosis in Facilities Providing Long-Term Care to the Elderly : Recommendations of the Advisory Committee for Elimination of Tuberculosis Source: Morbidity and Mortality Weekly Report (MMWR). 39 (RR-10): 7-20; July 13, 1990. Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, Office of the Morbidity and Mortality Weekly Report Series, 1600 Clifton Rd NE M/S C-08, Atlanta, GA, 30333, (404) 332-4555, http://www.cdc.gov. US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report discusses managing and preventing tuberculosis (TB) in facilities that provide long-term care for the elderly. It provides a brief epidemiological history of TB among elderly people in the United States, including those in nursing homes. General guidelines for prevention and control of TB in the areas of surveillance, containment, assessment, and education are provided. Recommendations for surveillance include a tuberculin skin testing program for all new residents and employees to detect TB infection and active TB, case reporting, and encouraging HIV counseling and testing. Containment recommendations include information about appropriate isolation and treatment of the elderly resident, and an overview of contact investigations for residents and staff and appropriate preventive therapy. A recordkeeping system that includes specific data for annual review and assessment is recommended. The report concludes with the role of the local health department in the management and prevention of TB in long-term care facilities for the elderly.
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Spinal Tuberculosis Source: Current Opinion in Orthopedics. 11(3): 196-201. June 2000. Summary: This journal article provides health professionals with information on the diagnosis and management of spinal tuberculosis. Tuberculosis of the spine is still a common disease in some endemic regions and is returning to developed countries. The diagnosis is usually made with a high index of suspicion in endemic areas in the presence of pain and appropriate clinical symptoms and signs of a systemic infection. Typical plain radiographic changes include destruction of two adjacent vertebral bodies, narrowing of the intervening disk, scalloping of the anterior vertebrae, and a fusiform paravertebral abscess shadow. The development of the polymerase chain reaction technique and magnetic resonance imaging (MRI) in the past decade has greatly improved diagnostic accuracy. MRI is useful in diagnosing early or multicentric lesions before plain radiographic changes become obvious. The aims of treatment in spinal tuberculosis are eradication of the infection, preservation or restoration of neurologic integrity, and prevention or correction of spinal deformity. Combination chemotherapy remains the most important and effective treatment, whereas surgical intervention can help in achieving earlier fusion and less late deformity. Early results of spinal instrumentation with or without fusion appear to be promising in further enhancing good outcome. 1 figure, 2 tables, and 54 references. (AA-M).
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Primary Pancreatic Tuberculosis Source: Missouri Medicine. 88(11): 766-768. November 1991. Summary: This article describes the first reported case that fulfills the diagnostic criteria for primary pancreatic tuberculosis. After a detailed case presentation, the authors discuss extrapulmonary tuberculosis in general, the clinical presentation, and the diagnostic testing required to determine pancreatic tuberculosis. They also briefly review the literature covering this condition. Diagnostic tests considered include radiographic studies, ultrasound, CT guided needle aspiration of pancreatic masses, and exploratory laparotomy. 1 figure. 14 references.
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Tuberculosis and the Kidney Source: JASN. Journal of the American Society of Nephrology. 12(6): 1307-1314. June 2001. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Website: www.jasn.org. Summary: Tuberculosis of the kidney and urinary tract is, like other forms of the disease, caused by members of the Mycobacterium tuberculosis complex. This article reviews the clinical features of classical renal (kidney) tuberculosis, tuberculous interstitial nephritis, tuberculosis and glomerular disease, end stage renal disease (ESRD) caused by tuberculosis, tuberculosis developing in patients on hemodialysis and peritoneal dialysis, tuberculosis in transplant patients, genital tuberculosis, and hypercalcemia in dialysis patients. The authors also discuss laboratory diagnosis, pathology, the role of immunodeficiency in genitourinary tuberculosis, and treatment options. In developed nations, tuberculosis is relatively uncommon, but the risk of acquiring the disease is increased in immunosuppressed individuals, including patients on dialysis and recipients of kidney transplants. The signs and symptoms of renal tuberculosis mimic those of other infections of the kidney, so diagnostic awareness may prevent unnecessary morbidity (illness or complications). Tuberculosis may involve the
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kidney as part of generalized infection throughout the body or as localized genitourinary disease. The morphology (shape and appearance) of the lesions depends on the site of infection, the virulence of the organism, and the immune status of the patient. Modern short course antituberculosis drug regimens are effective in all forms of tuberculosis. However, special considerations apply to the treatment of tuberculosis in patients with impaired renal (kidney) function, as some drugs may not be metabolized properly. Surgical intervention is indicated in cases of advanced unilateral (involving one kidney) disease complicated by pain or hemorrhage and for bladder augmentation. 5 figures. 49 references. •
When to Consider Tuberculosis in Evaluating Hematuria Source: Consultant. 39(12): 3225. December 1999. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: Tuberculosis of the urinary tract is rare enough to justify the selective use of tuberculosis cultures when evaluating hematuria. Nonpulmonary (not in the lungs) tuberculosis accounts for only about 2 percent of diagnosed cases of tuberculosis. This brief article, one from a regular column that answers clinical questions, addresses the need to consider tuberculosis when evaluating a patient with hematuria (blood in the urine). The author recommends that physicians consider obtaining tuberculosis urine cultures for patients who are at increased risk for genitourinary tuberculosis. Such patients include immunocompromised persons and those with active pulmonary tuberculosis or a history of tuberculosis. A history of travel in or immigration from an area of high tuberculosis activity should also raise the index of suspicion. Readers are also encouraged to seek the advice of an infectious diseases consultant.
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Tuberculosis Remains an Important Factor in the Morbidity and Mortality of Hemodialysis Patients Source: Transplantation Proceedings. 30(3): 846-847. May 1998. Contact: Available from Appleton and Lange. P.O. Box 86, Congers, NY 10920-0086. (203) 406-4623. Summary: Patients with end-stage renal disease (ESRD) are considered moderately immunocompromised and are susceptible to mycobacterial infection, including tuberculosis. This article explores the incidence of tuberculosis, organ involvement, diagnostic parameters, and response to tuberculosis treatment in the hemodialysis population. Based on data from 3 years, the incidence of tuberculosis at the authors hemodialysis unit is 2 percent (23 of 1140 patients). Diagnosis of tuberculosis in these patients is difficult, and biopsy, an invasive procedure, was required for diagnosis in 14 cases in this study. Extrapulmonary involvement (in organs other than the lungs) was a frequent finding in this population. The authors stress that, in spite of treatment, the high mortality rate due to this disease underlines tuberculosis as a persistent and significant problem that cannot be underestimated for hemodialysis patients. Because of this, all possible diagnostic methods need to be used in this group, including RT-PCR studies and tissue biopsy. 1 figure. 1 table. 5 references.
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Renal Tuberculosis Presenting as a Large Perinephric Mass Source: Infections in Urology. 10(6): 171-172, 175. November-December 1997.
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Contact: Available from SCP Communications, Inc. 134 West 29th Street, New York, NY 10001-5399. (212) 631-1600. Fax (212) 629-3760. Website: http://www.scp.com. Summary: Tuberculosis (TB) infections most commonly affect the respiratory and genitourinary systems. In industrialized countries, between 8 and 10 percent of patients with pulmonary TB develop renal (kidney) TB, and 15 to 20 percent of the population in developing countries have Mycobacterium tuberculosis cultured from the urine. This article reports a case of a patient who exhibited an unusual case of renal TB presenting as a perinephric mass. A 56 year old man with a 3 year history of untreated hypertension presented with a 2 week history of low grade fever, 10 pound weight loss, and acute onset of right hemiparesis (muscular weakness on one side of the body). The patient had no history of TB or urinary symptoms. Muscle strength in the right arm and right leg were diminished. A 15 by 20 cm, well defined, round, nontender, mobile mass was found in the left upper quadrant and flank. Other findings on abdominal and chest exam were normal. Urinalysis revealed many white blood cells per high power field, but no bacteria. Intravenous pyelogram was performed: the upper and mid poles of the left kidney were absent on nephrogram, and delayed excretion of contrast from the lower pole was observed. The right kidney was normal. The patient underwent an uncomplicated left radical nephrectomy for suspected liposarcoma. The gross pathology revealed a hard, fibrotic mass measuring 24 by 18 by 12 cm, filled with yellow purulent material surrounding a dilated collecting system and a 2 cm calculus. The renal tissue culture grew M. tuberculosis. The patient did well postoperatively and was discharged on the fourth day after the operation. In this patient, computed tomography (CT scan) provided the first clue to the diagnosis by suggesting the inflammatory nature of the renal mass; the diagnosis was confirmed by culture. 2 figures. 12 references.
Federally Funded Research on Tuberculosis The U.S. Government supports a variety of research studies relating to tuberculosis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to tuberculosis. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore tuberculosis. The following is typical of the type of information found when searching the CRISP database for tuberculosis:
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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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Project Title: A CENTRE FOR TUBERCULOSIS RESEARCH AND EDUCATION AT THE* Principal Investigator & Institution: Beyers, Nulda; University of Stellenbosch Stellenbosch, South Africa Stellenbosch, Timing: Fiscal Year 2002; Project Start 22-SEP-2002; Project End 21-AUG-2003 Summary: (provided by applicant): Southern Africa has the highest tuberculosis incidence in the world and South Africa is one of the 22 countries in the world that account for 80% of the global TB burden. The Western Cape province of South Africa has one of the highest reported tuberculosis incidences in the world at 500/100,000 population/year. TB, particularly in association with HIV/AIDS, is one of the major problems confronting sub-Sahara Africa where TB is the leading killer of people living with HIV. The Stellenbosch University Faculty of Health Sciences recently chartered a Centre for Tuberculosis Research and Education (CENTRE) with the mission of significantly contributing to the control of tuberculosis through purposeful interdepartmental and multidisciplinary research, education and training in collaboration with other national and international institutions. The CENTRE aims among others are 1. to enhance the collaboration and communication among TB and TB/HIV/AIDS researchers within the University as well as with other research collaborators in the Western Cape, South Africa and southern Africa, and 2. to improve the structured and unstructured education and training of graduate and post-graduate (Masters, Ph.D. and post-doctorate) students and young researchers who investigate adult and pediatric TB and TB/HIV/AIDS in southern Africa. The CENTRE is expected to have a significant impact on the training of researchers with a specific focus of understanding the dynamics of the rapidly spreading HIV/AIDS epidemic in southern Africa and its effect on the TB epidemic. The grant funds are intended to fund the work of a Steering Committee consisting of members from the CENTRE, the Harvard School of Public Health, and other potential co-operating partners. The Steering Committee with the CENTRE Director as Chairman will lead the development of a 2003 Strategic Plan for Graduate & Post-graduate Education in TB/HIV/AIDS Research. By the end of one year the CENTRE Director will prepare and assemble a Phase II Comprehensive Agreement application to fund the subsequent implementation of the 2003 Strategic Plan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A NEW TARGET FOR ANTI-TUBERCULOSIS AGENTS, FAS 1 Principal Investigator & Institution: Welch, John T. Chemistry; State University of New York at Albany 1400 Washington Ave Albany, NY 12222 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): As a sentinel disease for the diagnosis of AIDS, early reports of tuberculosis complicating AIDS seemed to indicate the disease was a result of reactivation of a previous infection, however today the picture of tuberculosis as a complication of AIDS has changed dramatically. The development of multidrug resistant strains of M. tuberculosis and the prospect of nosocomial transmission make the development of new, better tolerated therapies ever more important. It is the inclusion of pyrazinamide (PZA), an agent with a unique sterilizing activity, with isoniazid and rifampin (RIF) in current treatment regimens that constitutes the basis for 6-month short course therapy for M. tuberculosis (Mtb).l Surprisingly for a clinical agent, a detailed understanding of the mechanism of action of PZA continues to elude researchers. Recently the surprising observation was made that an analog of PZA, 5-
Studies 11
chloropyrazinamide (5-CI-PZA), inhibits fatty acid synthetase I, (FAS 1) in Mycobacterium tuberculosis. This observation has been confirmed independently in other laboratories. In prokaryotes, the synthetase is typically composed of at least seven peptides that represent the individual enzyme components and are generally classified as Type II synthases. However in mammals and mycobacteria, the synthase activity is carried out by single high-molecular weight, multifunctional peptide chains which are known as Type I synthases. In cell free extracts of Saccharomyces cerevisiae not only was the activity of 5-CI PZA confirmed to be very comparable with that of the wellknown inhibitor cerulenin in blocking the activity of FAS 1 it was also found that other pyrazinamide analogs also apparently inhibit FAS 1. The hypotheses to be tested in this proposal are that characterization of the mechanism of 5-CI-PZA on the inhibition of FAS 1 can lead to the development of better anti-mycobacterial agents and, secondly, that this inhibition process will be sensitive to structural variations of the pyrazinoic or nicotinic acid structure. The utility of the observed anti FAS activity can be enhanced by developing an understanding of the nature of the FAS 1 inhibition process so that this activity can be employed in the design of novel anti-tuberculous agents. As it is known that treatment of microbes with type I FAS inhibitors increases the sensitivity of those microbes to downstream inhibitors in a synergetic fashion, the development of antimycobacterial agents that act on FAS 1 and that can be used in combination with the aforementioned downstream agents may have a profound effect on improving tuberculosis treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: A NEW TUBERCULIN FOR THE DIAGNOSIS OF TUBERCULOSIS Principal Investigator & Institution: Einck, Leo; Sequella, Inc. 9610 Medical Center Dr, Ste 200 Rockville, MD 20850 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 29-SEP-2003 Summary: (provided by applicant):Accurate diagnosis of tuberculosis (TB) infection is one of the pillars of effective TB control programs. The current tool to diagnose infection with Mycobacterium tuberculosis is the tuberculin skin test (TST). Because of the crossreactive nature of purified protein derivative (PPD) of tuberculin, TST currently does not discriminate between infection with M. tuberculosis, vaccination with M. bovis BCG and sensitization with non-tuberculous mycobacteria found in the environment. The recent achievements in the field of bacterial genomics enable us to undertake a new approach to formulate a M. tuberculosis-specific tuberculin and to overcome poor TST specificity. Comparative genomic analyses show that the M. tuberculosis genome includes regions that do not exist in M. bovis BCG (RD regions). Thus, we can tailor a new, M. tuberculosis-specific tuberculin by selecting from the pool encoded by the RD regions those antigens that elicit TB-specific, cell-mediated immune responses. Our specific aims are 1) Identification of candidate antigens. Gene selection will be based on published results of comparative genomic analyses, BLAST protein homology searches, and Southern blot analyses. 2) Antigen screening in guinea pigs. Antigens will be selected that induce skin test reactions in tuberculous guinea pigs but not in control animals sensitized with M. bovis BCG and with non-tuberculous mycobacteria. 3) Antigen evaluation in human TB. Antigens selected in guinea pig studies will be evaluated for the ability to induce in vitro lymphoproliferation and cytokine secretion by peripheral blood mononuclear cells (PBMC) of M. tuberculosis-infected persons but not by PBMC of negative control individuals (BCG vaccinees, patients having nontuberculous mycobacterioses, and healthy, PPD-negative individuals). Antigens selected in the proposed Phase I studies will be used to formulate a multi-antigen tuberculin to
12 Tuberculosis
be taken to human clinical trials during Phase II work. PROPOSED COMMERCIAL APPLICATION: 2.1 Billion people harbor a TB infection. UNICEF reports that tuberculosis poses a serious risk to Asia's sustained socioeconomic development. In a recent National Intelligence Estimate, the Central Intelligence Agency singled out drugresistant TB-and especially its incidence among immigrants-as a potential threat to national security. Salomon and Murray report that world expenditure on TB therapy and diagnosis was $4.1 Billion (USD) in 1998. Diagnosis of TB worldwide is by sputum smear, with 50% accuracy. This new diagnostic is desperately needed. Short term markets will be in developing countries where the test will replace the current skin test as an adjunct diagnostic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VACCINE
A
PLANT-DERIVED,
MULTI-COMPONENT
TUBERCULOSIS
Principal Investigator & Institution: Walmsley, Amanda; Plant Biology; Arizona State University P.O. Box 873503 Tempe, AZ 852873503 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Tuberculosis is the leading cause of death due to a single infectious agent among adults in the world. The HIV-AIDS pandemic has had a strong influence on the incidence of tuberculosis in the developing world, greatly increasing the annual risk of developing tuberculosis in HIV positive individuals and contributing to the spread of tuberculosis in the community. The current tuberculosis vaccine, bacillus Calmette-Guerin (BCG) has a variable protective efficacy and can cause serious, even fatal disease in immunocompromised patients. An effective, inexpensive, easily distributed and administered subunit vaccine is required for the control of tuberculosis. The goal of this project is to investigate the ability of plant-derived, tuberculosis antigens to induce immune responses appropriate for the protection of mice against tuberculosis. The success of this project will be the first step in our overall goal of developing an inexpensive, subunit vaccine that will enable control of tuberculosis (TB) in humans including immunocompromised individuals. Investigations will include the ability of plants to correctly process and express protective antigens against Mycobacterium tuberculosis; verification of the mucosal immunogenicity of the resulting plant-derived antigens; characterization of the induced immune response(s) in mice and guinea pigs and the ability of the plant-derived antigens to protect animals from challenge with M. tuberculosis. Synthetic, plant optimized coding regions have been constructed for the tuberculosis antigens Ag85B and ESAT-6. These synthetic coding regions have been fused to the B and A2 subunits of the heat labile enterotoxin (LT) of enterotoxigenic Escherichia coil (ETEC) to promote targeting to mucosal lymphoid tissues. The resulting fused coding sequences were cloned into plant expression vectors for future Agrobacterium-mediated transformation of tomato (Lycopersicon esculentum L. cv "TA234). Expression, correct folding and concentration of the antigens in plant materials will be verified through Western analysis and enzyme linked immunosorbent assays (ELISA). Plant lines displaying high antigen expression, or elite plants, will be cloned, and transferred to the TB Research Materials and Vaccine Testing Contract at Colorado State University to be tested for mucosal immunogenicity and protective ability in mice trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
Studies 13
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Project Title: A RAPID SERODIAGNOSTIC TEST FOR TUBERCULOSIS Principal Investigator & Institution: Lyashchenko, Konstantin P.; Chembio Diagnostic Systems, Inc. 3661 Horseblock Rd Medford, NY 11763 Timing: Fiscal Year 2001; Project Start 15-JUL-1998; Project End 30-NOV-2002 Summary: (Adapted from Applicant's Abstract): Control of tuberculosis (TB), a disease that causes 3 million deaths a year worldwide, requires rapid methods for timely diagnosis. The goal of the proposed work is to develop a simple, rapid, accurate and inexpensive serodiagnostic assay for active TB using a thin-layer immunochromatography (TLIC) format and multiple recombinant antigens of Mycobacterium tuberculosis. Serodiagnostic tests for TB require multiantigen cocktails because of patient-to-patient variation in recognition of antigens by serum antibodies. Phase I studies have already identified eight antigens suitable for cocktail development and demonstrated that TLIC methodology is applicable to multiantigen-based TB serodiagnostics. Work proposed for Phase II is expected 1) to advance test development in terms of antigen composition and assay conditions, 2) to validate the diagnostic performance of selected cocktails in different TB cohorts and control groups, and 3) to establish methodologies for batch production of antigens. The goal of Phase II studies is to develop a test having a specificity close to 100% and a sensitivity of 90% in smearpositive pulmonary TB. The commercial opportunities for a rapid serodiagnostic TB test having the proposed specifications are immense. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ADJUNCT VITAMIN A THERAPY FOR TUBERCULOSIS AND HIV/AIDS Principal Investigator & Institution: Semba, Richard D. Ophthalmology; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2003; Project Start 15-SEP-1998; Project End 28-FEB-2006 Summary: (provided by applicant): Tuberculosis is one of the leading causes of mortality worldwide, accounting for an estimated three million deaths annually. Micronutrient deficiencies are common during HIV infection and during pulmonary tuberculosis, and micronutrient deficiencies are associated with impaired immunity and increased morbidity and mortality. Despite adequate chemotherapy for tuberculosis, the morbidity and mortality of HIV-infected adults with pulmonary tuberculosis remains extremely high. The goal of this ongoing Phase III randomized, double-blind, controlled clinical trial is to determine whether a daily multivitamin (vitamins and minerals) supplement can reduce morbidity and mortality of HIVinfected adults with pulmonary tuberculosis in Malawi. All participants receive standard tuberculosis chemotherapy for eight months as per the Malawi National Tuberculosis Control Programme, and the total duration of follow-up in the trial is twenty-four months. The trial has a Community Advisory Board which consists of local community members and participants. The original sample size of the trial was reduced to 500 HIV-infected adults in order to complete enrollment within the study period and deal with a budget reduction. Interim analyses conducted for the NIAID HIV Therapeutic Clinical Trials Data and Safety Monitoring Board (DSMB) at NIH show that the trial has been conducted with steady enrollment, good adherence to supplementation, and high follow-up. The DSMB has recommended that the sample size of this trial be increased to have at least 80% power to detect a 20% reduction in mortality. To meet this recommendation, we propose to increase the sample size to 840
14 Tuberculosis
HIV-infected adults with pulmonary tuberculosis. The trial also includes 300 HIVnegative adults with pulmonary tuberculosis in order to reduce stigmatization. If this study demonstrates that a multivitamin supplement can reduce morbidity and mortality of HIV-infected adults with pulmonary tuberculosis, this appropriate, low cost intervention could be integrated with tuberculosis treatment to improve health and survival of HIV-infected individuals in developing countries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AGING AND IMMUNITY IN TUBERCULOSIS Principal Investigator & Institution: Orme, Ian M. Professor; Microbiology; Colorado State University Fort Collins, CO 80523 Timing: Fiscal Year 2001; Project Start 01-SEP-1986; Project End 30-SEP-2002 Summary: (Adapted from the applicant's abstract): Tuberculosis is still relatively common in the elderly, probably reflecting the very high incidence of skin test positivity of the population in the first third of the century, and the fact that many of these individuals are still alive and generally healthy at the present time. As they age, however, such individuals run the risk of developing recrudescence of latent tuberculosis, while nonsensitized individuals run the risk [especially if institutionalized] of contracting a primary tuberculosis infection. The basis of the susceptibility of the aged to tuberculosis infection or recrudescent disease is still poorly understood, but is believed to reflect age-associated changes in the cell-mediated immune response to the organism. Work specifically in the investigator's laboratory supports this contention by showing a series of defects in the CD4 TH1 IFN-secreting T cell pathway associated with protection and memory immunity to the disease. Hence, using a realistic low dose aerosol infection model in aging mice, the investigators have identified specific lesions such as the low expression of adhesion markers on CD4 T cells, and the absence of a pulmonary IL-12 response needed to enhance IFN secretion by such cells. In the proposed study, they intend to continue to define the cellular response in the old lung to tuberculosis, including the use of new markers such as CD49E and CD95. In addition, they intend to resolve the nature of the recrudescent event, framed on new evidence that the capacity of a given M.tuberculosis isolate to promote local TNF and chemokine production may directly correlate with the nature of the granuloma response and its potential breakdown as the mouse ages. Further issues to be addressed include the role of the predominant TH2/IL-4 environment in old mice [an environment that includes unusual IL-4 secreting CD4+NK1. 1+ and CD8+ T cell populations] in potential interference with TH1 responses, which they will investigate in part by using aging IL-4 gene disrupted mice, and the potential reversal or delay of endogenous reactivation of disease in the old lung by administration of a sub-unit vaccine preparation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ALCOHOL, TB AND AIDS Principal Investigator & Institution: Mason, Carol M. Medicine; Louisiana State Univ Hsc New Orleans New Orleans, LA 70112 Timing: Fiscal Year 2001; Project Start 25-SEP-1997; Project End 31-AUG-2003 Summary: APPLICANT'S ABSTRACT: During the late 1980's, the previous decline in tuberculosis ceased and rates began to rise, heralding a resurgence of disease. Human immunodeficiency virus infection is largely responsible for the excess number of cases. A co-factor for TB infection is alcohol consumption. Alcohol is immunosuppressive, and
Studies 15
facilitates acquisition of pulmonary infections through malnutrition, greater propensity for indulging in high risk behaviors, and alteration of normal host defenses. Defense alterations include changes in immune effector cell populations and down regulation of cytokine production and/or function, which are critical components in the containment of intracellular pathogens, such as Mycobacterium tuberculosis. We hypothesize that alcohol adversely alters pulmonary host defense mechanisms against Mycobacterium tuberculosis by disrupting early cytokine interactions [tumor necrosis factor (TNF), interleukin (IL)-12, and interferon (IFN)-gamma] which are critical in the orchestration of effective Th1 CD4+ lymphocyte cell-mediated responses to contain the mycobacteria. We will test this hypothesis in a murine model of acute and chronic alcohol consumption and M. tuberculosis infection, initially employing mycobacterial lipoarabinomannan (LAM; a cell wall component) and nonviable organisms as probes, and subsequently utilizing an in vivo model of M. tuberculosis infection. To achieve this, we propose the following: Specific Aim 1: To test the prediction that alcohol consumption suppresses the pulmonary production of early cytokines in response to mycobacterial antigens in mice. Specific Aim 2: To test the theory that alcohol, through disruption of early cytokine pathways, impairs the development of Th1-directed cellmediated immunity to viable M. tuberculosis infection. Specific Aim 3: To demonstrate that defective antimycobacterial cell-mediated host defenses can be enhanced with IFNgamma organ specific cytokine gene therapy in an animal model. Our goal is to elucidate the mechanisms by which alcohol consumption further diminishes host resistance to M. tuberculosis infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AN EFFICIENT BACTERIAL VECTOR-BASED TUBERCULOSIS VACCINE Principal Investigator & Institution: Szumanski, Maria Bw.; Veterinary Technologies Corporation 1872 Pratt Dr Blacksburg, VA 24060 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 31-MAY-2002 Summary: (Adapted from Applicant's Abstract) Tuberculosis (TB) still remains a major global health threat; worldwide, it is responsible for over 3 million deaths annually. In lieu of the emerging multi-drug resistant Mycobacterium tuberculosis strains, control of TB through an effective vaccination is of a paramount importance. Although Mycobacterium bovis strain BCG is widely used for TB prophylaxis, its protective effect has recently been shown to be far below the necessary level to protect populations efficiently. A strong ThI type of cell mediated immune response is crucial for protection against M. tuberculosis infections. Several proteins of M. tuberculosis that are involved in stimulating a protective immune response have been identified and their genes have been cloned and sequenced. The overall objective of the proposed research project is to develop a highly efficacious and safe vaccine for TB. Specifically, the company proposes to prepare an effective vaccine against tuberculosis by expressing previously identified protective protein(s) of M. tuberculosis in Brucella abortus strain RB51, a bacterial vector with unique adjuvant properties and can stimulate a strong Th1 type of immune response. In the phase I part of the project, the company intends to i) construct recombinant RB51 strains that express 85A and ESAT-6 antigens of M. tuberculosis and ii) immunize mice with irradiated recombinant RB51 vaccines and characterize their antigen-specific antibody and cell-mediated immune responses to confirm that a Th1 type of immune response is induced. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
16 Tuberculosis
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Project Title: ANTI TUBERCULOSIS CANDIDATE VACCINE TESTING IN RHESUS MONKEYS Principal Investigator & Institution: Gormus, Bobby J.; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001 Summary: Eight normal RM were inoculated with MTB via fiberoptic bronchoscope. Four received the less virulent H37Rv strain and four received the highly virulent Erdman strain via fiberoptic bronchoscope. Both monkeys that received the high dosage of H37Rv (6 X 106 cfu) developed extensive multifocal expansile and coalescing granulomas with broad central zones of necrosis, neutrophilic infiltration, and mineralization in the inoculated right lobe of the lung by 5 and 11 weeks (wk) postchallenge. Monkeys receiving the low dose of H37Rv (30 cfu) had granulomatous lesions in the bronchial lymph nodes 18 wk after infection. Lesions suggest that low doses of M. tuberculosis H37Rv are controlled, at least in the short term, by natural defenses in the simian lung and that challenge with higher doses of bacteria produces significant tissue response without evidence of septicemic spread. Two high dose (150 cfu) Erdman recipient monkeys developed extensive granulomatous pneumonia, pleuritis, and bronchial node necrosis with microgranulomas in the liver, kidney, and other sites in 7-9 weeks. The appearance of pneumonia and time course were roughly comparable to disease produced by high dose (>106) H37Rv. The 2 low dose Erdmaninoculated monkeys (15 cfu) remained clinically normal 9 weeks post-challenge and at 19 wk had minimal clinical manifestations, but fibrotic granulomatous pulmonary lesions with spread to other tissues. We conclude that chronic disease can be established by low dose Erdman inoculation with a wider distribution of lesions being produced compared to the H37Rv strain. FUNDING Base Grant, Venture Research PUBLICATIONS Didier PJ, Blanchard JL and Gormus BJ. Pulmonary Tuberculosis in Normal Rhesus Monkeys Produced by M. tuberculosis H37Rv. Am J Soc Trop Med Hyg 57:156, 1997 [Abstract]. Didier PJ, Blanchard JL and Gormus BJ. Chronic Tuberculosis Produced by Low Dosage of M. tuberculosis (Erdman) in Rhesus Monkeys. Am J Soc Trop Med Hyg 59:361, 1998. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANTIMICROBIAL PEPTIDES IN RESISTANCE TO TUBERCULOSIS Principal Investigator & Institution: Kisich, Kevin O.; National Jewish Medical & Res Ctr and Research Center Denver, CO 80206 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Infections with drug resistant strains of Mycobacterium tuberculosis and most strains of Mycobacterium avium are challenging to treat chemotherapeutically. As HIV infection and the AIDS epidemic spreads, adequate treatment of mycobacterial infections in both immunocompetent and immunocompromised patients becomes increasingly difficult. Additional understanding of innate and immune mechanisms of resistance as well as new antibiotics will be important for designing new, more effective treatment regimens for mycobacterial infection. We hypothesize that small, cationic human antimicrobial peptides (AMP), defensins and cathelicidin stored in granules of human polymorphonuclear leukocytes (PMN), and secreted from epithelia play important roles in resistance to mycobacterial infection, and may be adaptable for chemotherapeutic use. Human neutrophil peptides 1,2, and 3 (HNP 1,2, and 3) have shown to be antimycobacterial for laboratory and clinical isolates of M. tuberculosis and M. avium in
Studies 17
vitro, and we have confirmed this in our laboratory. We propose to extend these observations by fully characterizing the anti-mycobacterial activity of human AMP, examining the relationship between binding of AMP to mycobacteria and antimycobacterial activity, and evaluating the relationship between resistance to human AMP and pathogenicity. We will also examine pharmacological interactions between human AMP and first-line anti-tuberculosis drugs for mycobacteria in liquid and macrophage cultures. The proposed studies are designed to fill an important gap in our knowledge of how mycobacteria evade the innate immune system. Understanding of the relative sensitivities of mycobacteria will help us understand how mycobacteria survive their first encounter with the antimicrobial peptides in pulmonary secretions and in responding neutrophils. Correlation of AMP sensitivity with binding of the peptides will help determine whether and how AMP sensitivity is related to pathogenicity. In addition, the proposed studies will define the potential of AMP to participate in the anti-mycobacterial response of human macrophages, or whether intracellular mycobacteria are protected from exposure to AMP. These studies will further our understanding of how endogenous anti-mycobacterial substances may enhance resistance to infection, and will also reveal whether these substances may be adaptable to chemotherapeutic use for treatment of mycobacterial infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BCG + HSP, A NEW TUBERCULOSIS VACCINE Principal Investigator & Institution: Nikonenko, Boris; Sequella, Inc. 9610 Medical Center Dr, Ste 200 Rockville, MD 20850 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2004 Summary: (provided by applicant): This proposal describes research that will examine the safety and efficacy of a novel strain of BCG in which the heat shock repressor gene has been deleted, resulting in the overexpression of a heat shock protein (hsp70). Heat shock proteins show a good deal of promise in the protection against and treatment of tuberculosis, and this novel BCG strain produces a T-cell response indicative of a more protective immune response. The Specific Aims of this Phase I proposal are: 1. In a guinea pig model of tuberculosis (TB), we will compare the efficacies of (1) intradermally administered (i.d.) BCGdeltahspR; (2) i.d. parent BCG; (3) subcutaneously administered (s.c.) BCGdeltahspR; (4) s.c. parent BCG; and (5) no vaccination (control). 2. In a mouse model of tuberculosis, we will compare the efficacies of (1) BCGdeltahspR administered subcutaneously; (2) parent BCG, administered subcutaneously; and (3) no vaccination (control). We believe it is important to test this vaccine in several different strains of mice that represent a spectrum of susceptibility to TB, as it is not known which strain might be the best model of TB in humans. Therefore, we will test the efficacy of rBCGdeltahspR in C57BI6, DBA/2, and CBA. 3. We will examine the safety of this modified BCG as compared to the parent BCG. We will infect mice and guinea pigs with each BCG strain and examine lungs for pathology, and count the CFU of BCG still present. We will also examine the antibiotic sensitivity of this rBCGdeltahspR to 10 commonly used TB drugs to ensure that the genetic manipulations performed have not made it less sensitive to drug treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BINDING AND PRESENTATION OF LIPID ANTIGENS BY CD1B Principal Investigator & Institution: Porcelli, Steven A. Associate Professor; Microbiology and Immunology; Yeshiva University 500 W 185Th St New York, NY 10033
18 Tuberculosis
Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 30-JUN-2004 Summary: (Adapted from Investigator's Abstract): Recent studies have identified the CD1 family of cell surface glycoproteins as novel antigen presenting molecules encoded by genes located outside of the major histocompatibility complex. Identification of naturally occurring antigens presented by CD1 has revealed the surprising finding that these prominently include a range of foreign lipids and glycolipids, such as several that are known to exist in the cell walls and membranes of pathogenic mycobacteria. Among the currently known CD1-presented antigens, the best structurally characterized are the mycolic acids and their monoglucosylated analogue, glucose monomycolate (GMM). These compounds have a lipid structure that is unlike any found in mammalian tissues, and occur abundantly as a major outer cell membrane component in a variety of pathogenic bacteria, including Mycobacterium tuberculosis. Recognition of these lipids appears to be a frequent feature of CD1b-restricted M. tuberculosis-specific T cells in humans, suggesting that T cell responses to mycolic acids and GMM may play a significant role in the protective host response to this important pathogen. Studies in the current proposal will assess whether mycolic acids or GMM are among the immunodominant T cell antigens of M. tuberculosis in humans infected with this bacterium, and will seek to clarify the molecular basis for the presentation and recognition of these novel T cell antigens. A combination of preparative and synthetic chemistry will be used to generate a range of structural analogues of mycolic acids and GMM. These will be studied for their ability to be recognized by CD1b-restricted T cells, and for their ability to bind directly to CD1b proteins. In addition, the structural basis for the binding of these antigens to the CD1b protein will be analyzed by carrying out site directed mutagenesis of residues forming the predicted ligand binding groove of CD1b. These studies will lead to a detailed understanding of the fundamental rules governing the interaction of a newly recognized class of T cell antigens with their antigen presenting molecule. The identification and detailed analysis of this newly recognized pathway for T cell antigen recognition is likely to be important for understanding the human immune response to M. tuberculosis and related pathogens, and has potential implications for future vaccine development efforts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOSYNTHESIS OF THE MYCOBACTERIAL PEPTIDOGLYCAN Principal Investigator & Institution: Pavelka, Martin S. Microbiology and Immunology; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: (Adapted from the Applicant's Abstract): Tuberculosis is the leading cause of death in adults due to an infectious organism. By the end of this century there may be as many as 90 million new cases of tuberculosis resulting in up to 30 million deaths. The failure of antimicrobial therapy and the dangerous association between tuberculosis and AIDS have brought renewed interest in studying M. tuberculosis, the organism responsible for this disease. A better understanding of the basic biology of the organism and the development of new anti-mycobacterial drugs are important goals of mycobacterial research. The cell envelope is an outstanding characteristic if the mycobacteria, consisting of a variety of polysaccharides such as arabinogalactan, lipoarabinomannan, and peptidoglycan, along with several different types of lipids including various glycolipids and the mycolic acids. The peptidoglycan layer of the cell envelope serves as the anchor for the principal components of the cell envelope and provides shape and structural integrity to the cell. The long-term goal of this proposal is a deeper understanding of the biosynthesis and assembly of the mycobacterial cell
Studies 19
envelope. The specific goal of this proposal is to understand more about the genetics and biosynthesis of the peptidoglycan layer of the envelope. The specific aims of this proposal are: 1) Determining the significance of N-glycolylation of the mycobacterial peptidoglycan. 2) Investigating the architecture of the peptidoglycan and the role it plays in the organization of the cell envelope. 3) Using beta-lactam antibiotics as tools to probe mycobacterial peptidoglycan biosynthesis. For the aims of this proposal, the Pi will study M. tuberculosis and M. smegmatis as a model organism using the techniques of classical bacterial genetics, molecular biology and biochemistry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIVATION
CATALASE-PEROXIDASE
CATALYSIS
IN
ANTIBIOTIC
Principal Investigator & Institution: Magliozzo, Richard S. Chemistry; Brooklyn College 2900 Bedford Ave New York, NY 11210 Timing: Fiscal Year 2001; Project Start 15-JUN-1998; Project End 31-MAY-2003 Summary: (adapted from applicant's abstract) The major role of the propose research is to explain the catalytic function of Mycobacterium Tuberculosis catalase-peroxidase, a heme-enzyme, in the activation of the antimycobacterial antibiotic, isoniazid (isonicotinic acid hydrazide). The specific aims include identification of the proximal ligand to heme iron in catalase-peroxidase, characterization of the spin state and coordination number of the heme iron in the resting enzyme, identification of hypervalent enzyme intermediates, and kinetic analysis of the reaction of these intermediates with isoniazid. Of special interest is the potential catalytic competence of oxy-ferrous catalase- peroxidase, and the potential for peroxynitrite to activate the enzyme. The role of selected amino acid residues in the catalytic mechanism an in isoniazid binding will be evaluated through examination of the properties of two mutant catalase-peroxidase enzymes identified from clinically isolated, isoniazid resistant M. tuberculosis strains. Inhibition of another M. tuberculosis enzyme, a fatty acyl enoyl reductase (the inhA protein) thought to be a target of drug action, by isoniazid activated catalase-peroxidase, will also be investigated. Other aims address the Mn(II)-peroxidase activity of catalase-peroxidase considered important because Mn(III) is an efficient single electron oxidant of isoniazid. The techniques of optical stoppedflow spectroscopy, resonance Raman, and electron paramagnetic resonance spectroscopies will be applied in the experimental protocols. The results of the proposed studies will advance a detailed understanding of the action of a first line antibiotic in current use to treat tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CD1-TARGETED VACCINATION AGAINST TUBERCULOSIS Principal Investigator & Institution: Modlin, Robert L. Professor; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The long-range goal of this project is to develop and validate the CD1-based vaccine technology platform to immunize humans against microbial pathogens. This approach is based on the knowledge that several of the CD1 proteins have specific targeting sequences that direct their traffic into endosomal compartments, structures also critical for antigen presentation by MHC class II molecules to CD4+ T cells. We will determine whether this novel vaccine strategy can induce protective immunity against Mycobacterium tuberculosis, a worldwide killer,
20 Tuberculosis
and now because of multi-drug resistant tuberculosis, a potential agent of a bioterrorist attack. We propose to determine the trafficking pattern of CD1 chimers in antigen presenting cells including monocytes and dendritic cells. The ability of CD1 targeting to be used in immunization in humans will be assessed by studying the immune response to an M. tuberculosis antigen ESAT-6. In addition, the ability of ESAT-6/CD1 fusion constructs to immunize human T cell responses in vitro will be investigated. To determine whether ESAT-6/CD1 chimers can induce protective immunity, ESAT6/CD1 fusion constructs will be used to immunize mice, which will be subsequently challenged with virulent M. tuberculosis. The studies proposed will help develop and test the efficacy of CD1-based DNA vaccines for the prevention of infectious disease, including those from natural pathogens and bioterrorist attacks. Specifically, it should be possible to develop a new approach to the prevention of tuberculosis, including multidrug resistant tuberculosis, in humans. Finally, the CD1-based vaccine technology should prove useful in the vaccination against microbial pathogens in which MHC class II-restricted presentation of antigen to CD4+ T cells is required for host defense. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CD8 T CELLS AND IMMUNITY TO TUBERCULOSIS IN OLD MICE Principal Investigator & Institution: Turner, Joanne; Assistant Professor; Microbiology, Immunology & Pathology; Colorado State University Fort Collins, CO 80523 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2003 Summary: (provided by applicant): The elderly are more susceptible to many infectious diseases, and yet vaccinating this population is less effective when vaccines that are designed for young individuals are used. To design a vaccine that specifically targets an aging immune system it is first necessary to understand how the aging immune response differs from younger individuals when it encounters a pathogen. Using the aging mouse model of tuberculosis we have found that old mice express a transient early resistance to infection that correlates with the rapid presence of CD8 T cells within the lungs. This identifies a previously unrecognized novel immune mechanism in old mice that is clearly absent from the lungs of young mice. Using the low-dose aerosol infection model of tuberculosis we will characterize this CD8 T cell population further by determining the signals that rapidly recruit it to the lungs, and the mechanism by which it mediates early resistance to infection. Finally, we will use vaccine strategies known to elicit antigen specific CD8 T cell responses to mycobacterial antigens to see if these cells can then be detected within the CD8 cell population recruited into the lungs of old mice after infection with M. tuberculosis. Studies will be carried out in a new BSL-3 facility at Colorado State University and will use old wild type and genedisrupted mice from our existing in-house aging mouse colonies. The technical approaches in the proposed studies will use a combination of flow cytometry, FACS cell sorting, immunohistochemical staining, and real-time PCR, to address the proposed Aims. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CD8+ T CELL RESPONSE IN RESISTANCE TO TUBERCULOSIS Principal Investigator & Institution: Bushkin, Yuri; Associate Member; Public Health Research Institute 225 Warren St Newark, NJ 07103 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: Tuberculosis (TB) is a chronic infectious disease caused by the intracellular bacterial pathogen Mycobacterium tuberculosis. Hence, cell- mediated immunity rather
Studies 21
than antibodies is the critical protective immune response against M. tb. Studies with animal models of TB suggest that the major histocompatibility complex (MHC) class Irestricted CD8+ T-cell response complements host defenses mediated by activated macrophages and CD4+ T cells, and has an important role in successful resolution of mycobacterial infections. However, in humans the role of CD8+ T cells has not been fully addressed. We have developed an in vitro assay that is based on a novel computerdriven algorithm predicting MHC class I ligands (peptides) with a proven high accuracy. Our assay can measure the presentation of predicted peptides by proper MHC class I alleles, and thus allows for identification of the epitopes recognized by CD8+ T cells. Thus, the overall objective of these studies is the analysis of the role of CD8+ T-cell response in resistance to TB. First, secreted mycobacterial proteins with known sequences will be analyzed by the computer program for the presence of potential CD8+ T-cell epitopes. Presentation of these predicted M. tb. -derived peptides by MHC class I will be determined in our peptide-binding assay with an antigen transporter-deficient cell line expressing HLA alleles of interest. This analysis will be extended to HLA alleles predominant in populations with high incidences of TB and HIV infection. Second, this methodology will be used in quantitative and qualitative analysis of the MHC class Irestricted CD8+ T-cell immune responses to M. tb. -derived peptides in PPD+ healthy donors and TB patients. The frequencies of memory CD8+ T cells in the peripheral blood and activated cytotoxic T lymphocytes in the bronchio-alveolar lavage will be measured. Comparison of CD8+ T-cell effector functions in TB patients vs. PPD+ healthy donors, and also in PPD+/HIV-infected and active TB/HIV- infected patients will determine the correlation between the CD8+ T-cell responses and resistance to M. tb. infection in these patients. Finally, M. tb. -specific CD8+ T cell clones will be isolated and functionally characterized. These T cell clones will be used to study the requirements for MHC class I-restricted presentation of M. tb. antigens by macrophages infected in vitro with viable bacilli. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CD8+ T CELLS AND MYCOPLASMA TUBERCULOSIS Principal Investigator & Institution: Canaday, David H. Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 30-JUN-2004 Summary: This application for a mentored scientist award (KO-8) seeks 5 years of funding for research training in the cellular immunology and cell biology of M. tuberculosis infection for David H. Canaday, M.D. Research training will be provided by W. Henry Boom, M.D. and Clifford V. Harding, M.D.-Ph.D. in the Division of Infectious Diseases and the Department of Medicine at Case Western Reserve University. The research proposal which will provide the focus for Dr. Canaday's training is outlined below. M. tuberculosis is spread from person to person by inhalation of aerosolized mycobacteria. Most healthy people do not develop clinical tuberculosis. Instead, cellular immune responses become activated and are able to successfully control the active infection. T cells play a crucial role in regulating the cellular immune response. T cell subsets(CD4+, CD8+, gammadelta+), are activated by mycobacterial antigens, yet little is known about the roles and function of the different T cell subsets in the protective immune response to M. tuberculosis. While CD4+ T cells have been the focus of many studies, CD8+ T cells are an important accessory T cell subset in the protective immune response to M. tuberculosis. Recent studies by us and others have demonstrated that human CD8+ T cells serve as CTL for M. tuberculosis infected macrophages, produce IFN-gamma and are activated by mycobacterial
22 Tuberculosis
antigens. The broad goal of the current studies is to determine the repertoire of mycobacterial proteins which stimulate human CD8+ T cells, to examine the antigen processing mechanism the macrophages use to present M. tuberculosis antigens on MHC class I molecules, and to determine the function of CD8+ T cells in patients with active tuberculosis. The Aims are: Aim 1. To determine the mycobacterial proteins and peptides recognized by human alphabeta TCR+ CD8+ T cells. Aim 2. To determine the mechanism(s) used by M. tuberculosis infected macrophages to process and present mycobacterial proteins by MHC class I molecules. Aim 3. To characterize the functional CD8+ T cell responses to specific proteins and peptides from in patients with active M. tuberculosis infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELL ENVELOPE BIOSYNTHESIS IN M TUBERCULOSIS Principal Investigator & Institution: Glickman, Michael S. Medicine; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 07-DEC-2001 Summary: This proposal outlines a career development plan that consists of intensive research experience and didactic training in bacterial pathogenesis. The institutional environment is scientifically rich and well suited for the training of young physicianscientists. The ultimate goal of this period of intensive research training is to train the candidate as an independent investigator on a medical school faculty. Tuberculosis, caused by Mycobacterium tuberculosis, is the single leading cause of death from an infectious disease in the world today. Three million die each year from Tuberculosis and one third of the world's population is infected with M. tuberculosis MTB. The cell envelope of MTB is a complex structure composed of hydrophobic lipids, mycolic acids, cord factors, and Lipoarabinomannan and is thought to contribute to the virulence of the organism. Despite substantial investigation into the ultrastructure and chemical composition of the mycobacterial cell envelope, the contribution of specific cell walls constituents to mycobacterial virulence remains poorly defined. The importance of the cell envelope to the viability of the mycobacterial cell is emphasized by the observation that several antimycobacterial drugs including Isoniazid are thought to exert their bacteriacidal effect through inhibition of cell envelope biosynthesis. This proposal outlines a series of experiments designed to investigate the role of the cell envelope of MTB in pathogenesis through the generation and characterization of mycobacterial mutants deficient in the synthesis of cell envelope constituents. Using a recently developed transposon mutagenesis system, a series of insertional mutants will be generated and screened for alterations in their cell envelope composition. Morphologic, immunologic, and functional approaches to the isolation and characterization of cell envelope altered mutants will be used. Isolation and characterization of such mutants will likely yield important insights into the role of the mycobacterial cell envelope in the pathogenesis of Tuberculosis and the interaction of the tubercle bacillus with host cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CELL MIGRATION IN TUBERCULOSIS INFECTION Principal Investigator & Institution: Chan, John R. Associate Professor; Medicine; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The granuloma plays an important role in host defense against M. tuberculosis. The mechanisms that regulate the formation and
Studies 23
maintenance of the tuberculous granuloma are, however, poorly understood. Chemokines and chemokine receptors play an essential role in cell migration in both physiological and pathophysiological states. Emerging evidence suggests a role for chemokine and chemokine receptors in regulating the granulomatous response during infection. M. tuberculosis has the ability to modulate chemokine and chemokine receptor expression in both in vitro and in vivo systems. Tumor necrosis factor-alpha (TNF-alpha) is essential for the control of tuberculosis, and is a potent regulator of chemokine expression and leukocyte trafficking. We have shown that neutralizing TNFalpha in mice with persistent tuberculosis results in disease recrudescence associated with granuloma disorganization and diffuse cellular infiltration in the lungs. Based on these observations, we propose to test the hypotheses that: i) chemokines and chemokine receptors play an important role in orchestrating cell migration and granuloma formation in tuberculosis; and ii) TNF-alpha regulates the granulomatous response by directing the trafficking of immune cells at the site of infection via regulation of specific chemokines and chemokine receptors. Because of the importance of Type 1 T cells in host defense against M. tuberculosis, efforts will be focused on examining a subset of chemokines and receptors that can modulate migration of these T lymphocytes. Murine tuberculosis models, as well as immunohistochemical, laser microdissection, and realtime PCR techniques will be used to characterize the expression of these specific chemokines and receptors during tuberculous infection. Mice with disruption of specific chemokine receptor genes and ligand neutralizing reagents will be exploited to dissect specific chemokine network. Similar techniques, in conjunction with in vitro cell migration assays and the TNF-alpha neutralization model of murine reactivation tuberculosis, will be employed to evaluate the effects of TNFalpha on the expression of specific chemokines and receptors, as well as on migration of T cells and monocytes during tuberculous infection. These studies should yield valuable information that will shed light on the roles of chemokines and receptors on cell migration, granuloma formation, and host defense in tuberculous infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELL WALL BIOGENESIS-TARGET FOR NEW ANTI-TB DRUGS Principal Investigator & Institution: Mcneil, Michael R. Professor; Microbiology; Colorado State University Fort Collins, CO 80523 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 31-AUG-2007 Summary: (Provided by applicant): In this competing continuation, mycobacterial cell wall metabolism is targeted as a route to new tuberculosis drugs. In one approach, essential cell wall biosynthetic enzymes are targetted. It is proposed to prepare M. tuberculosis luciferase reporter strains that respond specifically to inhibitors of the following essential enzymes: rhamnosyl transferase (WbbL), galactofuranosyl transferase (GlfT), dTDP-Rha formation enzymes (RmIB-D), and the UDP-Galf formation enzyme (Glf). In addition, direct enzyme assays amenable to screening for inhibitors will be developed for WbbL and GlfT (such assays are already in place for RmIB-D and Glf). It is further proposed to identify the genes encoding the three enzymes that form the arabinosyl donor, decaprenylphosphoryl-D-arabinose, show that their corresponding enzymes are essential, and prepare M. tuberculosis luciferase reporter strains and enzyme assays for use in finding inhibitors of them. In the second approach it is hypothesized that compounds that activate or deregulate the cell wall degrading arabinases and peptidoglycan hydrolyases can act more quickly than inhibition based drugs and thereby shorten tuberculosis therapy. Thus newly discovered M. tuberculosis endogenous arabinanases (of unknown function) that cleave
24 Tuberculosis
cell wall arabinan will be purified and their genes identified. The effect of overexpressing these enzymes in M. tuberculosis will be tested; it is hoped the effect will be lethal. Reporter strains of M. tuberculosis to detect small molecules that up regulate the expression of the arabinanases will be prepared. The presence of a cell wall metabolic enzyme complex containing these arabinases (which can potentially be disrupted for therapy) will be searched for using a novel cross-linking reagent, cyanogen complexes of peptidoglycan synthetic and degradative enzymes, after covalent crosslinking with cyanogen, will be isolated. The identity of all proteins present in the complex will be determined by LC/MS and how individual proteins interact in the complex will be determined for the long-term goal of disrupting the complex to release the peptidoglycan cleaving enzymes. We will test M. tuberculosis for increased arabinase activity after exposure to novel highly active ethambutol like compounds (the presence of endogenous arabinase was first recognized during ethambutol treatment). Finally, large numbers of novel Betalactams will be tested for their action against M. tuberculosis with and without ethambutol like compounds anticipating that some will strongly stimulate cell wail degradation and bacterial death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELLULAR TUBERCULOSIS
NECROSIS
INDUCED
BY
MYCOBACTERIUM
Principal Investigator & Institution: King, C Harold. Medicine; Emory University 1784 North Decatur Road Atlanta, GA 30322 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 14-SEP-2003 Summary: (provided by applicant): A key step in the pathogenesis of M tuberculosis is its ability to cause caseating necrosis, parenchymal lung destruction, and cavity formation, which develop into the characteristic necrotizing bronchointerstitial pneumonia and bronchiolitis of tuberculosis. M tuberculosis is cytotoxic to epithelial cells in vitro, and we have shown that this cytotoxicity is associated with cell membrane permeation to lactose dehydrogenase and is mediated by necrosis of lung epithelial cells after infection with virulent mycobacteria (Dobos, K. M., Quinn, F. D. and King, C. H. 2000, Infect. Immun. 68:6300-6310). Interestingly, the attenuated M bovis BCG does not induce necrosis in this epithelial cell model suggesting that necrosis is related to the virulence of mycobacteria. Our working hypothesis is that M tuberculosis possesses factors that cause necrosis. We intend to identify the genes that encode or synthesize such factors and determine their functions. Towards this goal, we have been successful in isolating two such (necrosis-deficient) mutants with insertions into genes that have no known function by screening a transposon library of the Erdman strain of M tuberculosis (TN5370) for mutants that have lost their ability to cause cell membrane permeation and necrosis. Both nec mutants possess extremely interesting phenotypes when grown in mice. The first mutant (necA) appears to be highly attenuated for growth and virulence in SCID mice. This is an important result as it suggests that we have identified a gene whose product either directly causes necrosis or induces necrosis and thus should enhance our understanding of tuberculosis pathogenesis. Interestingly, the second mutant (necB) appears to kill SCID mice more rapidly than the parental strain. We intend to characterize these mutants, characterize the functions of the gene products, and extend this mutant isolation strategy to identify a large battery of mutants defective for necrosis of host cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
Studies 25
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Project Title: CHARACTERIZATION OF ACID INDUCED PROMOTERS OF M. TB Principal Investigator & Institution: Saviola, Beatrice J. Basic Sciences; Western University of Health Sciences Health Sciences Pomona, CA 91766 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2005 Summary: (provided by applicant): Tuberculosis exacts an enormous burden in morbidity and mortality on the global population. With the advent of the HIV epidemic and multiple drug resistances, disease due to tuberculosis has increased leading to a need for research into the basic mechanisms of pathogenesis. The long-range goal of this proposal is to understand how Mycobacterium tuberculosis, the causative agent of tuberculosis, can sense environmental stresses, up regulate critical genes, and survive in the hostile environment of the host. When M. tuberculosis invades a host it infects human macrophages. M. tuberculosis can also be found within host granulomas that have been shown to have an acidic pH. The putative promoter regions of the M. tuberculosis genes lipF and Rv0834c have been identified to be upregulated in response to acidic pH. The specific aims of this proposal are to: 1) characterize the putative promoter regions of lipF and Rv0834c to better understand how acid induced promoters are regulated 2) determine if lipF and Rv0834c are required for mycobacteria to resist acidic stress and identify additional stresses which may upregulate these genes. The expectation is that this work will result in the characterization of acid responsive promoter regions and provide the groundwork for the eventual identification of a general mechanism by which M. tuberculosis can resist environmental stresses such as acidic stress. This work is significant because it will contribute to a greater understanding of mycobacterial stress response and ultimately survival and persistence in the host during infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHARACTERIZATION OF MYCOBACTERIAL AUTOLYSINS Principal Investigator & Institution: Deng, Lingyi; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, MA 02118 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2002 Summary: (Adapted from the Applicant's Abstract): Mycobacterium tuberculosis remains the bacterial leading cause of death worldwide and multidrug-resistant strains have emerged as a new problem in both developed and developing countries. The cell wall of M. tuberculosis has a unique, complex structure and is extraordinarily thick, rigid, and hydrophobic. Because of these characteristics, it is highly impermeable to ordinary antimicrobial agents. Bacterial autolysins are enzymes which are capable of hydrolyzing the bacterial cell wall and are associated with normal bacterial cell division, growth, and autolysis. Little is known about the autolysins of mycobacteria. The central hypothesis of this proposal is that mycobacterial cell wall autolysins are essential for the growth and survival of the organisms and can be exploited as new targets for antimycobacterial agents. In preliminary studies, the investigators have (i) prepared a mycobacterial cell lysate that hydrolyzed the cell wall polysaccharide; (ii) observed that ethambutol treated mycobacteria have increased cell wall hydrolysis; and (iii) identified an open reading frame (ORF) in the M. tuberculosis genome that is highly homologous to a Bacillus subtilis cell wall hydrolases, i.e., an N-acetylmuranoyl-L-alanine amidase. The investigators now propose the following: AIM1. The putative M. tuberculosis amidase gene noted above will be amplified by PCR, cloned and expressed. If the protein is confirmed to have the predicted enzymatic activity, then its functional and biochemical characteristics will be determined and the expression properties of the gene
26 Tuberculosis
will be analyzed. AIM 2. (a) Develop rapid and sensitive in situ phenotypic assays and apply these to screening for cloned mycobacterial autolysins expressed in E. coli. (b) Develop improved zymography and cell-free enzymatic assays and apply these to the isolation and purification of putative hydrolases. Purified enzymes will be analyzed for structural information (e.g. N-terminal sequence, quantitative protein mass as determined by MALDI/TOF mass spectroscopy), which will be used to identify the encoding gene in the published M. tuberculosis genome sequences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHARACTERIZATION OF MYCOBACTERIAL SIGMA FACTORS Principal Investigator & Institution: Husson, Robert N.; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001; Project Start 01-JUN-1995; Project End 28-FEB-2005 Summary: (provided by the applicant): The long-term goal of this research is to investigate the role of the alternative sigma factors SigD, SigE, SigH and SigM in the regulation of Mycobacterium tuberculosis gene expression and virulence. The underlying hypothesis of this research is that extracytoplasmic function (ECF) sigma factors of M tuberculosis play an important role in the regulation of gene expression during the interaction of this organism with the host during infection, and that this regulation is important for the virulence of this organism. This proposal has four complementary specific aims. The first aim is to complete construction of sigma factor mutant strains of M tuberculosis and to compare the survival of these mutants vs. the parental strain H37Rv following in vitro oxidative and nitrosative stresses that may be relevant to infection. The second aim is to compare the virulence of these mutants vs. H37Rv in macrophage and mouse models of infection. Mutant strains will be complemented to verify that any phenotypes observed in these experiments result from the disruption of the sigma factor gene that was mutated. The third aim is to investigate the role of these sigma factors in regulating M tuberculosis gene expression, focusing on the use of microarray technology, supplemented with bioinformatic and traditional molecular genetic methods. The fourth aim is to investigate the role of specific sigma factor-regulated genes in M tuberculosis virulence, by examining their expression and by constructing and testing M tuberculosis strains with mutations in these genes. These investigations are expected to identify regulatory networks and specific genes that are important in M tuberculosis virulence. This research thus has the potential to generate new insights into the pathogenesis of M tuberculosis infection, and may provide the basis for new approaches to the control of tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHARACTERIZATION TUBERCULOSIS
OF
THE
SIGE
REGULON
OF
M
Principal Investigator & Institution: Posey, James E.; U.S. Centers for Disease Control & Prev Control and Prevention Atlanta, GA 30333 Timing: Fiscal Year 2001; Project Start 01-APR-2001 Summary: (provided by the applicant): The experiments outlined in this proposal are designed to elucidate the sigE regulon of M. tuberculosis and the role it plays in the infection process. Recent data demonstrate the induction of sigE when M. tuberculosis is phagocytized by the macrophage. The in vivo signal and the genes regulated by SigE are not known. The objectives of this proposal are to: (1) determine if SigE is required for intracellular survival in macrophage, (2) identify genes regulated by SigE, and (3)
Studies 27
characterize the regulation of sigE at the transcriptional and post-translational level. A delta sigE strain of M. tuberculosis will be constructed, and its ability to survive and replicate in the macrophage will be assessed. This strain will also be used to identify genes that are regulated by SigE. The expression of sigE will be controlled in the strain by cloning this gene downstream of an acetamide inducible promoter located in a shuttle vector. The protein expression profiles of strains harboring this plasmid in the presence and absence of acetamide will be compared to identify genes regulated by SigE. To assess the regulation of sigE, a delta orf1 strain of M. tuberculosis will be constructed, and the levels of SigE in wild type and this strain will be compared by western blot. The transcript levels of sigE in both strains also will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLINICAL INVESTIGATIONS IN LUNG HOST DEFENSES Principal Investigator & Institution: Schluger, Neil W. Associate Professor of Medicine & Public; Medicine; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001; Project Start 20-SEP-1999; Project End 31-JUL-2004 Summary: Tuberculosis remains the world's leading infectious cause of death, and the rise of multidrug resistant tuberculosis and the interaction of the TB and AIDS epidemics worldwide are creating a public health threat of massive proportions. In recent years, we have pursued studies aimed at elucidating ways in which the host immune response to tuberculosis may offer protection from the disease, as well as ways in which inflammatory responses can be modified to improve outcomes in patients with multidrug resistant tuberculosis. We have demonstrated that the cytokine interferon (IFN) gamma plays a major role in human host defense against tuberculosis; a detailed understanding of immune mechanisms upstream and downstream from IFN's action in patients should provide significant insight into protection against tuberculosis infection and disease. To that end, three specific aims are planned: Specific aim 1: To assess, by determining the types and levels of chemokine present in bronchoalveolar lavage fluid of patients with tuberculosis, the signals in the lung which may cause recruitment of immune effector cells associated with an effective host response. Specific aim 2: To assess the state of activation of antigen presenting cell as well as immune effector cells in the lungs of patients with tuberculosis compared to controls. Specific aim 3: To assess changes in the pulmonary host response after administration of interferon gamma by aerosol to clearly define the mechanisms by which IFN causes clinical improvement in tuberculosis patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CLINICAL RESEARCH IN TUBERCULOSIS Principal Investigator & Institution: Chaisson, Richard E. Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: This application for a Midcareer Investigator Award in Patient-Oriented Research is submitted by Richard E. Chaisson, M.D, Professor of Medicine, Epidemiology and International Health at the Johns Hopkins University. The applicant completed subspecialty training in infectious diseases and clinical epidemiology in 1987. Since that time, he has built a successful and productive research program within the Johns Hopkins AIDS Service, a multidisciplinary clinical care enterprise for adults with HIV infection. In addition, he has organized and led the clinical and research efforts of the Baltimore City Health Department Tuberculosis Clinic, and has undertaken field
28 Tuberculosis
trials in HIV-related tuberculosis in Haiti and South Africa. In 1998 Dr. Chaisson was promoted to Professor and began a refocusing of his academic activities and commitments. This application is intended to support this effort. Dr. Chaisson has relinquished the directorship of the AIDS Service and has appointed a replacement director of the Tuberculosis Clinic in order to devote his full attention to clinical research in tuberculosis and HIV infection. Dr. Chaisson has founded the Johns Hopkins University Center for Tuberculosis Research, an interdivisional, multidisciplinary program dedicated to improving global tuberculosis control through innovations in diagnosis, treatment and prevention. The centerpiece of this initiative is field trial comparing alternative tuberculosis control strategies in communities within high-incidence countries, funded under the US Agency for International Development's Infectious Disease Initiative. This trial will be conducted in several countries and will randomly assign communities to one of three tuberculosis control strategies: i) directly observed therapy (DOT) for active cases; ii) DOT plus screening of household contacts for active disease; and iii) DOT plus screening and preventive therapy for household contacts. This trial will provide important insight into effective strategies for global tuberculosis control. The applicant is also Principal Investigator of the Baltimore Tuberculosis Trials Consortium site, and a funded investigator in other studies of tuberculosis epidemiology and control. With support under this award, he will develop an integrate program in tuberculosis research utilizing the clinical and laboratory resources of the Baltimore Tuberculosis Clinic, the Johns Hopkins University and sites in developing countries with high tuberculosis incidence. Moreover, he will serve as mentor to junior faculty in infectious diseases and related fields who are beginning academic careers in patient-oriented research. A mentoring program organized to enhance professional development and independent scholarly activity will be undertaken with two recent faculty recruits. An award under this program will substantially enhance the research and mentoring capabilities of the applicant, and will contribute to the generation of new knowledge essential for the control of tuberculosis worldwide. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONJUGATION AND RECOMBINATION IN MYCOBACTERIA Principal Investigator & Institution: Derbyshire, Keith M.; Wadsworth Center Empire State Plaza Albany, NY 12237 Timing: Fiscal Year 2001; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: Mycobacterium tuberculosis accounts for more deaths worldwide than any other infectious agent. Recent increases in the number of cases have been associated with the spread of the AIDS virus and the appearance of drug-resistant strains of M. tuberculosis. The development of new treatments for mycobacteria requires an understanding of the biology of these bacteria and the ability to manipulate their genomes to determine the genetic basis of pathogenesis and drug resistance. In M. tuberculosis, studies have been hindered by inefficient methods for the introduction of DNA into and between strains, and by the low frequency of targeted recombination. In particular, the ability to make site-directed changes within the M. tuberculosis genome is crucial for understanding the role of particular genes in virulence. We propose to characterize a novel conjugation system that can transfer chromosomal DNA between strains of Mycobacterium smegmatis and use it as a tool for the analysis and transfer of DNA between mycobacteria. This naturally occurring system could offer an efficient method for the introduction of DNA into the slow-growing pathogenic mycobacteria. Furthermore, by examining conjugation between different species of mycobacteria we
Studies 29
will assess its promiscuity and possible role in the spread of drug resistance. Finally, we have identified three M. tuberculosis genes that are highly homologous to those encoding the RecBCD pathway of recombination in Escherichia coli, which is the major pathway for conjugal recombination and double-strand break repair. We intend to characterize these genes to facilitate the development of a defined homologous recombination system in M. tuberculosis. These goals will be achieved by: 1. Cloning and characterizing the cis-acting sequences necessary for conjugal DNA transfer. 2. Identifying the trans-acting protein functions necessary for transfer. 3. Monitoring conjugal transfer from M. smegmatis into other mycobacterial species including the slow-growing pathogenic species. 4. Developing a defined allele-exchange system by characterizing the RecBCD pathway of M. tuberculosis Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTACT-MEDIATED HOST RESISTANCE TO M TUBERCULOSIS Principal Investigator & Institution: Silver, Richard F. Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2003 Summary: Tuberculosis remains an international health problem of immense proportions, as one-third of the world's population is currently infected with the causative organism, Mycobacterium tuberculosis. Cell-mediated immunity, involving the interaction of sensitized lymphocytes with M. tuberculosis-infected mononuclear phagocytes, can contain the organism, resulting in the finding that the great majority of otherwise healthy individuals do not develop active tuberculosis following infection. HIV-positive individuals have greatly increased susceptibility to the development of active disease following infection with M. tuberculosis. Furthermore, tuberculosis is often an early complication of HIV infection which precedes marked declines in CD4+ T-cell counts. In contrast to studies of other intracellular pathogens, in vitro addition of activating cytokines does not mediate significant reduction in the intracellular growth of M. tuberculosis. Utilizing a method of quantitative infection of human mononuclear phagocytes with virulent M. tuberculosis in which the interactions of lymphocytes with these infected cells can be characterized, preliminary studies indicate that addition of lymphocytes to cultures of M. tuberculosis-infected monocytes is more effective at limiting intracellular growth than is transfer of the supernatants of those cultures. It is hypothesized that cell-to-cell contact involving the interactions of specific cell surface molecules is necessary to maximally activate human mononuclear phagocytes to contain intracellular growth of M. tuberculosis. This hypothesis will be addressed in the following Specific Aims: 1) To determine the contact-dependent mechanisms by which antigen-specific CD4+ T-cells activate bactericidal functions of M. tuberculosis-infected mononuclear phagocytes; 2) To determine whether maximal CD4+ T cell-mediated activation of M. tuberculosis-infected mononuclear phagocytes requires sequential or interactive effects of cell contact and cytokine production; and 3) To determine whether CD8+ T-cells, gammadelta T-cells, and NK cells mediate contact-dependent activation of M. tuberculosis-infected mononuclear phagocytes, to compare the mechanisms used by these effector populations to those of CD4+ T cells, and to determine the role of Fas/FasL-mediated cytotoxic effector mechanisms on killing of M. tuberculosis within human mononuclear phagocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
30 Tuberculosis
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Project Title: CONTROL OF BACTERIAL TOXINS BY VIRUSES AND PLASMIDS Principal Investigator & Institution: Holmes, Randall K. Professor and Chair; Microbiology; University of Colorado Hlth Sciences Ctr Uchsc at Fitzsimons Aurora, CO 800450508 Timing: Fiscal Year 2001; Project Start 30-SEP-1976; Project End 31-MAR-2005 Summary: (Adapted from the Applicant's Abstract): The long term goals of this project are to determine molecular mechanisms for virulence regulation in pathogenic bacteria and to develop new methods to treat bacterial infections. The investigators will study Corynebacterium diphtheriae, a paradigm for toxin-mediated bacterial infections, and Mycobacterium tuberculosis, a prototype for intracellular bacterial infections. These very different bacterial pathogens produce closely related, iron-activated, global regulatory proteins that govern virulence: the diphtheria toxin repressor (DtxR) and the iron-dependent regulator (IdeR), respectively. The investigators will determine the molecular basis for function of DtxR, IdeR and the homologous regulator SirR from Staphylococcus epidermidis. The investigators will use structure-based design to develop new antimicrobial drugs called "super-activators" that will target DtxR, IdeR or their homologs; activate them by iron-independent mechanisms; and inhibit production of virulence factors that are negatively regulated by iron- and DtxR-related repressors. The development of IdeR as a novel target for antimicrobial therapy could address the urgent global need for improved treatment of tuberculosis. The investigators will characterize the genes and gene products that are iron-regulated and under control of DtxR and IdeR, both to provide new insights into the pathogenesis of diphtheria and tuberculosis and for development of additional classes of antimicrobial agents. Specific Aim I will analyze structure and function of DtxR, IdeR and SirR. The investigators will investigate the molecular basis for repressor-operator interactions, for iron-independent super-repressor activity, and for domain function in biological activity of these regulatory proteins. Specific Aim 2 will characterize the DtxR and IdeR regulons in C. diphtheriae and M. tuberculosis. The investigators will develop an allelic exchange system for C. diphtheriae, characterize the DtxR and IdeR regulons by proteomic and molecular genetic methods, assess physiological functions of DtxR and IdeR domain 3, and investigate atypical phenotypes among clinical isolates of C. diphtheriae. Specific Aim 3 will develop super-activators of DtxR and IdeR by structure-based design. The investigators will design combinatorial peptide libraries, test them for super-activator function, identify individual peptides with activity, determine the structural basis for that activity, and develop better super-activators by iterative application of these methods. The investigators will also use molecular genetic methods to identify novel mechanisms for super-repressor activity and new lead compounds for development as tools against these bacterial infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--INTERNATIONAL Principal Investigator & Institution: Remick, Scot; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001 Summary: Since 1988, an interactive and multi-disciplinary team of investigators at the Case Western Reserve University and the Tuberculosis Research Unit have effectively and creatively fostered the development of scientific, clinical, laboratory, and education programs in the area of infectious disease (tuberculosis, HIV-AIDS) with investigators at the Makerere University (MU) in Kampala, Uganda and the AIDS Control Program of
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the Ugandan Ministry of Health. The intent of this application is to continue to build on this program by expanding expertise within the center for AIDS research at CWRU and create an International Clinical Coordinating Center (ICCC). The core facility will provide an administrative structure with which to coordinate and considerably expand upon the international collaborative endeavors of CWRU and to foster realistic and meaningful clinical advances to clinicians, scientists, and other healthcare providers in Uganda with the emphasis on certain aspects of the HIV/AIDS pandemic. The creation of the ICCC core facility represents an unprecedented and exciting opportunity to join basic and clinical researchers from six-NIH designated centers at CWRU inclusive of: The Tuberculosis Research Unit, Dr. J.J. Ellner, Director; University Hospitals Ireland Cancer Center (UHICC), Dr. James Wilson, Director; Skin Disease Research Center (SDRC), Dr. Craig Elmets, Director; AIDS Clinical Trials Unit (ACTU), Dr. Michael Lederman, Director; Fogarty AIDS International Training and Research Program, Dr. Christopher Whalen, Director; and the Center for AIDS Research (CFAR), Dr. Stuart Le Grice, Director. The specific aims of this proposal arena to enhance interaction between Ugandan and CWRU clinicians and scientists in the HIV/AIDS are inclusive of tuberculosis, medical mycology, AIDS- related malignancies, and primary HIV vaccine development; to coordinate research activities in the field, clinic, and hospital settings in Kampala, Uganda and research programs/laboratories at CWRU; and to create an environment in Uganda for collaborative research suitable for realistic and meaningful technology transfer. Key research projects that would be funded by the International Core are DNA metabolizing enzyme targeted therapy (CA62502, J. Wilson), Viral etiology and cellular signals in AAKS (CA43703, J. Wilson), preparation for AIDS vaccine evaluation AI35173/CPV1, J.J. Ellner); Preventative therapy for TB in Uganda(CCU50671605, J.J. Ellner); Tuberculosis prevention and control unit (AI45244, J.J. Ellner); Impact of TB on HIV infection in Uganda (AI32414, C. Whalen). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COST EFFECTIVE CONTROL OF TUBERCULOSIS IN THE US Principal Investigator & Institution: Brewer, Timothy F. Assistant Professor of Medicine; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2003 Summary: In the mid-1980's, the long-standing historical decline in tuberculosis cases in the United States reversed itself and case rates began to rise. With the tuberculosis epidemic came the recognition that this disease was becoming increasingly concentrated in defined segments of the overall population. Though total case rates are falling again, groups in the US at significantly higher risk for tuberculosis than the general population exist. It is unknown whether the current recommendations for the control of tuberculosis in the US general population are as effective for these groups. To address this issue, a desktop Computer based mathematical model has been developed to simultaneously project tuberculosis cases and deaths over a l 0 year period using the best available epidemiological data. By adapting this model for US groups at increased risk for tuberculosis, this project will evaluate tuberculosis control strategies for four high risk groups. The groups are persons infected with human immunodeficiency virus, health care workers, immigrants, and the homeless. For each group, a database of inputs based on the epidemiology of tuberculosis within that group will be created. These databases will draw on the published literature and available government information such as that provided by the Centers for Disease Control and Prevention revised report of verified case of tuberculosis. The following tuberculosis control strategies will be evaluated singly and in combinations: increased coverage and improved efficacy of
32 Tuberculosis
preventive therapy, increased coverage and improved efficacy of treatment, increased effectiveness of contact tracing, and the introduction of bacille Calmette-Guerin vaccination. The robustness of the model results will be assessed in sensitivity analyses by simultaneously varying all inputs using Latin hypercube sampling. The combination of mathematical modeling and epidemiology provides the most complete evaluation of TB control measures among these high risk groups to date, and forms a basis for improving approaches to control this epidemic among these populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CRYSTALLIZATION OF THE GALACTOSYLTRANSFERASE FROM MTB Principal Investigator & Institution: Reynolds, Robert C.; Southern Research Institute Birmingham, AL 35205 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): This application is in response to PAS-02-031 for a supplement to our current NIAID-funded program AI45317 entitled Glycosyltransferases as Drug Targets in Mycobacteria. This supplemental program will involve the expression, purification, and crystallization of the galactosyltransferase (Rv3808c) from Mycobacterium tuberculosis. The galactosyltransferase adds galactofuranose units to the growing galactan, a polysaccharide that anchors the mycolylarabinan superstructure and is critical to mycobacterial cell wall integrity in the harsh environment of the human macrophage. This effort is responsive to the announcement in that it supplements our current program by applying modern structural biology techniques to obtain a structure of a protein targeted for drug development under our current grant. This protein was not available at the time of our application, and the information provided through the application of the requested supplemental funds will give us a specific picture of the protein active site allowing more rapid development of drugs to target this critical mycobacterial enzyme. As well, this grant is responsive to the PA in that it addresses a new drug target in tuberculosis, and may have implications in the treatment of multi-drug resistant tuberculosis (MDRTB), a critical health problem worldwide. Tuberculosis and its drug resistant forms are the focus of two active NIAID Program Announcements (PA-99-124 & PA-01-113) and is considered a potential biological weapon by the Department of Defense. This application involves modern structural biology that may not be considered as innovative as recent techniques in bioinformatics, genomics, and microarray technology. This effort, however, is innovative in the choice of target and the impact that structural biology can have on our funded program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CYTOTOXIC RESPONSE TO HISTOCOMPATIBILITY ANTIGENS Principal Investigator & Institution: Bevan, Michael J. Professor; Immunology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 01-JUN-1990; Project End 31-DEC-2007 Summary: provided by applicant): Our goal is to investigate the CD4 and CD8 T cell response to pathogenic infectious agents to uncover basic principles of T cell biology in controlling these infections. Two contrasting models of intracellular bacterial pathogens are chosen to ask fundamental questions about how the immune system perceives, responds, contains and eliminates these pathogens. One model to be studied is virulent Mycobacterium tuberculosis delivered via aerosol to the lungs of mice. This organism
Studies 33
can survive inside vacuoles within macrophages and set up a chronic infection which can be contained, but not eliminated, by adaptive CD4+T cell immunity. The role of CD8+ T cells in controlling tuberculosis is controversial. Recombinant organisms producing a model antigen containing well-studied epitopes for CD4 and CD8 T cells will allow a study of the tempo of the T cell response, and provide new information on protection against what has been called the world's most successful pathogen. M. tuberculosis may infect one third of the world's population. The second intracellular pathogen we plan to use is a common food-borne pathogen, Listeria monocytogenes. Excellent mouse models exist already for the study of this Gram positive pathogen, where it appears that adaptive CD8+ T cell immunity is the critical force in eliminating the infection. L. monocytogenes is a candidate vaccine vector for the induction of CD8 immunity, for example, against tumor antigens. The massive response of CD8+ T cells to acute infection with Listeria and the generation of long-lived protective immunity may also require CD4+ T cell help. The proposed studies are aimed at a greater understanding of the development of long-lived, protective immunity induced by this pathogen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT AND TESTING OF NEW TUBERCULOSIS VACCINES Principal Investigator & Institution: Horwitz, Marcus A. Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001; Project Start 01-APR-1991; Project End 31-AUG-2005 Summary: (Adapted from Applicant's Abstract) Mycobacterium tuberculosis, the primary agent of tuberculosis, infects one-third of the world's population and kills 3 million people annually, making it the world's leading cause of death from a single infectious agent. It is a leading cause of disease and death in AIDS patients, particularly in the developing nations of the world. The rapid global emergence of strains resistant to the major antibiotics used to treat tuberculosis poses a serious threat to public health. The highest priority in the fight against tuberculosis is the development of a vaccine that is more efficacious than the current vaccine - BCG. A vaccine more potent than BCG would have an impact on human health greater than virtually any other conceivable development in the fight against infectious diseases. Studies from this laboratory completed under the current grant established the importance of major extracellular proteins of M. tuberculosis in inducing both cell-mediated and protective immunity in the guinea pig model of pulmonary tuberculosis, a highly susceptible species that develops disease remarkably similar to human tuberculosis. Studies under the current grant also succeeded in developing technology for high level expression and secretion in native form of major M. tuberculosis extracellular proteins in a nonpathogenic rapidly growing heterologous host, allowing isolation and purification of 100 mg quantities of recombinant M. tuberculosis extracellular proteins for vaccine studies. In this grant application, we seek to build on the knowledge and experience gained in previous studies to develop a vaccine more potent than BCG in the highly relevant guinea pig model. We seek to develop and test live recombinant vaccines including recombinant BCG expressing major M. tuberculosis extracellular and cell-associated proteins and new non-live particulate vaccines formulated as liposomes and microspheres. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENT OF A TUBERCULOSIS CURRICULUM Principal Investigator & Institution: Jones, Brenda E. Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, CA 90033 Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-SEP-2003 Summary: The goal of this proposal is to develop and implement comprehensive, interdisciplinary curricula on tuberculosis for health care providers in academic and community settings. We will first establish interdisciplinary curricula at a Health Sciences campus, train faculty to disseminate these curricula, and adapt the curricula for use in the community. Our specific aims are: 1) Establishment of comprehensive, interdisciplinary tuberculosis curricula at a Health Sciences campus. The target audience will include physicians, physician assistants and nurses who care for most tuberculosis cases in urban areas, and primary care providers who evaluate most patients for tuberculosis infection. As part of this aim, we will use a Telemedicine system that allows transmission of high-quality images and interactive videoconferencing between faculty at a central location and trainees at geographically separate sites. The effectiveness of the tuberculosis curricula will be measured by: (1) objective tests of factual knowledge and clinical decision-making skills, using written tests and structured clinical examinations; (2) evaluation of changes in clinical practice patterns, using focused chart reviews. 2)Training Health Sciences faculty to provide instruction in tuberculosis. Faculty will be trained to disseminate the curricula developed in aim 1. Regularly scheduled forums will be established to provide ongoing education and discussion among trainees and faculty, and the quality of faculty teaching will be assessed and improved through evaluations by trainees, peers and experts. 3) Expansion of educational efforts to the community. Using the educational infrastructure of Tuberculosis Control of Los Angeles county, we will adapt the tuberculosis curricula developed in aim 1 for delivery to community health care providers, including those who work with populations in which special problems are encountered, including the homeless, immigrants, HIV-infected persons and inmates of correctional institutions. Computer-based interactive programs using CD-ROM technology and/or the Internet will be used for some target audiences. Supervisory physicians and nurses at Tuberculosis Control will be trained to disseminate these curricula. The efficacy of these curricula will be assessed by objective measures of clinical decision- making skills and clinical practice patterns. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENT OF AN IMPROVED MYCOBACTERIA CULTURE MEDIUM Principal Investigator & Institution: Somoskovi, Akos L.; Life Biomed, Llc 2800 Millers Way Dr Ellicott City, MD 21043 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 14-SEP-2004 Summary: (provided by applicant): The clinical signs and symptoms of tuberculosis are not specific. Therefore, laboratory methods play a crucial role in establishing the diagnosis, monitoring the therapy and preventing transmission of the disease. Laboratory results must be not only accurate, but also rapidly available. However, the culture techniques most commonly employed world-wide for the diagnosis of tuberculosis are time-consuming. Recently it has been shown that the spent culture supernatant of Mycobacterium tuberculosis and active components (phopholipids and peptides) derived from it can enhance the growth of tubercle bacilli and allow small inocula to initiate growth in liquid culture. The aims of the proposed study are: (1) To
Studies 35
evaluate the growth enhancing/resuscitating factors as additives to current liquid and solid medium culture systems using lab strains of M. tuberculosis. Experiments will be carried out in both liquid media (7H9, 7H12B Bactec and MGIT) and solid medium (7H1 1 agar), with different inoculum sizes on both fresh and 01 cultures. Serial dilutions of a fresh culture representing the varying bacterial load of smear positive and smear negative clinical specimens can provide information about the growth enhancing effect of the examined agents, while inocula from old cultures will enable investigation of the resuscitation effect of the agents. (2) To evaluate the effect of opitmal growth enhancing factors on drug susceptible and drug-resistant clinical isolates of M. tuberculosis. The effect of selected phospholipids and peptides (based on the results of the above-detailed experiments) will also be studied both on 50 drug susceptible and drug-resistant clinical isolates. (3) To evaluate the effect of growth enhancing factors on drug susceptibility testing. Drug susceptibility testing will be performed on media containing the growth enhancing factors to rule out any interference and to determine the appropriate MIC values. At the end of the Phase I study the optimal components will be selected for formulation of a new culturel medium with commercial potential for improved diagnosis of tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT OF IMMUNE EVASION IN TUBERCULOSIS Principal Investigator & Institution: Ernst, Joel D. Professor; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001 Summary: Acquired immunity to intracellular pathogens depends on T cell recognition of HLA-bound microbial peptides. Pathogens that occupy phagosomes are controlled by CD4+ cells that recognized microbial peptides bound to HLA class II. While these interactions occur in response to Mycobacterium tuberculosis, they are only partially efficacious: the human immune system is unable to completely resolve infection with M. tuberculosis. M. tuberculosis has been found to inhibit class II antigen presentation, but the mechanisms has not been determined. The goal of this project is to define the mechanism of inhibition of class II antigen present in human macrophages infected with M. tuberculosis. We have found that M. tuberculosis causes a decrease of cell surface class II (HLA-DR) in macrophages, without a decreased in the total cellular HLA-DR pool. This suggests that M. tuberculosis alters trafficking of class II. We will further characterize the decreased surface expression of class II by determining whether it is directly related to the number of intracellular M. tuberculosis and by comparing expression of HLA-DR on infected macrophages and dendritic cells. We will test the hypothesis that HLA-DR is sequestered in M. tuberculosis phagosomes, and will determine whether HLA-DR is sequestered due to failure of exchange of exogenous peptides for CLIP. We will also further characterize the functional effects of M. tuberculosis down-regulation of HLA-DR. We will determine whether down-regulation of class II inhibits CD4+ cell recognition of extracellularly loaded M. tuberculosis antigens and whether M. tuberculosis antigens and whether M. tuberculosis inhibits allogeneic responses. Finally, we will test the hypothesis that inhibition of class II antigen presentation is an inherent property of mycobacteria by comparing the response of CD4+ T cell lines that recognize a DR3-restricted epitope of M. tuberculosis hsp65 when it is expressed by mycobacteria or by an alternative vehicle. We anticipate that our results will provide new information on the pathogenesis of tuberculosis, and may identify alternative means of delivering M. tuberculosis antigens for vaccination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENT OF SYSTEM FOR TREATMENT OF TUBERCULOSIS Principal Investigator & Institution: Tsukamoto, Takuji; Chemica Technologies, Inc. 325 Sw Cyber Dr Bend, OR 97702 Timing: Fiscal Year 2001; Project Start 05-SEP-2001; Project End 28-FEB-2003 Summary: Tuberculosis causes a staggering burden of mortality world-wide, killing 2 million people annually. To cure tuberculosis, prolonged therapy of at least 6 months is required, because antituberculosis drugs do not penetrate well into macrophages, which are a major reservoir of M. tuberculosis. To devise antituberculosis medications that will shorten the duration of therapy, we will use microparticles to target the delivery of enzyme-cleavable lipophilic derivatives of isoniazid and rifampin to infected macrophages. Once inside the macrophage, the microparticles degrade and release the lipophilic drugs, which are then transported across the M. tuberculosis cell envelope. Our specific aims are: 1. To synthesize and characterize palmitic acid derivatives of isoniazid and rifampin. 2. To determine the rates of esterase or amidase hydrolysis of these derivatives. 3. To evaluate the capacity of these derivatives to kill M. tuberculosis. If this proposal is successful, a phase II proposal will be submitted to perform additional studies to evaluate these agents combined with microparticles in cell culture systems in vitro and in animals. This project will explore the feasibility of a strategy that can be applied to the treatment of infection caused by many intracellular organisms, including viruses, fungi and parasites. PROPOSED COMMERCIAL APPLICATIONS: The technology we will develop in this program has the potential to significantly improve the treatment of diseases due to pathogens that reside in macrophages, such as tuberculosis and HIV infection. In the treatment of tuberculosis, targeted-delivery systems of enzyme- cleavable lipophilic drugs are presently not available. This strategy has the potential to increase the efficacy of treatment, reduce the dosage of drugs required, reduce side effects of treatment, improve patient compliance, and minimize development of drug resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DIABETES AND TUBERCULOSIS PILOT Principal Investigator & Institution: Perez, Adriana; Assistant Professor; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, TX 77225 Timing: Fiscal Year 2003; Project Start 03-MAR-2003; Project End 29-FEB-2008 Summary: Screening for Mycobacterium tuberculosis infection in those at high risk for developing clinical tuberculosis (TB) is a key strategy of the Centers for Disease Control and Prevention (CDC) to control the spread of TB in the US. This is particularly important at the US/Mexico border, where converging socioeconomic and demographic factors contribute to the higher burden of TB when compared to the US national average. This region also has high prevalence of type II diabetes (DB), which has long been known to predispose to active tuberculosis. Based on this information, we hypothesize that DB contributes to the burden of TB in the Hispanic population from four Texan counties along the Mexican-American border. Four counties in the Lower Rio Grande Valley (LRGV) will be analyzed in this pilot project: Hidalgo, Cameron, WilIacy and Starr. A secondary analysis of the Texas hospital discharges during 2001 will be implemented using ICD 9 codes for case and control selection. Unconditional multiple logistic regression analysis will be used to evaluate the relationship between tuberculosis and tentative associated factors. Health production functions will be estimated, using unconditional multiple logistic regression as well. The specific aims of the project are: Aim 1: Determine the degree of association of DB and TB in Hispanics in
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the LRGV Aim 2: Determine the strength of the association between TB and its associated risk factors (besides DB), with emphasis on underlying medical conditions. Aim 3: Estimate health production function that will identify relevant socio-economic indicators of TB and DB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIAGNOSIS & PATHOGENESIS OF TUBERCULOSIS: AIDS OPPORTUNISTIC INFECTION Principal Investigator & Institution: Didier, Peter J.; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001 Summary: The objective of this pilot project is to continue the characterization of the tuberculosis model in rhesus monkeys. We previously found that high dose inoculation (six million bacteria) of Mycobacterium tuberculosis H37Rv and Erdman strains produced lethal lung disease within five to ten weeks. Monkeys developed clinical signs of dyspnea, coughing, anorexia, and weight loss 4-6 weeks after inoculation. Skin testing with Old tuberculin became mildly positive after 5 weeks while PPD skin tests remained negative. Animals developed extensive necrotizing granulomatous lesions in the inoculated half of the lung with spread to the contralateral lung and bronchial lymph node in animals with H37Rv, and to the liver and kidney in animals with the Erdman strain. Animals vaccinated with culture filtrate from H37Rv and challenged with two million bacteria developed the same clinical disease as unvaccinated controls. However, low dosage inoculation of a pair of animals with each strain (<300 Erdma n, <30 H37Rv) failed to produce clinical disease within 18 weeks. Lesions in three of four animals were confined to the bronchial lymph node. To confirm this finding, four more animals per strain have been inoculated with low dosages of bacteria. All animals have strongly positive skin tests but remain clinically normal four weeks after inoculation. Characterization of this model by culture, blastogenesis, flow cytometry, and cytokine detection continues. Results contradict old literature and indicate that tuberculosis in rhesus monkeys may present as a chronic disease based on the dose of the inoculum. This suggests that future studies using low dose inoculation will be feasible in SIVinfected monkeys to study tuberculosis as an opportunistic infection. FUNDING Venture Research PUBLICATIONS Scollard DM, Didier PJ, Dietrich MA, Bohm Jr RP. Selective increases in CD45RO(+) CD38(+) T cells in 1? and 2? responses to BCG in rhesus macaques. [Abstract]. Proceedings of the 9th International Immunology Congress, San Francisco, CA, July 23-29, 1995. Scollard DL, Didier PJ, Bohm Jr RP. A method to assess changes in rhesus lymphatic T cells in vivo during local immune responses. [Abstract]. Second Annual Molecular Biology and Biotechnology Conference, Baton Rouge, LA, February 9-10, 1996. Didier PJ, Blanchard JL, Gormus BJ. Pulmonary tuberculosis in normal rhesus monkeys infected with Mycobacterium tuberculosis H37Rv. [Abstract #159]. Amer Soc Trop Med Hygiene, 57(3):156, 1997. Didier PJ, Blanchard JL. Chronic tuberculosis produced by low dosage of M. tuberculosis (Erdman) in rhesus monkeys. [Abstract #734]. Amer Soc Trop Med Hygiene 59(3):361, 1998. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DIAGNOSTICS FOR AIDS-RELATED PEDIATRIC TB, PERU Principal Investigator & Institution: Oberhelman, Richard A. Professor; Tropical Med & Parasitology; Tulane University of Louisiana New Orleans, LA 70118
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Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant)Tuberculosis is the major infectious cause of mortality among AIDS patients in the developing world, and HIV infection has been shown to increase mortality from tuberculosis five-fold in parts of Subsaharan Africa. Increasingly, HI V-infected children in developing countries are becoming infected with Mycobacterium tuberculosis (Mtb) and dying at an early age, presenting new dilemmas that differ from those facing adults with HIV-Mtb coinfection. The diagnosis of pediatric TB is complicated by inefficient and expensive methods to recover Mtb and vague diagnostic criteria. This project will evaluate novel approaches to the diagnosis of AIDSrelated pediatric TB in a hyperendemic setting using 1) rapid, cost-effective Mtb culture and susceptibility methods based on direct microscopic observation techniques and 2) alternative non-invasive specimens such as nasopharyngeal aspirates (NPA) and stool to detect Mtb. An optional component will assess improved rapid detection of Mtb by a semi-nested polymerase chain reaction assay (N2 PCR), a technique appropriate for regional reference laboratories in developing countries. Our preliminary data show a high correlation between culture results and N2 PCR results in adults (sputum PCR) and children (stool and NPA PCR) with tuberculosis, and mean time to detection of Mtb by our microscopic observation method was 9 days (at a fraction of the cost of rapid methods used in the U.S.). This is a collaborative effort between PRISMA, a Peruvian private voluntary organization, two U.S. universities (Tulane and Johns Hopkins), and a Peruvian university (Cayetano Heredia). Two hundred-sixty children with pulmonary disease meeting clinical criteria for TB disease (including at least 100 HIV-infected) from the Hospital del Nino, Lima, Peru, and 260 age-matched controls from both high- and low-risk communities will be enrolled. Mtb will be detected in gastric aspirates (cases only), NPAs, and stool by new and traditional culture methods and by N2 PCR. Children with a positive N2 PCR but without clinical evidence of TB requiring antituberculous therapy will be followed longitudinally. These new diagnostic methods have tremendous potential to improve and simplify the diagnosis of pediatric tuberculosis in low-income countries with limited laboratory resources. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFICIENCY
DIETARY
DEFICIENCIES
AND
TUBERCULOSIS
VACCINE
Principal Investigator & Institution: Mcmurray, David N. Professor; Medical Microbiol & Immunology; Texas A&M University Health Science Ctr College Station, TX 77843 Timing: Fiscal Year 2001; Project Start 30-SEP-1982; Project End 31-JAN-2005 Summary: The ultimate aim of this project is to elucidate the mechanisms by which protein deficiency interferes with vaccine-induced resistance to pulmonary tuberculosis. New tuberculosis vaccines will be tested, ultimately, in malnourished humans. Thus, the focus of this project has never been a more urgent research priority. Previous work with a highly relevant guinea pig model, employing low-dose aerosol exposure to virulent Mycobacterium tuberculosis, has revealed diet-induced defects in trafficking, activation, and interactions of immune cells. The recent acquisition of cDNA clones for guinea pig chemokines (MCP-1, IL- 8, RANTES) and cytokines (IFNgamma, TNFalpha, TGFbeta, and IL- 1beta) provides a unique opportunity to apply molecular biological approaches to test four hypotheses: (a) protein deficiency affects trafficking of immune cells into inflammatory exudates by interfering with the production/function of chemokines; (b) abnormal granuloma formation in protein-deficient guinea pigs results from alterations in the production/function of TNFalpha; (c) failure of immune lymphocytes from protein- deficient guinea pigs to activate macrophages to suppress
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intracellular M. tuberculosis is due to decreased production/function of paracrine (IFNgamma) or autocrine (IL- 1beta, TNFalpha) cytokine signals; and (d) TGFbetamediated suppression of T lymphocytes and/or deactivation of macrophages leads to loss of control of intracellular mycobacteria in protein deficiency. Recombinant proteins and polyclonal antibodies will be produced for each of the chemokines and cytokines. Protein- deficient and well-nourished, BCG-vaccinated or nonvaccinated guinea pigs will be challenged by the pulmonary route and levels of these molecules assessed in freshly isolated or cultured cells by Northern blot and RT-PCR (for mRNA), or by bioassay (TNFalpha, TGFbeta) or ELISA. A tuberculous pleuritis model, previously established in the laboratory, and bronchoalveolar lavage will be used to assess the role of chemokines by instillation of recombinant chemokines or specific anti-chemokine antibodies. The effects of recombinant TNFalpha or anti-TNFalpha on granuloma formation will be determined. TGFbeta activity will be blocked in vivo by the injection of anti-TGFbeta antibodies or recombinant decorin. These experiments will provide important new insights into the contributions of these molecules to loss of tuberculosis vaccine efficacy observed in malnourished subjects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIRECT DETECTION OF DRUG RESISTANT MTB WITHOUT PCR Principal Investigator & Institution: Wu, Whei K.; Applied Gene Technologies, Inc. 6190 Cornerstone Ct E, #101 San Diego, CA 921214701 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JAN-2003 Summary: (provided by applicant): Drug resistance is a significant problem in the fight against the bacterial pathogen Mycobacterium tuberculosis. Resistance to rifampin, a first-line antituberculosis drug, is almost always the result of mutations in the rpoB gene of the pathogen. In order to speed the diagnosis of drug resistant tuberculosis, it is possible to detect these mutations by a variety of available methods. However, all such methods require the PCR reaction, which is too expensive for routine use in most countries. There is a critical need for new diagnostic methods that detect genetic markers of rifampin resistance at a fraction of the cost of current methods. Our Tessera Array Technology detects single-copy chromosomal genes of M. tuberculosis without the need for PCR amplification. The method involves high-affinity labeling of pathogen DNA in crude or partially purified lysates, hybridization of the labeled DNA to sequence-specific probes, and detection of the labeled, hybridized DNA. A test for detecting M. tuberculosis has been developed by AGTI and is currently in pre-clinical trials. We propose to expand the test for simultaneous taxonomic detection of M. tuberculosis and genotypic detection of mutations that cause rifampin resistance. The specific aims of Phase I of the project are to adapt the Tessera platform to accommodate probes for rpoB; to enhance test sensitivity by optimizing cell lysis methods; and to conduct a non-clinical trial on known rifampin-sensitive and rifampin-resistant clinical isolates of M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DISSEMINATED TUBERCULOSIS IN HIV INFECTION Principal Investigator & Institution: Von Reyn, C Fordham. Medicine; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, NH 03755 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: Disseminated infection (mycobacteremia) with Mycobacterium tuberculosis (dMTB) has been documented by our group in 10-25 percent of patients with HIV
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infection in Africa using lysis- centrifugation blood cultures. Unlike pulmonary tuberculosis (pMTB), most cases of dMTB are not recognized and death ensues rapidly. Thus, in developing countries dMTB may be a more important cause of HIV-associated mortality than pMTB. Risk factors for dMTB have not been identified and it is not known if most cases are due to primary infection, reactivation or re- infection. We hypothesize that most cases of dMTB are due to primary MTB infection in patients without prior infection with MTB or non-tuberculous mycobacteria (NTM). Mycobacterial immunization in early HIV infection is a potential strategy to prevent dMTB. Mycobacterium vaccae (MV) is an investigational vaccine prepared by heat inactivation of an NTM, and has been shown to be protective against MTB in several animal models. Studies conducted by our group indicate that a 5-dose series of MV is safe in patients with HIV infection and induces a durable cellular immune response to MTB antigens in persons with prior BCG immunization. Our hypothesis is that MV immunization will reduce the risk of HIV-associated dMTB by 50 percent. Our specific aims are: (1) to define risk factors for HIV-associated disseminated tuberculosis and to assess the relative contributions of primary infection, reactivation and re-infection in the pathogenesis of disseminated tuberculosis, and (2) to assess the safety and efficacy of a 5-dose schedule of inactivated MV vaccine for the prevention of HIV-associated pulmonary and disseminated tuberculosis in persons with prior BCG immunization. 2274 HIV-positive patients with prior BCG immunization and 100 HIV-negative controls will be entered in a 5-year study in Zambia. Baseline evaluation will include history, chest x-ray, dual skin tests with purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS), and whole blood assay for interferon-gamma production in response to MV sonicate, PPD, ESAT-6 (a protein antigen unique to MTB) and MTB antigen 85. Subjects with PPD reactions greater than or equal to 5 mm will receive 6 months of prophylaxis with isoniazid. All subjects will be randomized 1:1 to receive a 5dose series of MV or placebo over 12 months with repeat skin test and in vitro studies at 14 months. Subjects will be followed every 3 months for 3-5 years to assess new pMTB (microbiologic or clinical diagnosis) or dMTB (microbiologic diagnosis). All isolates will have susceptibility tests and IS6110 DNA fingerprinting performed. Potential risk factors for dMTB, including baseline PPD test results, will be assessed in placebo and vaccine groups. Vaccine efficacy against dMTB and pMTB in HIV-positive subjects will be determined, and post immunization interferon gamma responses used to identify a surrogate marker of efficacy. The proposed study has important implications for the reduction in mortality from HIV-associated tuberculosis and for design of future trials of new vaccines against tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DNA GYRASE AND QUINOLONE RESISTANCE IN TUBERCULOSIS Principal Investigator & Institution: Drlica, Karl A. Associate Professor; Public Health Research Institute 225 Warren St Newark, NJ 07103 Timing: Fiscal Year 2001; Project Start 30-SEP-1993; Project End 30-JUN-2003 Summary: (Adapted from the applicant's abstract): Drug resistance is a major problem for anti-tuberculous chemotherapy and is one of the main reasons why compounds such as fluoroquinolones are not first line agents. Two recent advances, using a variety of bacteria, encourage refinements of fluoroquinolones. First, resistance arises stepwise from mutations in two independent targets, DNA gyrase and DNA topoisomerase IV. Thus a first step resistant gyrase mutant can be used to screen new fluoroquinolones for derivatives that require two mutations to confer resistance. Since double mutations occur less frequently that single mutations by many orders of magnitude, resistance to
Studies 41
the new compounds should arise very rarely. Second, the double mutant concept was experimentally validated: a C8-methoxyl group reduced the acquisition of resistance by at least three orders of magnitude. Two approaches are proposed to define how these principles apply to fluoroquinolone resistance in Mycobacterium tuberculosis. In one, fluoroquinolone structural variants will be examined for their ability to prevent resistance. Prevention of resistance will be correlated with avid killing of moderately resistant strains 1) in pure culture under growing and non-growing conditions, and 2) inside cultured human macrophages. The generality of the conclusions will be tested using a wide variety of clinical isolates of M. tuberculosis. In the other approach, resistance will be studied by examining nucleotide sequences of genes encoding gyrase and topoisomerase IV. Mutants will be selected for resistance to various fluoroquinolone congeners, some of which are already known to elicit different alleles. Selected mutants will be tested for 1)cross-resistance, 2) adaptation to changing environment, and 3) invasion of human macrophages. Already available are many new compounds, two novel assays (killing resistant mutants and prevention of resistance), a human macrophage infection system, and a large collection of clinical isolates of M. tuberculosis. Significant progress is expected toward finding fluoroquinolones that will prevent resistance from arising in M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DRUG DEVELOPMENT FOR MDR-M TUBERCULOSIS Principal Investigator & Institution: Dick, James D. Pathology; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2003; Project Start 15-MAR-2003; Project End 28-FEB-2008 Summary: (provided by applicant): Tuberculosis is one of the oldest and most common infectious diseases of man. The disease is epidemic with approximately 1.8 billion people or one third of the world's population currently infected. The HIV epidemic and the emergence of multi-drug resistant M. tuberculosis (MDR-TB) has led to a critical need for the discovery and development of new and effective therapeutic agents for the treatment and control of tuberculosis. The b-sulfonylcarboxamides are a novel class of compounds which have potent in vitro activity against pathogenic mycobacteria with minimal inhibitory concentrations (MICs) ranging from 0.78 micrograms per ml to 12.5 micrograms per ml for M. tuberculosis, including MDR-TB. In addition, these compounds are highly specific for pathogenic mycobacteria, maintain activity in the presence of human serum, and are not cytotoxic for mammalian cells at 40 times their MIC for M. tuberculosis. Recent studies in our laboratories have demonstrated the antimycobacterial activity of the b-sulfonylcarboxamides to be the result of inhibition of a potentially unique pathway/target involved in central energy metabolism. The longterm objectives of this grant proposal are to determine the molecular target and mechanism of action of this novel class of compounds, with subsequent optimization of drug structure, synthesis, and preclinical drug development. This will be accomplished through: (1) characterization and identification of the target/pathway using available genomic and proteomic technologies, (2) confirmation and validation of candidate target(s) through microbiologic, biochemical, and genetic comparisons between resistant and susceptible mycobacteria, (3) determination of the three dimensional structure of the identified target, (4) design and synthesis of optimum small molecule inhibitors of the identified target/pathway (5) in vitro and in vivo toxicity and efficacy testing in a murine model of tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DRUG DISCOVERY FOR PERSISTENT TUBERCULOSIS Principal Investigator & Institution: Sacchettini, James C. Professor & Wolfe-Welch Chair; Biochemistry and Biophysics; Texas A&M University System College Station, TX 778433578 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Tuberculosis (TB) is the leading cause of death by an infectious disease in the world. The synergy between TB and AIDS is also very apparent. TB is the primary cause of death for individuals co-infected with the human immunodeficiency virus (HIV). HIV infection is the greatest single risk factor known for progression from TB infection to active TB disease in developing nations, where as many as 40-80% of individuals with the acquired immunodeficiency syndrome (AIDS) will also develop TB. Conversely, coinfected patients with active TB show enhanced viral replication and accelerated progression of AIDS. Although Tb is a treatable disease, current chemotherapy regimens require a complex strategy of 3 drugs for at least six months. Such prolonged therapy is necessary because conventional drugs are poorly effective against a sub-population of latent and drug-tolerant bacterial 'persisters'. Most patients will not adhere to this treatment regimen. Patients who default suffer increased rates of treatment failure, relapse, and drug resistance. New drugs against persisting mycobacteria are urgently needed to counter the problem of patient non-compliance. The development of new drugs would be greatly facilitated by the identification of bacterial 'persistence factors' as candidate drug targets. A significant step towards this goal was our recent demonstration that the glyxoylate shunt enzyme isocitrate lyase, ICL, is essential for persistence of Mycobacterium tuberculosis, in vivo. In addition, we have demonstrated that ICL is expressed at high levels in M. tuberculosis living in murine macrophages. Building on these observations, we will take a multi-discipline approach to define the role of the glyoxylate shunt and fatty acid catabolism in persistence. Enzymes found essential to persistent organisms will be characterized and used in high throughput drug screening and structure based drug-design. Promising lead compounds will be tested for safety and efficacy in a mouse model of chemotherapy, latency, and relapse. Indeed, the primary goal of this proposal is to develop new chemotherapeutics for the treatment of persistent M. tuberculosis infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DRUG RESISTANT TUBERCULOSIS Principal Investigator & Institution: Montellano, Paul; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2002; Project Start 01-SEP-1997; Project End 31-AUG-2007 Summary: Drug resistant tuberculosis is a major opportunistic infection in AIDS patients and resistance to the available drugs is growing. Tuberculosis infection both increases the infectivity of the HIV virus and is a major cause of death in AIDS patients. This project focuses on the role of selected oxidation-reduction processes in the development of Mycobacterium tuberculosis drug resistance and the use of this information for the design of new antitubercular agents. Isoniazid, a first line drug, is activated by the KatG catalase peroxidase to a reactive intermediate. This intermediate, or one of its further reaction products, is responsible for interaction with the cell wall biosynthetic enzymes InhA and KasA-AcpM, the ultimate targets of the drug. Resistance to isoniazid is largely caused by mutations that disable KatG and is associated with the enhanced expression of AhpC and AhpD, two unrelated non-heme alkylhydroperoxidases (peroxiredoxins) that compensate for the loss of KatG. Inhibition
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of AhpC/AhpD in conjunction with isoniazid treatment is a potentially useful mechanism for counteracting isoniazid resistance. In the expiring grant period, AhpC and AhpD were cloned, expressed, and partially characterized and the crystal structure of AhpD was determined. Building on these results, further structural and mechanistic studies are to be carried out with AhpC/AhpD, and this information is to be used to develop potent and selective inhibitors of these two proteins. Ethionamide is another antitubercular prodrug. It is activated by the enzyme EtaA rather than by KaG but the activated species also appears to act at the level of InhA andor KasA-AcpM. Ethionamide resistance is due to impairment of EtaA activity and is associated with elevations in AhpC/AhpD similar to those observed with isoniazid. We have cloned and expressed EtaA and shown it to be a flavoprotein that catalyzes two sequential step in the activation of ethionamide and other thioamide drugs. We propose to complete characterization of EtaA, including the nature of the reactive intermediate, the mechanisms of its interactions with InhA and KasA-AcpM, and its biological importance. The information is to be used to synthesize agents that inhibit one of these two target proteins and, if warranted, EtaA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DRUG TRANSFERASES
TARGETING
M.
TUBERCULOSIS
ARABINOSYL
Principal Investigator & Institution: Lee, Richard Edward. Assistant Professor; Pharmaceutical Sciences; University of Tennessee Health Sci Ctr Health Science Center Memphis, TN 38163 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-MAY-2003 Summary: (adapted from applicant's abstract): Tuberculosis is still a major cause of morbidity and mortality worldwide with the number of cases rising due to the HIV pandemic and the emergence of drug resistant strains. To combat these problems more effective antibiotics must be developed with better pharmacokinetics and lower toxicity than the drugs currently used. It is the aim of this proposal to study the chemistry, biochemistry and genomics of arabinose metabolism in M. tuberculosis and the effects of the front line drug ethambutol on the important mycoloylarabinogalactan (MAG) biosynthetic cascade. MAG is a unique lipidated polysaccharide surrounding and protecting the tubercular bacilli from the host immune system where it has found its evolutionary niche. The proteins involved in MAG biosynthesis are excellent drug targets because they are essential for growth of the organism and are unique to mycobacteria. However, a fundamental lack of knowledge of the genes involved prevents these targets from being developed. This proposal initiates the synthesis of advanced cell wall mimetic acceptors and the development of new arabinosyl transferase assays. Using these assays the relationship between the alpha (1-3) arabinosyl transferase activity and the frontline drug ethambutol will be defined. These assays will also allow detailed analysis of the mechanism of beta (1-2) arabinosyl transfer and aid in identification of the beta (1-2) transferase. The role of the protein encoded embCAB operon in arabinan biosynthesis will be explored, and its sensitivity to ethambutol and novel antimycobacterials examined. Most importantly the knowledge gained from these studies will initiate a thorough medicinal chemistry effort involving these targets for the development of new, more effective and less toxic treatments against tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EARLY PULMONARY HOST DEFENSE IN M. TUBERCULOSIS INFECTIO Principal Investigator & Institution: Sherman, David R. Senior Scientist; Pediatrics; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: Although a lung is a portal of entry for this M. tuberculosis and chronic pneumonia is the most common disease caused by M. tuberculosis infection, the specific nature of the pulmonary host response to this pathogen is relatively unknown. The central goal of the studies outlined in this proposal is to determine whether components of the early pulmonary immune response are critical determinants for resistance or susceptibility to disease caused by M. tuberculosis. The specific aims will address the role of TNF-alpha, beta chemokines and the B7/CD28/CTLA4 costimulation pathway in the initiation and amplification of the pulmonary host response to aerosol infection with M. tuberculosis. Preliminary studies using transgenic mice with a local inhibition of TNF-alpha in the lung (SPCTNFRIIFc mice) indicate that blockade of TNF-alpha selectively in the lung results in early deaths, severe lung pathology and an alteration of antigen specific immunity. These studies also indicate that transgenic mice with local inhibition of the immune response in the lung are a useful model to study pulmonary host defense. Further studies are proposed to compare the response that develops in the lung vs. regional lymph nodes in wildtype and SPCTNFRIIFc mice. To investigate the role of beta chemokines in the pulmonary host defense, transgenic mice that secrete a virally encoded inhibitor of all chemokines has been generated. The phenotype of these mice will be determined then used to investigate the role of beta chemokines in the initiation of the pulmonary host response to M. tuberculosis. To investigate the role of the B7/CD28/CTLA4 costimulation pathway in the initiation and amplification of the pulmonary host response to M. tuberculosis, transgenic mice that secrete an inhibitor of the B7/CD28/CTLA4 co stimulation pathway will be generated, characterized then used in experiments examining the immune response to M. tuberculosis. To determine the relative importance of the intrapulmonary component of the immune response vs the systemic immune response, in each of the project specific aims, mice will be included with both local inhibition of the immune response and systemic inhibition. In the studies examining the pulmonary host response to M. tuberculosis, infections will occur via the aerosol route because inhalation is the usual route of infection in humans. The primary endpoints will include bacterial burden, lung histology, survival and the phenotypic and functional characteristics of the immune response. The proposed studies should advance the existing knowledge of the specific nature of the pulmonary immune response to M. tuberculosis, will directly test the role of these mediators in host defense against M. tuberculosis, suggest important targets for novel therapies and elucidate role of specific mediators of the host immune response that are critical for the induction of an antigen specific immune response by candidate vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EDUCATION IN TUBERCULOSIS--A NEED IN PUERTO RICO Principal Investigator & Institution: Rodriguez, William; U.S. Dept/Vets Affairs Medical Center Affairs Medical Center San Juan, PR 00933 Timing: Fiscal Year 2001; Project Start 01-JUL-1997; Project End 30-JUN-2002 Summary: During the last seven years we have seen dramatic changes in the epidemiology and incidence of tuberculosis in the United States. Despite improved
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methods of diagnosis and treatment, tuberculosis is increasing. Likewise, in Puerto Rico, tuberculosis cases have increased and occur disproportionately in certain high risk groups as HIV-infected persons. Over the last 3 decades as tuberculosis cases diminished, so did tuberculosis education. Medical students at the University of Puerto Rico School of Medicine, as well as housestaff, postgraduate fellows, and faculty receive an inadequate amount of training in tuberculosis and tuberculosis control. Moreover, the Puerto Rican community has little means of learning about this increasing public health threat. The primary goals of the curriculum development program in this application are the following: 1) to provide an integrated curriculum in tuberculosis that emphasizes principles and practices relevant to tuberculosis control at all levels of medical education; 2) to improve tuberculosis education in Puerto Rican community focusing on the providers caring for ("high risk" clients; 3) to develop a faculty capable of providing high quality tuberculosis instruction. The proposed curriculum development plan involves the following major components; a) creation of a multidisciplinary advisory committee; b) development of instructional materials that emphasize the importance of tuberculosis and tuberculosis control in case-based problem solving sessions; c) increased didactic and case-based teaching during the clinical rotation of medical students as well as housestaff postgraduate fellows; d) training of faculty responsible for tuberculosis education; e) improved continuing education in tuberculosis for community physicians and health care workers through a number of innovative courses and collaborations with the Department of Public Health and other community organizations. Research related to tuberculosis control will be fostered by support of student research projects as well as the continuation of the candidate's research program and the many collaborations that will result from this award. Evaluation of the curriculum development program will be conducted by an experienced group of physician and health educators through a stepwise and analytical manner. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFLUX INHIBITORS FOR MYCOBACTERIUM THERAPIES Principal Investigator & Institution: Markham, Penelope N. Director of Research; Influx, Inc. 2201 W Campbell Park Dr Chicago, IL 60612 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 31-DEC-2001 Summary: (Verbatim from Applicant's Abstract): New drugs are desperately needed for tuberculosis both to reduce the long duration of treatment and to cure and stop transmission of multiple-drug-resistant Mycobacterium tuberculosis. Recent studies, including the completion of the TB genome sequence, suggest that efflux pump inhibitors may play a significant role in the intrinsic resistance of M. tuberculosis to most common antibiotics. Influx has identified several low molecular weight inhibitors of the NorA efflux pump in Staphylococcus aureus which demonstrated synergistic activity with ciprofloxacin and which dramatically reduced the frequency of emergence of ciprofloxacin-resistant mutants. In preliminary in vitro experiments with M. tuberculosis, two of these compounds demonstrated marked synergy when combined with two tetracyclines and a macrolide. We propose to a) test additional congeners of these inhibitors to determine structure-activity relationships with respect to M. tuberculosis, b) determine the substrate specificity of the effected efflux pump by testing for synergy with a wide variety of antimicrobials, c) determine the effect of the inhibitors on the frequency of emergence of drug-resistant mutants and d) with a variety of TB drug-susceptible and resistant clinical isolates, and e) assess synergistic activity of inhibitors with antimicrobial agents in a macrophage model of TB infection. It is
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anticipated that these studies will result in the identification of one or more lead compounds that would be assessed for activity in animal models of acute and chronic TB in a phase II project. In addition these compounds would serve as starting points for synthesis of additional congeners. PROPOSED COMMERCIAL APPLICATION: The envisioned commercial product is a combination of tetracycline, a macrolide, or possibly another antibiotic with an efflux pump inhibitor. This combination can form a powerful anti-TB agent which can be effective against resistant strains and prevent further emergence of resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EMERGING MDR TUBERCULOSIS ACROSS THE US/MEXICO BORDER Principal Investigator & Institution: Mccormick, Joseph B. None; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, TX 77225 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant) Our application will create dynamic databases to analyze and generate preliminary data on the precise patterns of transmission of tuberculosis (TB), especially multidrug resistant tuberculosis (MDR-TB), across South Texas and North Eastern Mexico. This will be achieved through a binational consortium that will share social, demographic, and geographic data on tuberculosis cases from each of their respective areas. The aims of the consortium are 1) aggregate existing sociodemographic, drug resistance and molecular fingerprinting databases currently held separately by consortium members 2) merge, geocode and analyze the aggregated database 3) establish common protocols and procedures for testing of drug resistance, extraction of M. tuberculosis DNA, and molecular characterization of isolates 4) evaluate social network analysis as a method for improving the tracking of MDR-TB transmission. These analyses link individual cases over 3-5 years with molecular fingerprints, drug susceptibility patterns, sociodemographic characteristics and geographic location, allowing regional understanding of the distribution and dynamics of DR and MDR-TB transmission across the border. These data will be used to improve control techniques and become the basis of hypotheses that will be tested in future, more elaborate research applications. These applications will include epidemiologic and translational research studies using common protocols for binational projects in emerging diseases, specifically MDR-TB. The geographic area of the consortium encompasses 5 counties of the Lower Rio Grande Valley (LRGV) from the Gulf of Mexico to Laredo, and the Mexican border states of Tamaulipas and Nuevo Leon. The consortium will be led by the Dean and faculty of the University of Texas School of Public Health Regional Campus at Brownsville, less than a mile from the border and contributing expertise in molecular microbiology, epidemiology, biostatistics, social network studies and spatial-temporal analyses. Leading tuberculosis researchers in Houston, San Antonio and Monterrey will play key roles in strengthening the capacity to conduct specialized public health, epidemiologic, and molecular based research on MDR-TB in the study area. Border consortium participants are from all the public health investigatorities responsible for TB elimination in both countries. An important defense of MDR introduction by bioterrorism is understanding how transmission of these organisms may differ from non resistant TB (if at all) and detailed knowledge of local strains of MDR that will allow quick distinction between known circulating strains of MDR TB and newly introduced strains. This application will be instrumental in addressing all of these issues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENHANCEMENT OF TUBERCULOSIS VACCINE BY THYMOSIN Principal Investigator & Institution: Tuthill, Cynthia W.; Sciclone Pharmaceuticals, Inc. 901 Mariner's Island Blvd San Mateo, CA 94404 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): Tuberculosis (TB) is a chronic infectious disease. Although most of the earths' 5.7 billion inhabitants have received the attenuated M. bovis BCG vaccine, many have still become infected and are at risk for developing clinical disease. The difficulty of compliance with lengthy and costly treatment regimens, coupled with the emergence of multi-drug resistant strains and the global AIDS crisis, have contributed to an emerging tuberculosis pandemic. An effective prophylactic vaccine is desperately needed. Most recent vaccines use non-viable bacterial proteins, lipids, or DNA; these require added adjuvants to generate a T helper 1 cellular response. We propose to evaluate the effects of thymosin, a synthetic 28 amino acid peptide with demonstrated Th1 immunomodulator properties, as an adjuvant. A well-characterized murine aerosol model of infection will be used with viable, virulent M. tuberculosis. We will evaluate the effect of thymosin on the level of antigen-specific IFNg production by circulating T cell populations; the reduction of bacterial load in lung and spleen; and conduct histopathological analyses of lung tissues to determine immune responsiveness and protective granuloma formation. Findings that indicate superior performance to BCG vaccinated controls will provide the basis for further evaluations in the more sensitive guinea pig model of infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EXPRESSION OF TUBERCULOSIS IN THE LUNG Principal Investigator & Institution: Ellner, Jerrold J. Professor and Executive Vice President; Medicine; Univ of Med/Dent Nj Newark Newark, NJ 07103 Timing: Fiscal Year 2001; Project Start 30-SEP-1993; Project End 31-JUL-2005 Summary: (Adapted from the Applicant's Abstract): Mycobacterium tuberculosis infects a third of the worlds' population and TB is the leading cause of morbidity and mortality due a single infectious agent. However, only 5-10% of M. tuberculosis-infected subjects without an underlying immunodeficiency develop disease during their lifetimes. Therefore protective immunity is induced in the majority of subjects. Understanding correlates of protection against M. tuberculosis in humans is needed to better direct efforts in the development of antituberculosis vaccines. The PI suggests that increased susceptibility to M. tuberculosis infection by patients with IFNgamma receptor I deficiency and successful therapeutic use of IFNgamma in refractory mycobacterial infections indicates the importance of IFNgamma in immunity against mycobacteria. However, during the previous funding period the PI found increased levels of IFNgamma in the lungs of patients with TB. Thus, the question is raised as to the effectiveness of IFNgamma and/or involvement of other factors in protective immunity. In the present competitive renewal application, the PI proposes to define pulmonary correlates of protective immunity by comparing several immunological parameters in TB patients, healthy household contacts of TB patients (tuberculin skin test positive), and community control subjects. Bronchoalveolar and blood mononuclear cells obtained from each study subject will be utilized to characterize antigen-specific cytokine induction, killing of M. tuberculosis, CTL activity against M. tuberculosisinfected targets and mediators involved in these effector functions (iNOS, granzyme, perforin, granulysin, FasL) (specific aim 1). According to the PI, this first part of the work should identify correlates of protective immunity as differences between
48 Tuberculosis
protective immune responses (in skin-test-positive, healthy household contacts) and failed immune responses (patients with TB). Correlates of protection identified in aim #1 should then be used to assess induction of protective immunity and chemokine expression by vaccination of humans with BCG. Two strains of BCG having different efficacy and reactogenicity, and two routes of vaccine administration (oral and intracutaneous) will be compared (specific aim 2). The PI states that this proposal attempts to define new parameters of immunological protection in humans and to rationally assess the impact of BCG strain variation and the route of BCG administration on the induction of protective immunity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTION OF CD8 T CELLS IN TUBERCULOSIS Principal Investigator & Institution: Flynn, Joanne L. Associate Professor; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-MAR-2007 Summary: (provided by the applicant): The immune response against Mycobacterium tuberculosis results in control, but not elimination, of infection. T cells are a crucial component of this response. This proposal extends our current work on examining the CD8 T cell subset and the effect of these cells in tuberculosis. It is clear that the naturally induced immune response is insufficient to resolve a M. tuberculosis infection. Understanding how the CD8 T cell response develops and is modulated over the course of infection may provide clues to augmenting this response to provide better control of infection. In this proposal, we will focus on following CD8 T cell responses to specific antigens, focusing on the function of the CD8 T cells at various times post-infection. Specifically, cytokine production and cytotoxic ability will be tested during acute, chronic, memory and reactivation states. Our hypothesis is that the CD8 T cell response and function wane during a chronic infection, and boosting this response would result in improved control of the infection. In addition, preliminary data indicates a role for CD4 T cells in maintaining CD8 CTL function, and the mechanisms responsible for this will be investigated. Our long term goal is to have a clear picture of the CD8 T cell response in tuberculosis, including antigen specificity, function, evolution, and maintenance. This information will impact directly on vaccine development, since it appears that stimulation of both CD4 and CD8 T cells will be necessary to provide adequate protection against tuberculosis. To this end, our specific aims are: Aim 1. To examine evolution in the antigen specific CD8 T cell responses during M. tuberculosis infection. Aim 2: To investigate the function of CD8 T cells in M. tuberculosis infection. Aim 3: To assess the development, maintenance and function of memory and recall CD8 T cell responses in tuberculosis. Aim 4: To determine the effects of CD4 T cells on CD8 T cell maintenance and function in tuberculosis. Animal models will be used in these studies, and we have adapted a variety of functional assays for CD8 T cells for use with lung cells. These complementary aims will provide a definitive picture of the CD8 T cell response in tuberculosis, and contribute to a greater understanding of the challenges facing vaccine development and design against this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNTIONAL GENOMICS OF INTERFERON FOR TUBERCULOSIS Principal Investigator & Institution: Pine, Richard I. Assistant Member; Public Health Research Institute 225 Warren St Newark, NJ 07103
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Timing: Fiscal Year 2001; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: Interferon-gamma (IFNgamma) is a cytokine released by TH1 lymphocytes in tuberculosis and is an essential mediator of the cellular immune response, producing macrophage activation. Signaling is transduced through activation of STAT-1, a latent transcription factor, and leads to induced expression of other transcription factors. STAT-1 and the other transcription factors like IRF-1 together increase expression of effector genes such as iNOS. We have been conducting a clinical trial of aerosolized IFNgamma as treatment for pulmonary tuberculosis and have reported that patients with multi-drug resistant tuberculosis improved on this regimen. We now report that aerosolized IFNgamma induces STAT-1 and IRF transcription factors in lung cells. Treatment also markedly reduces HIV-1 levels in the lungs of AIDS patients with tuberculosis, providing further evidence of enhanced lung immunity produced by pharmacological doses of IFNgamma. THP-1 macrophages and alveolar macrophages are similar with regard to induction of STAT-1, IRF-1 or IFR-9 (also called p48 and ISGF3-gamma) after infection with M. tuberculosis (M.tb) or IFNgamma treatment. THP-1 macrophages respond to IFNgamma with increased IRF-9 mRNA but do not change its transcription, demonstrating that IRF-9 is up-regulated by posttranscriptional mechanisms such as splicing or message stability. We used functional genomics to identify other IFNgamma responsive genes. Of 4375 genes present on a high density filter array, 48 were induced and 13 were repressed after 4 hours of IFNgamma stimulation. Only 15 of these 61 genes have been reported to be responsive to IFNgamma Finally, with the goal of assaying genome wide transcription rates, we have developed a novel assay for transcription using Br-UTP labeled nascent RNA. Our goal is to identify genes unique to the cellular immune response during tuberculosis in vivo and genes induced or repressed by IFNgamma and/or M.tb. ex vivo and in vivo. We propose to use functional genomics to identify the genes induced and repressed in: 1) THP-1 macrophages infected with M.tb and/or treated with IFN-gamma in vitro 2) Alveolar macrophages infected with M.tb and/or treated with IFNgamma ex vivo and 3) Bronchoalveolar lavage cells from tuberculosis patients before and after aerosolized IFNgamma. We will then assay transcription rates of the genes that are IFN responsive to define the contribution of transcriptional and post transcriptional regulation to mRNA abundance. We hypothesize that like IRF-9, other genes important to the IFNgamma response are post-transcriptionally regulated in macrophages. This analysis will further the understanding of cellular immunity in tuberculosis and gene expression regulated by IFNgamma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE EXPRESSION IN MYCOBACTERIUM TUBERCULOSIS Principal Investigator & Institution: Clark-Curtiss, Josephine E. Research Associate Professor; Biology; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Tuberculosis, one of the great scourges of humankind, is the leading cause of death worldwide from a single infectious disease. Although the incidence of TB has again begun to decline in the U.S., TB remains a significant health problem in this country, most frequently affecting the elderly, the homeless, individuals with AIDS and immigrants from nations where TB is endemic. Although the causative agent of TB, Mycobacterium tuberculosis, was identified a century ago, knowledge about fundamental physiological capabilities, the genetics and the mechanisms of pathogenicity of M. tuberculosis is only now beginning to emerge. We have identified
50 Tuberculosis
several genes which are expressed by M. tuberculosis H37Rv when the bacilli are growing in human macrophages in culture, but which are not expressed by the bacilli when they are growing in laboratory broth culture. We hypothesize that these genes and their products may be important in the survival and growth of M. tuberculosis in macrophages and may contribute to the pathogenicity of the tubercle bacilli. We propose to (1) determine the contribution of specific macrophage-expressed gene products to survival and growth of M. tuberculosis in macrophages by molecular and genetic characterization of genes on a cosmid that appear to be coordinately expressed, a putative response regulator gene, and mceD, a gene that has been shown to enhance survival of E. coli in cultured macrophages; and (2) to identify and characterize genes and gene products of M. tuberculosis that are expressed at early times after phagocytosis, at late times, and throughout growth in human macrophages in culture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE MACROPHAGES
EXPRESSION
OF
M.TUBERCULOSIS
WITHIN
Principal Investigator & Institution: Mcdonough, Kathleen A. Research Scientist; Wadsworth Center Empire State Plaza Albany, NY 12237 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: (Adapted from the Applicant's Abstract): The long term objective of this proposal is to gain a better understanding of how Mycobacterium tuberculosis establishes infection so that effective strategies can be developed to prevent it. A multidisciplinary approach will focus on the interaction of tubercle bacilli with macrophages at the molecular, genetic and cellular levels, with an emphasis on M. tuberculosis gene expression within macrophages. The specific aims are: 1) Identifying M. tuberculosis genes that are induced when bacteria are within macrophages by 2D gel electrophoresis coupled with mass spectrometry. 2) Identifying class-specific regulatory motifs among intracellular induced promoters using a combination of molecular and computational techniques. 3) Characterizing the roles in the M. tuberculosismacrophage interaction of selected intracellular induced M. tuberculosis genes. Assays will include bacterial survival, replication and trafficking in macrophages. 4) Assessing the role of cAMP signaling in M. tuberculosis within macrophages by defining the distribution and expression among mycobacteria of genes encoding novel cyclase and cyclic NMP binding proteins; estimating the minimum number of cAMP-responsive proteins using 2D gels; and determining the effects of a novel adenylate cyclase gene knock-out on M. tuberculosis interaction with macrophages using tissue culture, microscopy, and 2D gel analyses. This work will contribute to our understanding of the factors needed for the establishment of tuberculosis infection and disease and will identify potential targets for tuberculosis vaccines, therapeutics, and diagnostic purposes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENES TUBERCULOSIS
FOR
METHY1-BRANCHED
WALL
LIPIDS
AND
Principal Investigator & Institution: Kolattukudy, Pappachan E. Professor and Directpr; Neurobiotechnology Center; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, OH 43210 Timing: Fiscal Year 2001; Project Start 15-JAN-2000; Project End 31-DEC-2003
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Summary: Resurgence of tuberculosis (TB) and other mycobacterial infections associated with AIDS threaten human health world-wide. Emergence of drug resistant TB makes it critical to discover new drug targets. Cell walls of Mycobacterium tuberculosis contain a variety of unusual lipids with many types of multiple methylbranched fatty acids that are unique to pathogenic mycobacteria. These lipids are thought to play important roles in the ability of the pathogens to resist antimicrobial agents and evade the defense reactions of the host. Biosynthesis of these unique lipids containing multiple methyl-branched fatty acids could offer ideal targets for new anti mycobacterial drugs. Genomic sequencing revealed that a remarkably unique feature of the mycobacterial genome is that it contains an unusually large number of genes involved in lipid metabolism. Based on the homology to mycocerosic acid synthase (mas) we have identified two classes of polyketide synthase (pks)-like genes which contain a full complement of active site domains that should be involved in the catalysis of all of the steps required for the synthesis of multimethyl- branched fatty acids: Class 1 mas-like genes mas-like genes (msl1, msl2 and msl3) that are highly homologous to mas and Class 2 (msl4m msl5, msl6 and msl7) which show a lesser degree of homology to mas. These open reading frames (ORFs) most probably encode the more than eight classes of methyl-branched fatty acids found in M. tuberculosis. To elucidate the function of these genes and to examine their possible role in the host-pathogen interaction, we propose to pursue the following specific aims: 1) Determine the functions of Class 1 mas-like genes, ms1, msl2 and msl3 of M. tuberculosis by characterization of their products expressed in M. smegmatis, and by determination of the biochemical and functional consequences of their disruption. 2) Determine the functions of Class 2 (msl4, msl5, msl6 and msl7) mas-like genes in M. tuberculosis genome, by characterization of their products expressed in M. smegmatis, and by determination of the biochemical and functional consequences of their disruption. 3) Determine whether lack of specific lipids caused by the above gene-disruptions affects host-pathogen interaction and virulence. The results will help identify cell wall lipids critical for pathogenesis that might be suitable targets for new anti-mycobacterial drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC DISSECTION OF MYCOBACTERIAL INFECTION Principal Investigator & Institution: Schurr, Erwin; Associate Professor; Mc Gill University James Admin. Bldg., Room 429 Montreal, PQ H3A 2T5 Timing: Fiscal Year 2001; Project Start 14-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The objective of the studies proposed in this application is to identify genotypic combinations of mice and mycobacteria that result in significant alterations of host responses to experimental mycobacterial infection. Susceptibility or resistance to experimental infection will be defined by determination of median survival time, weight loss, mycobacterial load in the lung and spleen, and in addition various immunological parameters in lung and other tissues. In these experiments, the host genome will be varied by use of 37 recombinant congenic strains (RCS), which are derived from inbred progenitors that are either susceptible to tuberculosis (A/J, abbreviated A) or resistant to tuberculosis (C57BL/6J, abbreviated B). The AcB/BcA RCS are now fully inbred and genotyped with a dense set of genomewide microsatellite markers. These strains will be infected with a panel of Mycobacterium tuberculosis and M. bovis strains that have been deleted for genome regions associated with attenuation of BCG vaccines. The infection protocol in the RCS will reveal informative, significant deviations from the "expected" or "parental" disease phenotypes which signify the presence of quantitative trait loci (QTL) with strong effect
52 Tuberculosis
on phenotype expression and possibly specific gene(s) interaction between the host and pathogen. In RCS carrying QTL with strong effect on phenotype expression, changes in gene expression level in both lung macrophages and intracellular mycobacteria will be revealed by microarray analysis. The knowledge to what extent host responses in mycobacterial infections are a reflection of specific host pathogen combinations will be crucial for our understanding of the epidemiological flow of M. tuberculosis through an exposed population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC FACTORS AND SUSCEPTIBILITY TO TUBERCULOSIS Principal Investigator & Institution: Goldfeld, Anne E.; Cbr Institute for Biomedical Research 800 Huntington Ave Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 30-JUN-2004 Summary: The host factors and mechanisms involved in the pathogenesis of pulmonary tuberculosis in the setting of AIDS as well as in the normal host are poorly understood. The long term objective of this project is to further identify and to characterize host factors that predispose individuals to develop pulmonary tuberculosis. Preliminary data indicate an association of an HLA allele, the HLA-DQB1*0503 class II allele, with susceptibility to pulmonary tuberculosis in Cambodia. Specific Aim 1 will determine whether the same or different HLA alleles are associated with TB progression in a genetically distinct population from South Africa. The TNF-alpha gene occurs in the class III region of the major histocompatibility complex (MHC) and its protein product plays a critical role in the containment of tuberculosis infection. Studies will include the identification of polymorphisms and microsatellites in the tumor necrosis factor-alpha (TNF-alpha) gene, and their association to tuberculosis susceptibility. Specific Aim 2 will characterize the mechanisms of activation of the TNF-alpha gene by mycobacteria. By using the TNF-alpha gene promoter as a target, these studies could define the molecular mechanisms of the activation of this important gene by mycobacteria. Specific Aim 3 proposes to investigate the genetic and molecular determinants of anergy in the setting of pulmonary tuberculosis. This aim will investigate whether there is an HLA association with anergy or lack of DTH, and will characterize the cytokine profiles and T cell proliferative responses in anergic pulmonary tuberculosis patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: GENETIC TUBERCULOSIS
STUDIES
OF
HUMAN
SUSCEPTIBILITY
TO
Principal Investigator & Institution: Scott, William K. Associate Research Professor in Medicine; Medicine; Duke University Durham, NC 27706 Timing: Fiscal Year 2001; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Tuberculosis (TB) is currently and historically an enormous public health problem. Approximately one-third of the world's population are currently infected with Mycobacterium tuberculosis (M. tuberculosis) and TB accounts for over 25% of preventable adult deaths world-wide. Despite the high infection rate, only about 10% of people infected with M.tb ever become sick with active TB. Evidence suggests that progression to active TB is influenced by host genetic factors. For example, the epidemiology of TB suggests that genetic selection takes place after introduction of M. tuberculosis to the population; genetically susceptible individuals succumb to the infection and relatively resistant individuals survive to reproduce. As well, twin studies demonstrate higher concordance rates for TB among identical twins,
Studies 53
compared to fraternal twins. Mouse models of mycobacterial infection have identified several potential susceptibility loci, such as the gene named Nramp1, as well as several cytokine and cytokine receptor genes. Family-based linkage studies and case-control studies of candidate genes in humans suggest roles for these and other genes associated with development of TB in humans. In light of these observations, we propose a familybased association study of candidate genes for TB susceptibility. To accomplish the goal of identifying genes influencing susceptibility to TB we specifically propose to: 1) Ascertain 1,000 parent- child triads (500 Caucasian, 500 African-American) from North and South Carolina for genetic studies of TB susceptibility genes. 2) Test candidate genes in the first 500 parent-child triads. Multiple single nucleotide polymorphisms (SNPs) will be genotyped in each gene and analyzed using family- based tests of association; significant results will be followed-up in the remaining 500 triads. 3) Examine the relationship between candidate genes and other clinical variables such as PPD skin test results, disease severity, treatment relapse and failure, and presence of extrapulmonary disease. 4) Evaluate gene-gene and gene-environment interactions using multivariable models and data reduction techniques such as the multifactor dimensionality reduction (MDR) method. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC SUSCEPTIBILITY TO MYCOBACTERIUM TUBERCULOSIS Principal Investigator & Institution: Kramnik, Igor; Assistant Professor of Immunology & Infe; Immunology/Infections Diseases; Harvard University (Sch of Public Hlth) Public Health Campus Boston, MA 02460 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 30-JUN-2006 Summary: (provided by the applicant): It is projected that a total of 225 million new cases of tuberculosis will occur between 1998 and 2030. The outcome of primary infection with Mycobacterium tuberculosis (MTB) varies and, in immunocompetent hosts, imparts only a 10 percent lifetime risk of developing clinical disease. The significant variation in tuberculosis susceptibility among immunocompetent individuals remains unexplained. Differences in the outcome of tuberculosis infection in the setting of similar risk factors support a significant role of the host genetic background in predisposition to progression towards clinical disease. Therefore, identification of genetic factors associated with susceptibility to tuberculosis will have important implications for controlling the disease. We use a mouse experimental model of infection with virulent strain of MTB to characterize genes that are responsible for control of tuberculosis infection in immunocompetent hosts. We have identified and mapped to a 2 cM interval on mouse chromosome 1 a novel locus (sst1) that significantly contributes to control of growth of virulent MTB primarily in the lungs. Observations on its phenotypic expression demonstrate that genetic mechanisms controlling infection with virulent MTB are distinct from those that control an avirulent vaccine strain of M bovis BCG. Having generated a set of sst1-congenic inbred strains of mice, we propose to use them (1) to isolate the sst1-candidate genes by positional cloning; (2) to identify genetic polymorphism responsible for tuberculosis susceptibility; (3) to identify cells and functional pathways affected by the sst1 polymorphism. The proposed project will identify the nature and mechanism of action of the sst1 in mice, which in the future should permit isolation of its human homologue and the analysis of its role in tuberculosis susceptibility in humans. The understanding of genetically determined mechanisms that operate during the course of tuberculosis infection in the lung will provide new insights into the pathogenesis of tuberculosis and suggest improved strategies for treatment and prevention of the disease.
54 Tuberculosis
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC/IMMUNOLOGICAL BASIS OF TUBERCULOSIS AND ANERGY Principal Investigator & Institution: Delgado, Julio C.; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The purpose of this Clinical Investigator Development Award is to prepare the candidate, Dr. Julio C. Delgado, MD, for a career as an independent investigator in infectious diseases with a special emphasis on the genetic and immunological mechanisms associated with susceptibility to tuberculosis infection. The applicant proposes a 5-year training and research program that will prospectively identify novel host factors that predispose individuals to develop pulmonary tuberculosis in a population from Cambodia and characterize the events associated with the anergic state induced by tuberculosis infection in the intact human host. In Specific Aim 1, he will test the hypothesis that HLA molecules are functionally associated with tuberculosis progression and differential immune response to PPD and whether polymorphisms of the promoter region of certain cytokines are associated with impaired immune response against tuberculosis infection. In Specific Aim 2 and 3, he will characterize immunological and chromatin structural mechanisms associated with anergy to PPD in a cohort of tuberculosis patients from Cambodia with persistent and specific lack of response to PPD. Tuberculosis infection and pathogenesis are the result of a balance between the virulence of a particular invading organism and the host immune response. Susceptibility to tuberculosis in human populations is likely to be due to a complex interaction between several genetic, immunological and environmental factors. The experiments proposed in this application would attempt to identify host genetic factors and unveil abnormal immunological mechanisms leading to increase risk of clinical tuberculosis disease. It is anticipated that these results will be useful in the development of genetic and immune therapeutic strategies to combat tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: GENETICS OF M TUBERCULOSIS PERSISTENCE & DRUG TOLERANCE Principal Investigator & Institution: Gomez, James E. Lab/Infection Biology; Rockefeller University New York, NY 100216399 Timing: Fiscal Year 2001; Project Start 01-APR-2001 Summary: (provided by the applicant): One of the primary reasons that our arsenal of drugs has failed to lead to the successful control of tuberculosis is the ability of the etiologic agent, Mycobacterium tuberculosis (Mtb), to persist within the host tissues, where the drugs that readily kill this bacterium in vitro require prolonged periods of time to achieve similar effects. The extended duration of chemotherapy required to cure a human (6-12 months) is one of the greatest barriers to effective TB control. Poor patient compliance may lead to chronic infection, either active or latent, and the emergence of drug resistant Mtb. The underlying biology of persistent Mtb infection is poorly understood, and therefore, the objectives of this study are as follows: I) to better characterize the "persistent state" by examining drug efficacy and bacterial division at a variety of stages of infection in the mouse model; 2) to identify Mtb genes required for persistence in a mouse model using signature-tagged mutagenesis (STM); and 3) to identify Mtb genes that are required for the increased tolerance of Mtb to
Studies 55
chemotherapeutic agents in vivo, again using STM in the mouse model. Achievement of these aims will provide a basis for the rational development of novel therapeutics that target persistent bacilli, thereby shortening the time required to achieve a cure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLUTAMINE SYNTHETASE INHIBITORS FOR TUBERCULOSIS THERAPY Principal Investigator & Institution: Atkins, William M. Medicinal Chemistry; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2005 Summary: (Provided by the applicant:) Infection by Mycobacterium tuberculosis (MBT) is a significant complication experienced by many AIDS patients. Recently, the enzyme glutamine synthetase (GS) has become a new therapeutic target for MTB, due to the demonstration that secretion of enzymatically active MBT GS is required for survival and pathogenecity of the organism. The long-term goal of the proposed research is to develop inhibitors of MBT GS with potential therapeutic use. Many in vitro inhibitors of bacterial GS's have been documented, but none are useful clinically. In order to initiate MBT GS inhibitor design, a portion of this proposal is aimed at understanding its molecular properties, in comparison to the well studied E. coli GS. If comparable to the E. coli GS, then a new strategy will be pursued to obtain inhibitors that are more potent and selective than any previously described compounds. Specifically, the highly symmetrical ring structure of GS will be exploited to design a library of multivalent inhibitors which bind to the flexible loop on several subunits, in contrast to the monovalent inhibitors previously targeted individually to the active sites. The specific aims are: 1) To determine whether structural modification of the central loop on each subunit results in loss of enzyme activity. Because the modification of the central loop of the E. coli GS does lead to loss of activity, it is anticipated that this will be the case for MBT GS; 2) To design, synthesize and screen libraries of multivalent inhibitors targeted to the central loops of MBT GS, and to E. coli GS, for 'proof-of-principle.' Demonstration of the utility of multivalent inhibitors targeted to the central loops of MBT GS would provide a new rationale for GS inhibition and possibly for tuberculosis therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: GLYCOPROTEINS OF MYCOBACTERIUM TUBERCULOSIS Principal Investigator & Institution: Belisle, John T. Associate Professor; Microbiology, Immunology & Pathology; Colorado State University Fort Collins, CO 80523 Timing: Fiscal Year 2001; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: (Adapted from the Applicant's Abstract): In response to the NIH Program Announcement calling for more basic information regarding the biology, immunology and pathogenesis of this disease, the investigators present the hypothesis that past failures in vaccine development against tuberculosis have been due to the inability to emulate the immunogenicity of the whole bacillus due to failure to recognize the importance of appendages that covalently modify key protective protein antigens. The differential immunological reactivity of native and E. coli recombinant forms of mycobacterial proteins as well as our own preliminary data support this principle. Recently, the investigators provided definitive chemical proof that some M tuberculosis proteins are glycosylated. They have now extended these studies to demonstrate that the M tuberculosis proteome possesses a number of such structures and that glycosylation plays a direct role in immunological recognition of M tuberculosis
56 Tuberculosis
proteins, facts which now portend new approaches to vaccine and serodiagnostic antigen development. To address the issue of the contribution of aprotein components to immunological recognition of protein antigens, they will (i) exploit their proven strengths in protein chemistry to demonstrate the relative abundance of glycoproteins in the M tuberculosis proteome and provide a precise chemical characterization for a large number of these molecules; (ii) apply this structural information, some of which is already in hand, to immunological assays in both the human and murine systems, to provide a detailed understanding of how the host's acquired immune system responds to M tuberculosis glycoproteins; and (iii) initiate studies of the biosynthesis of the posttranslationally modified, and specifically mannosylated, proteins, which will yield information and new tools for full evaluation of the general biological, particularly immunological, significance of protein glycosylation and lipidation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GROWTH ACTIVATING FACTOR FOR MYCOBACTERIUM TUBERCULOSIS Principal Investigator & Institution: Griffin, John P.; Mycos Research, Llc 217 Racquette Dr, #6 Ft. Collins, CO 80524 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2002 Summary: (provided by applicant): In this proposal we are requesting funding for proof of principle research into Mycobacterial Growth Activating Factors (GAFs). The longterm objective of these studies is the production of a commercial product that would significantly reduce the time required for diagnosis and drug susceptibility screening of tuberculosis. The aims of this proposal are to: (1) establish the growth promoting characteristics of GAFs using both clinical and laboratory isolates of M tuberculosis. (2) Evaluate the potential use of GAFs in drug susceptibility testing. (3) Determine the effects of GAFs in a clinical setting. And (4) Evaluate derivatives of our defined peptides for potential activity and test for synergistic combinations. If successful, these products could lead to multiple innovative uses that range from the improvement of diagnoses in developing nations to significantly faster identification of efficacious therapeutic drug regimens. PROPOSED COMMERCIAL APPLICATION: MycoQuick Growth Media: A culture medium supplement that reduces the time required for the culture of slow growing mycobacteria species. This in turn will significantly reduce the lengthy time required for laboratory diagnosis of infection with M. tuberculosis. Rapid diagnosis will also permit the timely initiation of drug therapy in these patients and permit rapid drug resistance profiling. MycoQuice Diagnostic Kit: A diagnostic kit for M- tuberculosis, specifically targeted for use under laboratory conditions commonly encountered in developing nations. This product will incorporate the MycoQuick growth medium in pre-prepared assemblies with or without drugs commonly prescribed and antituberculosis therapy. MycoQuick Kit will facilitate both rapid diagnosis and drug susceptibility profiling in a format conducive for use under the less stringent conditions found in distant third world sites. This product may have a significant impact in these regions where tuberculosis is endemic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HEAT SHOCK PROTEIN BASED VACCINE FOR TUBERCULOSIS Principal Investigator & Institution: Mo, Annie Xy.; Antigenics, Inc. 34 Commerce Way Woburn, MA 01801 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 30-NOV-2003
Studies 57
Summary: (provided by applicant): Mycobacterium tuberculosis is a continuing health threat both in the United States and the rest of the world with an estimated two billion people currently infected worldwide. Antibiotic regimens requiring lengthy direct observation of patients and the emergence of drug resistant strains create a pressing need for novel therapies. One such novel therapy is the use of heat shock protein to adjuvant a tuberculosis peptide vaccine for optimal generation of cell-mediated immune response. Heat shock protein-peptide complexes are recognized by HSP receptors on antigen presenting cells. Peptides chaperoned by HSP are then represented by MHC Class I and II molecules leading to cell mediated immunity including stimulation of antigen-specific CD4+ and CD8+ T cells. Cell mediated immunity is an important major protective mechanism in tuberculosis. The ability of heat shock protein-peptide complexes to elicit T cell responses may address a shortcoming of traditional tuberculosis vaccines that primarily elicit antibody responses. The proposed product will consist of Mycobacterium tuberculosis antigens complexed in vitro to mammalian heat shock protein 70. Total cytosolic and culture filtrate fractions from M tuberculosis will be obtained and subjected to proteolysis with highly selective proteases to generate a large array of peptides containing T cell epitopes. Murine heat shock protein 70 will be complexed to the TB peptide extract and utilized as a vaccine. The product will be evaluated in mice for induction of cellular immune responses, assessed by antigen-specific cytotoxicity, cytokine response, and proliferation. The ultimate purpose of the research funded by this grant is to ascertain whether it will be possible to utilize the heat shock protein technology to generate a novel and efficacious therapeutic vaccine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HETEROGENEITY OF T CELLS IN M TUBERCULOSIS INFECTION Principal Investigator & Institution: Boom, W Henry. Professor of Medicine; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 01-FEB-1989; Project End 31-MAR-2002 Summary: (Adapted from the applicant's abstract): T cells have a critical role in regulating the protective immune response to Mycobacterium tuberculosis. As a result of studies supported by AI-27243, our understanding of the interaction between human T cells and macrophages in response to M. Tuberculosis has increased substantially during the last five years. First, M. Tuberculosis antigens activate three major T cell subsets from healthy tuberculin positive donors: V delta2 + gamma delta TCR bearing T cells (gamma delta T cells and CD8+ alpha beta (ab) TCR+ T cells (CD 8 T cells) in addition to CD4+ ab T cell receptor (TCR) bearing T cells (CD 4 T cells. Second, all three T cell subsets produce IFN-gamma and can serve as cytotoxic effector cells (CTL) against M. Tuberculosis infected macrophages, fitting into a Th-1 like pattern. These findings allow refinement of the model in which control of mycobacterial growth and maintenance of immunity requires the activation not only of CD4+ T cells and gamma delta T cells, but also of CD8+ T cells. This model postulates that there is a defined sequence of T cell subset recruitment and that the antigen processing mechanisms used by M. Tuberculosis infected mononuclear phagocytes are critical in the recruitment of T cell subsets and in determining the antigen repertoire recognized by CD4+, CD8+ and gamma delta T cells. In addition, the model postulates that both secretion of macrophage activating cytokines and CTL effector function are necessary for protective immune responses to M. Tuberculosis. There are three specific aims to test the postulates of this model: 1. To further characterize a 10-14KD M. tuberculosis antigen for V delta2+ gamma delta T cells, to determine if the antigen can be detected on the
58 Tuberculosis
surface of mononuclear phagocytes for presentation to V delta2+ gamma delta T cells and to determine if gamma delta T cells activated by this antigen enhance the production by mononuclear phagocytes of chemokines (MIP-1alpha/beta, RANTES) and cytokines (IL-12, IL-15) that promote T cell recruitment and differentiation into CTL. 2. To characterize the antigen processing pathways of M. tuberculosis antigens for class II MHC presentation to CD4+ T cells, using the 30kD 85B antigen as model antigen. 3. To characterize the repertoire of antigens, the antigen-processing pathway and CTL function of CD8+ T cells reactive to M. tuberculosis in comparison to CD4+ and gamma delta T cells. These studies will provide insight into the regulation of human T cell subsets involved in protective immunity to M. tuberculosis, which is necessary for the design of improved vaccines, and immunotherapies for tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HIV PREVENTION/ALCOHOL TREATMENT IN A RUSSIAN TB SAMPLE Principal Investigator & Institution: Fleming, Michael F. Professor; Family Medicine; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant): HIV infection, tuberculosis, and hazardous drinking are of increasing concern in Russia. While the number of officially registered cases of HIV infection as of October 31, 2000 was 69,120, experts expect an exponential increase in the number of Russian people infected with the human immunodeficiency virus in the next 10 years. Incident cases of TB and multi drug resistant tuberculosis in Russia are among the highest in the world. Mortality rates exceed 10% with over 125,000 persons receiving medical treatment for active TB in 1999. Hazardous drinking is common and a major source of morbidity and mortality in Russia. Alcohol use also complicates prevention and treatment programs for HIV infection and TB. Russia shares borders with 13 countries. The global health implications of a large reservoir of HIV infection and tuberculosis in a country that crosses 8 time zones is enormous. Now is the time to prevent the spread of HIV infection and tuberculosis in Russia and neighboring countries. Potential strategies include testing of HIV prevention programs (i.e., Project RESPECT) and treatment programs to reduce rates of hazardous drinking. This proposal is designed to increase our understanding of HIV risk factors, and to increase the role and treatment of alcohol use disorders in the prevention of HIV infection in the context of a TB treatment population. This proposal will conduct the following 3 studies in St. Petersburg and Ivanovo, Russia: a) a prevalence study designed to assess the frequency of HIV risk factors and alcohol use in a patient population being treated for tuberculosis (n=600); b) a naturalistic study designed to assess the effects of alcohol use on HIV risk behaviors and TB treatment outcomes (n=200); c) a combined day-treatment program for HIV risk reduction and alcohol treatment (n=80). The data from these studies will provide new information. The findings are expected to facilitate the development, testing and implementation of HIV prevention and alcohol treatment programs. It is hoped that these programs can reduce the spread of HIV infection and TB in Russia and neighboring countries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HIV/TB INTERACTION IN THE LUNG Principal Investigator & Institution: Weiden, Michael D. Medicine; New York University School of Medicine 550 1St Ave New York, NY 10016
Studies 59
Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 30-MAR-2004 Summary: We have shown that HIV-1 replication is suppressed in uninflamed lung and increased during tuberculosis. In vitro, we recently showed that monocytes increase HIV-1 replication after infection with M. tb. but, surprisingly, we now show M. tb infection inhibits HIV-1 replication in macrophages. Suppression of HIV-1 replication is associated with repression of the HIV-1 LTR and induction of ISGF-3, an interferonalpha/beta (IFN)-specific transcription-factor complex. Monocytes do not induce ISGF-3 after IFN treatment or infection with M. tb. Intact C/EBP sites in the HIV-1 LTR negative regulatory element (NRE) are required for promoter repression. Macrophages but not monocytes induce an inhibitory 16-kDa C/EBP-Beta isoform coincident with the HIV-1 LTR repression. Low-dose IFN-Beta represses the HIV-1 LTR and induces the 16kDa inhibitory C/EBP-Beta. During LTR repression, C/EBP-Beta is present in over 95 percent of the NRE/protein complexes. Mouse bone- marrow macrophages deficient in an IFN receptor do not produce the C/EBP-Beta repressor after an inflammatory stimulus. Taken together, these data suggest that, in vitro, proinflammatory stimulation of macrophages produces an antiviral IFN response that induces a C/EBP-Beta transcriptional repressor and inhibits LTR-mediated transcription. In vivo, alveolar macrophages from uninflamed lung are like macrophages treated with IFN-Beta in vitro; both strongly express inhibitory 16-kDa C/EBP-Beta and inhibit HIV-1 replication. Pulmonary tuberculosis abolishes C/EBP-Beta expression and induces a novel C/EBP DNA binding protein in involved lung segments of both HIV-1- infected and immunocompetent patients. Stat-1 homodimer (an IFN-gamma-specific transcription factor) is also induced, but only in immunocompetent tuberculosis patients. A plausible hypothesis for these observations is as follows: In the absence of inflammation, alveolar macrophages are primed by low doses of IFN-Beta. The cellular immune response in pulmonary tuberculosis disrupts this innate immunity, switching C/EBP expression in both HIV-1-infected and immunocompetent patients. The failure to produce IFNgamma in AIDS patients allows high-level viral replication. This proposal will investigate the regulation of IFN-mediated immunity in uninflamed lung and in tuberculosis. It will also model stimulation of viral replication in tuberculosis and assess how HIV-1 infection alters IFN response. It will investigate the mechanism and effects of inhibitory C/EBP-Beta induction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HOST & PATHOGEN DETERMINANTS OF M TUBERCULOSIS LATENCY Principal Investigator & Institution: Kaplan, Gilla; Full Member; Public Health Research Institute 225 Warren St Newark, NJ 07103 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Our aim is to define the host and bacterial factors that characterize the clinical and microbiologic latency which distinguish human tuberculosis. We hypothesize that in human tuberculosis, persistent/latent infection is associated with a different immune response than active chronic disease. For Mycobacterium tuberculosis to survive in the face of these varying host immune responses, it must alter its physiology through differential changes in gene expression. Thus a particular clinical state associated with a specific state of immunity will elicit a corresponding profile of genes expressed by the infecting organism ("molecular mirror"). We will utilize M. tuberculosis infected lung tissue obtained from surgical resection of TB patients with active disease, or asymptomatic persistent infection, or recurrent disease. These tuberculous lung specimens will be used to characterize the
60 Tuberculosis
host immune response by histology and immunohistology combined with real time RTPCR with molecular beacons to quantitate leukocyte gene expression in the lung. Our collaborator, Dr. John McKinney, will use the same tissues to identify the patterns of M. tuberculosis gene expression in each type of disease. In addition, we will use the rabbit model of M. tuberculosis infection to generate animals with either active disease or persistent asymptomatic infection (latency). Rabbits will be infected with clinical strains of M. tuberculosis of differing degrees of virulence to recreate the range of human disease. Tissues from rabbits with each form of the disease will be used to characterize the cellular response to infection in the lung and to elucidate the patterns of M. tuberculosis gene expression associated with either active disease or persistent asymptomatic infection (latency). We will also infect rabbits with M. tuberculosis mutants selected to be defective for persistence in murine models and establish whether these mutants retain their persistence defect in the rabbit model. By combining the results obtained from the rabbit studies and the human studies, we will validate our experimental animal model as a mirror of human disease and use the model to identify the molecular correlates of M. tuberculosis latency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HOST DEFENSE FUNCTIONS OF M. TUBERCULOSIS LIPOGLYCAN Principal Investigator & Institution: Chan, Edward D. Associate Professor; National Jewish Medical & Res Ctr and Research Center Denver, CO 80206 Timing: Fiscal Year 2001; Project Start 15-JUL-2001; Project End 31-MAY-2006 Summary: (Adapted from the Applicant's Abstract): Tuberculosis (TB) is the leading cause of death by an infectious agent. Macrophages play a pivotal role in the control of Mycobacterium tuberculosis through the expression of nitric oxide (NO.) and TNFalpha. NO plays an important mycobactericidal role in murine TB and is increasingly recognized to be important in humans. The overall hypothesis of this proposal is that macrophages, by specific surface receptor(s), recognize mycobacterial cell wall products to initiate iNOS- and TNFa-induction. Hence, the focus of this proposal is to: i) determine the receptor and signaling mechanisms which regulate iNOS and TNFa following exposure to the mycobacterial cell wall component lipoarabinomannan (ManLAM) and ii) to determine the significance of each of these components in an in vitro model of infection. Based on experiments showing that macrophages from the Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice produced significantly lower levels of NO than TLR4-intact C3H/HeN macrophages in response to IFNg + ManLAM, we hypothesize that ManLAM engages a TLR to induce iNOSNO*/ TNFa expression. Since non-mannose capped LAM (AraLAM) from M. smegmatis induced greater NO about expression than ManLAM, we hypothesize that ii) the exposed arabinose residues on ManLAM or AraLAM are the components of ManLAM that bind to its putative TLR. Since initial studies show that the mitogenactivated protein kinases (MAPKs) and NFkB signaling pathways regulate iNOS and TNFa expression, we hypothesize that the proximal kinase MAP/ERK kinase kinase (MEKK) is a pivotal regulator for ManLAM-induction of iNOS and TNFa. Lastly, because TLRs recognize pathogen-derived molecules and enhance host-defenses, we hypothesize that blocking one or more of the TLRs will enhance the growth of M. tuberculosis and inhibit NO* and TNFa expression. These hypotheses will be addressed by three specific aims: 1. To determine the ManLAM structures that mediate the induction of iNOS-NO*/TNFa and the receptor that mediates these ManLAM effects. 2. To investigate the role of the MAPK and NFkB signaling pathways in ManLAM- and other lipoglycan-induced iNOS-NO* and TNFa. 3. To elucidate the role of the TLRs,
Studies 61
MAPK and NFkB signaling pathways, and ManLAM in controlling the growth of M. tuberculosis in mouse and human macrophages and to correlate effects on growth with NO* and TNFa expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HOST DETERMINANTS OF INFECTIOUSNESS IN TUBERCULOSIS Principal Investigator & Institution: Fennelly, Kevin P. Assistant Professor; Medicine; Univ of Med/Dent Nj Newark Newark, NJ 07103 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Both experimental and epidemiological data suggest that there is a wide range of infectiousness among patients with tuberculosis. Although much research has focused on the virulence of the organism, little is known of the host determinants of infectiousness. A novel Cough Aerosol Sampling System (CASS) can isolate and quantify (viable airborne Mycobacterium tuberculosis from individual patients with pulmonary tuberculosis. We hypothesize that the production of viable aerosols of M. tuberculosis determined by this method is correlated with infectiousness. Our central hypothesis is that most of the variability of infectiousness in tuberculosis is explained by non-immunological host factors including the duration of antimycobacterial therapy with drugs to which the organism is susceptible, the strength and frequency of coughing, and the physicochemical properties of the sputum. The first specific aim is to correlate viability assessed by the air sampling method used in the CASS and infectiousness using the mouse and guinea pig models. The second aim is to determine if the infectiousness of tuberculosis decreases rapidly with appropriate antimycobacterial therapy. The third aim is to assess whether cough strength and frequency are associated with the quantity of viable aerosol. The fourth aim is to determine if infectiousness is associated with physicochemical properties of sputum. These data may alter clinical practice and public health control measures. Changes in tuberculous aerosol viability associated with drug therapy may provide insight into the basic biology of the mycobacterial cell wall. Similarly, the rapid changes in cough strength and frequency may suggest mechanisms in the pathophysiology of cough. Verifying the correlation between quantitative aerosol cultures and infectiousness using animal models may validate the use of the cough aerosol sampling system at the bedside. Data obtained from patients with tuberculosis may in turn validate the use of animal models of infection. This approach may open a new field of investigation of the host determinants of infectiousness, which could be extended to other respiratory infectious agents in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: HOST RESPONSE TO TB AND AIDS Principal Investigator & Institution: Rom, William N. Chief, Pulmonary and Critical Care Divis; Medicine; New York University School of Medicine 550 1St Ave New York, NY 10016 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2002 Summary: The recent tuberculosis (TB) epidemic in the United States has been fueled by several factors, including underfunded public health programs, overcrowding in urban homeless shelters and prisons, continuing immigration to the United States from countries with a high incidence of TB, and the HIV epidemic. The increased susceptibility to tuberculosis infection and disease among HIV-infected patients is directly related to impaired host immunity. In recent years, key components of the host
62 Tuberculosis
response to tuberculosis have been elucidated, and it now seems increasingly clear that a Th1-type T-lymphocyte response is associated with a good outcome in TB patients. In addition, there is increasing evidence that HIV-infected patients have impaired TH1 number and function, with a resultant deficiency of interferon-gamma (IFN-g), a key effector cytokine in host immunity in tuberculosis. This project proposes to study the role of T-helper cells in human tuberculosis, with a specific focus on the role of IFN-g in the pathogenesis of tuberculosis in patients with and without HIV infection. This project will study the role of Th1 cells in general and IFN-g in particular both at the clinical level as well as at the basic level so that we might understand both the regulation of gene expression of this cytokine as well as its interaction with other cytokines and inflammatory effector cells in the lung itself, both in HIV positive and negative patients. The specific aims are to: 1) modulate the Th phenotype in BAL cells and HIV-1 replication in active pulmonary tuberculosis by aerosol treatment with interferon-gamma; 2) investigate mechanisms by which IFN-gamma contributes to host defense against tuberculosis in HIV-positive and HIV-negative persons; and 3) analyze mechanisms of gene regulation effected by IFN-gamma treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HOST RESPONSES TO MYCOBACTERIUM INFECTION IN ZEBRAFISH Principal Investigator & Institution: Ramakrishnan, Lalita; Assistant Professor; Microbiology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Tuberculosis is the leading cause of death from infectious diseases worldwide, with increasing consequences due to the HIV epidemic. The existing vaccine, BCG, has marginal efficacy. Infection and disease are caused by the intracellular bacterial pathogen Mycobacterium tuberculosis. In the face of a complex immune response, the bacteria can persist indefinitely in granulomas, tight aggregates of highly differentiated macrophages and other immune cells. As with most infectious diseases, the impact of the different aspects of host immunity on tuberculous infection and disease are not well understood. To better understand the host responses to tuberculous infections, we will exploit the fact that Mycobacterium marinum, a close relative of M. tuberculosis is a natural pathogen of zebrafish, causing a tuberculosis-like disease. Zebrafish are genetically tractable vertebrates that are used as models of disease and development. We have exploited the optical transparency of the zebrafish embryo to visualize M. marinum infection of embryonic macrophages in real time. The infection parallels adult tuberculosis in many ways. We will use the zebrafish-M, marinum infection model to study the role of host immune genes in infection. We will use whole mount in situ hybridizations to determine which host immune markers thought to be important in tuberculosis, are expressed in the developing embryo. We will determine if their expression is changed during infection. We will inactivate these genes using morpholino technology and determine by real time visualization when and how they act in infection. We will determine their role for the different facets of infection, from early macrophage migration in response to M. marinum to granuloma formation. The ability to visualize infection in real time in zebrafish embryos with functional inactivation of individual host genes will allow us to study the role of the host immune system in unprecedented detail. The proposed experiments will inherently yield new information about the role of various immune genes in zebrafish development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
Studies 63
•
Project Title: HTS FOR PROTEIN SPLICING INHIBITORS AS TB DRUGS Principal Investigator & Institution: Paulus, Henry; Director; Boston Biotechnology Corporation 64 Grove St Watertown, MA 02472 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2004 Summary: (provided by applicant): One-third of the world' s population (2 billion people) are infected with Mycobacterium tuberculosis and 5-10% of these suffer active tuberculosis, leading to nearly 3 million deaths annually. An alarmingly growing number of patients in developed country are suffering from multidrug-resistant TB, which is essentially refractory to therapy by existing drugs. The mainline antituberculosis drugs need thus be supplemented by additional drugs against new targets, until those, too, succumb to resistance mechanisms. The aim of the proposed research is to discover drugs that inhibit the post-translational processing of the M. tuberculosis DnaB and RecA proteins by protein splicing. The DnaB and the RecA proteins play essential roles in DNA replication and DNA repair, respectively. Because in virulent strains of M. tuberculosis these proteins are synthesized as inactive precursors that need to be activated by protein splicing, the inteins that interrupt these proteins and promote the protein splicing reaction constitute anti-tuberculosis targets. This application focuses on developing in vitro fluorescent assays for DnaB and RecA protein splicing based on the activation of Green Fluorescent Protein (GFP) from inactive fusions with the DnaB or RecA intein, which can be adapted as a high-throughput screening system for protein splicing inhibitors. Inhibitors found with these screens will be for specificity and antibacterial activity using both in vitro and in vivo assay systems. Preference will be given to inhibitors which inhibit splicing of the DnaB as well as the RecA intein so as to interfere both with DNA replication and DNA repair. Because protein splicing occurs only in unicellular organism and in mycobacteria as the only pathogens, such inhibitors should be highly specific antimycobacterial agents with no effect on other bacteria associated with humans nor on the human host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HUMAN AND TUBERCULIN COA BIOSYNTHETIC ENZYME STRUCTURES Principal Investigator & Institution: Izard, Tina; St. Jude Children's Research Hospital Memphis, TN 381052794 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 29-FEB-2008 Summary: (provided by applicant): Coenzyme A (CoA) is the major acyl group carrier for all organisms and is essential for cell survival. In bacteria, the last two reactions of CoA biosynthesis are mediated by the enzymes phosphopantetheine adenylyltransferase (PPAT), which generates dephospho-CoA (dPCoA), and dephospho-CoA kinase (DPCK), which yields CoA. In contrast, in higher eukaryotes a bifunctional enzyme, CoA synthase, catalyzes both of these final reactions. The substrate of PPAT is rate-limiting and the enzyme is feedback regulated by CoA, indicating that PPAT is an excellent target for developing novel antibiotics. We have solved the crystal structures of PPAT from Escherichia coli, which exists as a hexamer, and of PPAT bound to its substrates and to its product dPCoA. These studies identified the residues involved in substrate/product binding and revealed an in-line displacement catalytic mechanism. Finally, our Preliminary Studies of the PPAT:CoA crystal structure revealed an unusual mechanism of feedback inhibition of PPAT by CoA. The structure of the monomeric DPCK enzyme (from Haemophilus influenzae) has recently been solved and suggests an induced-fit reaction mechanism typical of kinases. Collectively, these
64 Tuberculosis
structures form the foundation for the design of PPAT- and DPCK-specific inhibitors, an important issue in the context of treating drug-resistant bacteria, in particular tuberculosis. Like other bacteria, Mycobacterium tuberculosis requires PPAT and DPCK, and although the catalytic mechanisms of tuberculin PPAT and DPCK are likely identical to their homologs in other bacteria, there are significant differences predicted for the structures of these enzymes, especially DPCK. Recombinant M. tuberculosis PPAT and DPCK proteins have been produced and we have crystallized tuberculin PPAT. Experiments in Specific Aims #1 and #2 will determine the native and substratebound crystal structures of M. tuberculosis PPAT and DPCK. In addition, the structures of tuberculin PPAT bound to its product dPCoA, and to its inhibitor CoA will be solved. The design of PPAT- and DPCK-specific inhibitors requires that they not inhibit human CoA synthase. The monomeric nature, predicted structure, and coupled catalytic functions of CoA synthase indicate that regulation of this enzyme is unique, and a novel N-terminal domain may play a regulatory role. Experiments in Aim #3 will determine the native and substrate-bound crystal structures of human CoA synthase. The proposed crystallographic studies are essential for the development of novel inhibitors that selectively target M. tuberculosis PPAT and DPCK. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HUMAN TUBERCULOSIS
T
CELL
RESPONES
TO
MYCOBACTERIUM
Principal Investigator & Institution: Lewinsohn, David M. Assistant Professor; Medicine; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2001; Project Start 15-SEP-1998; Project End 31-AUG-2003 Summary: Tuberculosis is the leading single cause of infectious disease mortality worldwide. Immunity to tuberculosis depends upon the cellular immune system. Hence, developing an improved vaccine will require characterization of T cell antigens recognized early during the course of infection, and an understanding of the mechanisms by which T cells recognize and respond to Mtb infected cells. Two novel proteins (TbH9 and 38.1) from Mtb that are potent T cells antigens have recently been cloned and expressed in our laboratory. We have found that these proteins elicit vigorous T cell proliferation and interferon-gamma production from healthy PPD positive individuals, and that one of these proteins is preferentially expressed in cells infected with live Mtb. However, little is known about the response to these proteins in persons who have been recently infected or in those with active tuberculosis. Additionally, several lines of evidence, including the susceptibility of mice rendered deficient in beta2 microglobulin to infection with Mtb, have suggested an important role for CD8+ cytotoxic T lymphocytes (CTL) in immunity to tuberculosis. Using peripheral blood derived dendritic cells infected with Mtb, we have isolated human CD8+ CTL clones to Mtb. This is the first demonstration of human Mtb specific CD8+ T lymphocytes, and further characterization of these cells will be an important part of this proposal. This proposal rests upon two major hypotheses: 1) Protective T cell responses to Mtb arise early in the course of infection and are associated with the production of interferon-gamma (IFN-gamma), and 2) MHC class Ia restricted and non restricted CD8+ CTL that recognize Mtb infected cells are generated during the course of infection. The specific aims are: 1) To characterize human Mtb specific T cell responses in diseased and healthy infected individuals. 2) To characterize human CD8+ T cell responses to Mtb. The research methods for achieving these goals include a collaborative project with Seattle-King County Tuberculosis Clinic to study human T cell responses to recombinant Mtb antigens during the evolution of disease. In addition, the relative
Studies 65
contribution of MHC class Ia restricted and non-restricted CD8+ CTL will be evaluated in healthy PPD positive individuals. The mechanisms by which Mtb gain entry into the MHC class Ia will be explored using selective inhibition of antigen processing. The mechanisms of antigen processing and nature of the antigen or MHC class Ia nonrestricted clones will also be evaluated. Finally, mammalian expression vectors for the proteins TbH9 and Ag 85b will be constructed, and used to elicit antigen specific CD8+ CTL. The proposed studies will allow for greater understanding of T cell responses to tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HUMAN TUBERCULOSIS
T
CELLS
ANTIGENS
OF
MYCOBACTERIUM
Principal Investigator & Institution: Reed, Steven G. Chief Scientific Officer; Infectious Disease Research Institute 1124 Columbia St, Ste 600 Seattle, WA 98104 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from the Applicant's Abstract): This proposal is aimed at identifying and characterizing T cell antigens of M. tuberculosis which may be important vaccine candidates. To identify novel Mtb antigens which may be relevant in protective immunity against tuberculosis we have used a variety of antigen discovery methods which emphasize expression cloning with anti-M. tuberculosis antisera and human T cells. Eight vaccine candidates (Mtb 8.4, Mtb 9.8, Mtb 9.9, Mtb 11, Mtb 19, Mtb 32, Mtb 39, Mtb 40) have so far been selected based on their ability to stimulate PBMC from donors infected with M. tuberculosis. These eight antigen genes will be evaluated as recombinant antigens or as naked DNA, alone or in combination, for immunogenicity and protection against tuberculosis in three animal models including cynomolgus monkeys, mice, and guinea pigs. These models will be used to assess T cell responses as well as protection. In addition, we will emphasize the use of human T cell expression cloning to identify other vaccine candidate antigens. These will be characterized in the in vitro and animal models as above. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOLOGICAL TUBERCULOSIS
BASIS
OF
SUSCEPTIBILITY
TO
Principal Investigator & Institution: Behar, Samuel M. Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: The long term objectives of this project are to understand the immunological and genetic basis for susceptibility to tuberculosis. As the effectiveness of cellular immunity to Mycobacterium tuberculosis determines whether infection evolves into clinical disease, a better understanding of the immune response and the genes that govern it will facilitate a more rational approach to development and use of vaccines, drugs, and biological therapy. An aerosol route of inoculation will be used to infect intact mice that are either inherently resistant or susceptible to tuberculosis. The local immune response in the lung will be compared to the systemic response in the spleen using a variety of techniques including the quantitation of T cell subsets, intracellular cytokines staining, and RNAse protection assays in order to define immunological parameters that indicate a protective immune response. Other investigations will ascertain which genetic loci are critical for disease resistance. With this insight, these techniques will be applied to interventional models to determine how different
66 Tuberculosis
treatment strategies modify the immune response during primary infection (in the case of vaccines and biological treatments) or after subsequent rechallenge (in the case of chemotherapy). Finally, two different models that approximate the cell mediated defects observed in HIV/AIDS will be examined to determine how the immune response is altered to M. tuberculosis infection in the absence of CD4 plus T cells, and whether therapeutic interventions can beneficially augment the innate and adaptive immune responses under these conditions. The specific aims are as follows: Aim 1. Characterize the immunological differences between mouse strains that are either resistant or susceptible to infection with Mycobacterium tuberculosis after aerosol inoculation. Aim 2. Determine the genetic derangements that correlate with susceptibility and resistance. Aim 3. Identify how the immune response to tuberculosis changes as a consequence of therapeutic interventions in an animal model. Aim 4. Characterize the immune response to tuberculosis in mouse models that simulate the abnormalities of cell mediated immunity typical of HIV/AIDS patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOLOGICAL DIAGNOSIS OF TUBERCULOSIS Principal Investigator & Institution: Gennaro, Maria L. Associate Member; Public Health Research Institute 225 Warren St Newark, NJ 07103 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract): The increasing worldwide incidence of tuberculosis, which is the leading cause of death from a single infectious disease, and its frequent association with HIV-1 infection have rendered current laboratory diagnostic methods inadequate. Microscopic examination of sputum has low sensitivity, and culture techniques are too slow. DNA sequence amplification by PCR is sufficiently sensitive only in patients with multibacillary pulmonary TB. New diagnostic methods are urgently needed. The PI believes that serology presents an attractive approach. Serodiagnostic tests are simple, rapid, inexpensive and do not require the presence of mycobacteria in the clinical specimens. The present lack of a highly accurate immunoassay for TV is primary due to insufficient knowledge of the humoral immune response to TV and to a limited availability of purified mycobacterial antigens. During the current funding period, the PI developed a panel of eleven recombinant, highly purified antigens of M. tuberculosis and found a remarkable patient-to-patient variation in antigen recognition. The PI has also developed a strategy for multi-antigen-based serodiagnosis of TB. Antigens will be selected for a multi-antigen cocktail for diagnosis of active TB in the general population by identifying antigens that are highly seroactive and that are recognized by sera from patients with paucibacillary and multibacillary pulmonary TB. To minimize false positive results due to immune responses that are not associated with active TB, antigens for the cocktail will be chosen from those that are preferentially recognized by active TB patients rather than asymptomatic tuberculin reactors, BCG vaccines, and individuals with inactive TB. Cocktail development will be pursued by assessing the behavior of selected antigens when combined in solid phase. Peptides displaying immunodominant, M. tuberculosis complex-specific B cell epitopes on highly seroreactive proteins will be utilized to minimize antigen interference or loss of assay specificity that may be observed when antigens are combined. Special emphasis will be placed on development of diagnostic assays for TV in children and in HIV-1infected individuals. Because of the rapid progression from infection to active TB in children, antigens recognized by serum antibodies in pediatric TB may not be the same as those recognized by the adult populations. The PI will select antigens recognized by sera from children with TB to develop serodiagnostic assays specific for pediatric TB.
Studies 67
Another high risk group for rapid disease progression and high TB-associated mortality is the HIV-1-infected population. The PI's studies indicate that, although the overall antibody response is decreased in HIV+ TB, recognition os certain antigens of M. tuberculosis is unaltered in the presence of concomitant HIV-infection. Based on these findings, the PI proposed to develop serodiagnostic assays that meet the special needs of this population. The PI also anticipates that they will be able to identify early serological markers of TB infection in household contacts of patients with active TB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOSUPPRESSION IN MYCOBACTERIAL DISEASES Principal Investigator & Institution: Toossi, Zahra J. Associate Professor; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 01-JAN-1982; Project End 31-JUL-2002 Summary: The investigators' observations to date indicate a central immunomodulatory role for transforming growth factor beta (TGF-beta), a potent immunosuppressive molecule, in human tuberculosis. The sustained support of research at CWRU has delineated mechanisms that may explain the failure of expression of protective immunity during active tuberculosis, and the paradox of skin test anergy in a disease caused by an organism with adjuvant-like properties. M. tuberculosis, its PPD, and its cell wall antigens induce monocytes to production of TGF-beta. TGF-beta is present in tuberculous granulomas and is produced by mononuclear phagocytes of patients with tuberculosis. TGF-beta affects several events in T-cell activation, inhibits the cytokines important in development of a TH 1-like response (IFN-gamma, IL-12), and directly suppresses the TH 1 cytokines (IL-2, IFN-gamma). Further, TGF-beta may promote the expression, or synergize with other suppressive mediators (IL-10), thus amplifying immunosuppressive circuits in situ. A natural inhibitor of TGF-beta, decorin, binds and inactivates TGF-beta and may be clinically useful in diseases such as tuberculosis that are associated with excess TGF-beta activity. Previous observations and the preliminary data support the following hypothesis; the polysaccharide and protein antigens of virulent M. tuberculosis bias the cytokine profile of mononuclear phagocytes towards excess TGF-beta activity. The immunopathogenesis of active tuberculosis involves altered regulation of T-cell activation by TGF-beta which may lead to growth arrest and/or apoptosis of T-cells and an attenuated TH1 response. Down modulation of TGFbeta activity, for example, using the natural inhibitor decorin is expected to enhance such a TH1 response, and, therefore, may be useful as an adjunct to chemotherapy. Specific Aims are: 1. To examine the role of interaction of intact M. tuberculosis through its 30 kD antigen and ManLAM, with fibronectin and mannose receptors on monocytes in expression and activation of TGF-beta. 2. To examine the modulation by TGF-beta of early events in T-cell activation, the growth arrest and/or apoptosis of T-cells stimulated by M. tuberculosis and its products; and the role of TGF-beta in initiating immunosuppressive circuits involving IL-10. 3. To characterize the T-cell dysfunction of patients with active pulmonary tuberculosis, its relationship to TGF-beta and other suppressive cytokines (IL-10) and its reversal by inhibitors of TGF- beta. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMPACT OF TUBERCULOSIS OF HIV INFECTION IN UGANDA Principal Investigator & Institution: Whalen, Christopher C. Associate Professor; Epidemiology and Biostatistics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106
68 Tuberculosis
Timing: Fiscal Year 2001; Project Start 01-JUL-1992; Project End 31-AUG-2004 Summary: (Adapted from Investigator=s Abstract) The World Health Organization estimates that 10 million HIV-infected individuals will die of tuberculosis (TB) during the decade of the 1990's. Although HIV-infected patients with TB respond to effective antituberculous therapy, their prognosis remains poor. Early deaths are often attributable to TB, but later deaths result from complications of HIV infection other than tuberculosis. Recent epidemiologic observations indicate that TB reduces survival and increases the rate of opportunistic infections in HIV-infected patients. Mounting evidence from immunologic and virologic studies supports the concept of copathogenesis in which immune activation triggered by tuberculosis, and mediated by cytokines such as tumor necrosis factor-alpha (TNFa), stimulates viral replication, increases viral load, and accelerates HIV infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INDUCTION OF TH1 IMMUNITY IN TUBERCULOSIS Principal Investigator & Institution: Salgame, Padmini; Associate Professor; Microbiology and Immunology; Temple University 406 Usb, 083-45 Philadelphia, PA 19122 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Prevention of infectious diseases through vaccination remains a priority goal for scientists and public health officials. The high risk of developing multidrug-resistant Mycobacterium tuberculosis is a serious limitation to drug therapy, and consequently development of efficacious vaccines is critical for the successful eradication of tuberculosis. Vaccination against tuberculosis would rely on the immune system's ability to generate an appropriate protective response that can then be successfully garnered when the host is challenged with M. tuberculosis. Although we know that Th1 immunity is critical for protection against tuberculosis, yet the cells and mechanisms that are involved in generating a protective Th1 immunity are far from completely understood. In this proposal we combine two complementary approaches, a hypothesis-driven and low-through put approach and a global microarray analysis to ask mechanistic questions regarding how protective Th1 immunity to M. tuberculosis is generated. Therefore the central goal of this proposal is to examine the mechanism for the distinct cytokine response from dendritic cells and macrophages following M. tuberculois infection, and study its impact on the development of M. tuberculosis-reactive CD4 + Th1 cells in vivo: from naive to effector. Overall we expect to obtain from these studies an integrated appreciation of the dynamics of induction of Th1 immunity in tuberculosis. Successful completion of these studies will provide innovative strategies for vaccine development and also provide new modalities of modulating the immune response to shorten chemotherapy and/or overcome drug resistance. The specific aims that will address the goals of the proposal are: Aim 1. Corroborate the theory that signaling from TLRs is sufficient for IL-12 production from dendritic cells, and that macrophages require an additional signal to synergize with TLR signaling for IL-12 production. Aim 2. Examine the molecular basis for differential IL-12 regulation in M.tuberculosis stimulated dendritic cells and macrophages. Aim 3. Test the hypothesis that dendritic cells are critical for Th1 cell priming, and that macrophages are elemental for initiating the granulomatous response. Aim 4. Compare the reprogramming of the dendritic cell and macrophage transcriptome in response to M.tuberculosis alone and in response to M.tuberculosis and interferongamma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
Studies 69
•
Project Title: INHIBITION TUBERCULOSIS
OF
MACROPHAGE
INNATE
IMMUNITY
IN
Principal Investigator & Institution: Kusner, David J. Associate Professor; Internal Medicine; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Tuberculosis (TB) is one of the world's greatest health problems, causing approximately 3 million deaths per year. Despite continuing increases in global morbidity and mortality, therapeutic and preventative options for TB remain severely limited. The central feature of TB pathogenesis is infection and intracellular survival of Mycobacterium tuberculosis (Mtb) within human macrophages. Following phagocytosis, Mtb evades the normally potent antimicrobial defenses of innate immunity by inhibiting the maturation of its phagosome to a microbicidal phagolysosome. The molecular mechanisms by which Mtb blocks phagosomal maturation and survives intracellularly are incompletely understood. The long-term goal of this project is to define the molecular mechanisms of tuberculous pathogenesis, to provide a foundation for improved therapies and vaccines. Recently, we demonstrated that live, virulent Mtb, but not killed Mtb, inhibit macrophage Ca2+signaling, and that this defect in host activation directly contributes to inhibition of phagosomal maturation and promotion of the bacilli's intracellular survival. Important gaps in our knowledge include: (1) the mycobacterial determinants responsible for inhibition of macrophage Ca2+-signaling, and (2) the macrophage targets of Mtbinduced inhibition during this critical phase of the host-pathogen interaction. The hypotheses are: (a) sphingosine kinase (SK) is a critical target of macrophage deactivation by live Mtb, and (b) inhibition of SK is causally related to defective Ca2+signaling, inhibition of phagosome maturation, and the survival of Mtb within human macrophages. We will investigate these hypotheses by pursuing the following Specific Aims: (1) Characterize the activation of macrophage SK during phagocytosis of killed Mtb and its role in Ca2+-signal transduction and phagosome maturation. (2) Determine whether inhibition of SK-mediatedCa2+-signaling by live Mtb is causally related to defective phagosome maturation and intracellular viability. In Aims 1 and 2, pharmacological, biochemical, and genetic approaches will be used to modulate specific signaling pathways. (3) Determine the component(s) of Mtb responsible for inhibition of macrophage SK- and Ca2+-mediated activation. A genetic approach of screening a transposon mutant library of Mtb and a biochemical approach of direct assessment of subcellular fractions of Mtb for effects on macrophage SK-andCa2+-mediated signal transduction will be undertaken. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITION M.TUBERCULOSIS
OF
MYOCOLIC
ACID
BIOSYNTHESIS--
Principal Investigator & Institution: Jacobs, William R. Investigator; Microbiology and Immunology; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 30-APR-2003 Summary: Tuberculosis and disseminated Mycobacterium avium cause significant morbidity and death in individuals with Human Immunodeficiency Virus (HIV) infection. Globally, tuberculosis is a leading cause of death for patients infected with HIV. The emergence of M. tuberculosis strains resistant to two or more anti-tuberculosis drugs have compromised control strategies. M. avium Complex (MAC) causes disseminated infection and increased mortality in up to 40 percent of patients with
70 Tuberculosis
AIDS. There is an urgent need to develop new, potent anti-mycobacterial drugs. Mycolic acids are integral and unique parts of the mycobacterial cell wall and the biosynthetic enzymes represent attractive targets for the development of novel drugs. Towards that goal, we are using a multi-disciplinary approach employing mycobacterial genetics, biochemistry, x-ray crystallography, molecular biology, organic chemistry and animal models to develop novel inhibitors. We have discovered a gene, named inhA, which was found to be a primary target to isoniazid (INH) and ethionamide (ETH). Point mutations within the structural gene, or overexpression of inhA confers INH- and ETHresistance in mycobacteria. Biochemical studies reveled that inhA encodes an NADHspecific enoyl-acyl carrier protein (ACP) reductase which prefers long chain fatty acids as substrates, consistent with its role in mycolic acid biosynthesis. The three dimensional structure of resistant and sensitive forms of InhA were determined. We demonstrated that INH is a pro-drug which, upon activation by a catalase-peroxidase forms a covalent adduct to NADH bound on the InhA enzyme. Armed with the knowledge of InhA structure and function, we have generated a series of long-chain fatty acid analog inhibitors that contain a triple bond between C2 and C3: the 2-alkynoic acids (KOAs). The KOAs inhibit the InhA enzyme and have activity against MAC, and against both INH- susceptible and INH-resistant M. tuberculosis. Furthermore, we have screened a combinatorial library of compounds against the InhA enzyme and identified two new classes of compounds with activity against InhA that inhibit M. tuberculosis and MAC growth. In this proposal, we intend to expand upon these successes and continue to elucidate the key targets of mycolic acid biosynthesis with the aim of developing novel drugs against M. tuberculosis and M. avium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITION OF TUBERCULAR MYCOTHIOL PATHWAYS Principal Investigator & Institution: Knapp, Spencer A. Chemistry and Chemical Biology; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, NJ 08901 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Drug-resistant tuberculosis now threatens a large portion of the earth's population, and the development of new treatments for tuberculosis infection has become a national and international priority. Mycobacterium tuberculosis depends on a low molecular weight thiol, "mycothiol," to maintain a reducing intracellular environment and to remove exogenous electrophilic agents. Disruption of the enzymatic pathways of mycothiol biosynthesis and/or mycothiolbased detoxification could leave M. tuberculosis vulnerable to drugs, oxygen, and other stress factors, and constitutes a new tactic for the control of tuberculosis. The objective of this project is to develop inhibitors of the mycothiol-related enzymes of M. tuberculosis, and eventually to design new and successful treatments for tuberculosis. Three enzymes will be targeted initially: mycothione reductase, mycothiol S-conjugate amidase, and inosityl GIcNAc deacetylase, although others, including a cysteine ligase and a cysteine transacetylase, could be added. This work will be guided by enzymatic assays conducted by collaborators using existing screens, and by preliminary results that already indicate that substantial structural simplification in designing mycothiol analogues is possible. First, the minimum substrate requirements for the M. tuberculosis enzymes will be defined. Then, inhibitors based on these minimum structures will be synthesized and evaluated. New methods for the synthesis of mycothiol-analogous compounds will be developed, and new ideas for enzyme inhibitor design will be explored. The most active compounds will be taken as leads for
Studies 71
further analogue development and for increasing the bioavailability, and metabolic stability in M. tuberculosis itself.
potency,
specificity,
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITORS OF SULFATE ASSIMILATION AS NEW THERAPY FOR TB Principal Investigator & Institution: Hemmerich, Stefan; Thios Biotechnology, Inc. 747 52Nd St Oakland, CA 94609 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 14-NOV-2003 Summary: (provided by applicant): Mycobacterium tuberculosis (M. tuberculosis) is a major pathogen of global importance. Despite the availability of chemotherapy and the Bacille Calmette-Guerin vaccine, M. tuberculosis continues to claim more lives than any other single infectious agent. Recent years have seen increased incidence of tuberculosis in both developing and industrialized countries, the widespread emergence of drugresistant strains and a deadly synergy with the human immunodeficiency virus. The limitation of current therapy originates from the widespread occurrence of antibiotic resistant strains and also the requirement for prolonged and uninterrupted administration of antibiotics. Thus, new classes of antibiotics are desperately needed. Sulfur-containing metabolites, including the essential amino acids cysteine and methionine, and the virulence factors mycothiol and sulfolipid-1, are crucial for the infectivity of M. tuberculosis. Their biosynthesis involves the sulfate assimilation pathway, which has no counterpart in humans. Since the enzymes in this pathway comprise a central hub of metabolism and are unique to bacteria, we propose that these enzymes are prime targets for anti-mycobacterial therapy. This proposal focuses on 5'adenosinephosphosulfate (APS) reductase (CysH) as a target for small molecule drug development. In preliminary work, we have 1) confirmed the APS reductase activity of M. tuberculosis CysH using genetic complementation in E. coli, and 2) demonstrated that genetic deletion of CysH from a pathogenic strain of M. tuberculosis renders the mutant unable to establish infection in a mouse model of tuberculosis. In specific aim 1 of this proposal we shall screen a compound library for inhibitors of M. tuberculosis sulfate assimilation using an E. coli complementation assay. In specific aim 2 we shall set up cell-free homogenous assays for recombinant M. tuberculosis CysH, examine our leads from the primary screen for their ability to directly inhibit this enzyme, and optimize these leads through medicinal chemistry. In specific aim 3 the best compounds will be examined using in vitro susceptibility studies of clinical isolates of M. tuberculosis. In phase II of this study, the inhibitor leads from our feasibility study will be examined for bacteriostatic and bacteriocidic efficacy in mouse models of tuberculosis. The long-term objective of this study is to develop novel antibiotics for more effective treatment of human tuberculosis and other mycobacterial diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: INNOVATIVE APPROACHES FOR TUBERCULOSIS CONTROL IN BRAZIL Principal Investigator & Institution: Lapa E Silva, Jose R.; Federal University of Rio De Janeiro Cidade Universitaria Rio De Janeiro, Timing: Fiscal Year 2002; Project Start 22-SEP-2002; Project End 21-SEP-2003 Summary: (provided by applicant): Tuberculosis is still an important cause of human suffering and economic loss in Brazil and beyond. A concerted effort to address all the questions related to TB control is needed, involving Universities and Health
72 Tuberculosis
Departments. The Millenium TB Network was organized in 2001 with the goal to generate new knowledge about the disease; to train highly qualified professionals with a critical view of the problem and to transfer the new information to the health system. For many years, leading American academic institutions working in Brazil recognized the importance of this initiative. The major goal of this proposal is to develop a competitive application for a Comprehensive ICOHRTA-AIDS/TB Cooperative Agreement linking Federal University of Rio de Janeiro and other collaborating sites in Brazil and Johns Hopkins University, Cornell University and UC Berkeley as collaborating sites in the U.S. The specific aims are 1) To establish a multilateral collaborative training program in tuberculosis control with investigators and physicians from Brazil and Johns Hopkins, Cornell, and Berkeley Universities.2) To establish a network system between the different institutions and individuals participating in the program in Brazil and USA in order to promote frequent consultation between the partners to define the type of didactic and laboratory training in health sciences pertinent to tuberculosis control. 3) To identify the needs in infra-structure, human rights protection, administration necessary to the establishment of a long-term term collaborative program on TB and AIDS/TB research. The major task of this new consortium will be to identify possible interactions between these partners, in order to guarantee efficiency in the actions. The goal will be to link separate projects, funded by several sources, into one multicenter and organized research and training program to address the TB problem at the national and, in the future, continental levels. During the planning year, projects that share similar objectives will be linked, needs at the collaborating sites, identified, and a common training and research agenda in TB will be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INTERNET CONNECTION FOR 5 TUBERCULOSIS INSTITUTIONS Principal Investigator & Institution: Miller, Paula F. Assistant Regional Director; Project Hope 255 Carter Hall Ln Millwood, VA 22646 Timing: Fiscal Year 2002; Project Start 15-JAN-2002; Project End 31-AUG-2003 Summary: (provided by applicant): The goal of the Five Country Internet Access Project is to provide TB specialists, medical faculty, and medical students in the Central Asia Republics (CAR) - Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan and Uzbekistan with access to up-to-date medical information and resources, particularly those relating to Tuberculosis diagnosis and treatment that are readily available on the Internet. The specific objects of the projects are to: 1) Purchase equipment and service for connectivity for 6 library/learning centers; 2) Train 25 project personnel and 4500 users for the Internet; 3) Provide extended Internet access to over 10,000 medical professionals; 4) Establish a Tuberculosis materials database in each country through downloading, cataloging and initiating distribution of lists of materials available from library/learning centers in each country via e-mail; (5) Provide an Internet search center for materials on Tuberculosis for TB specialists, primary health care professionals, nurses and others located in 30 remote e-mail- connected TB pilot sites of countries of the CAR through submission of requests to the central library/learning center. The World Health Organization has identified the lack of training and updated knowledge of TB among Primary Health Care staff as one of several constraints hampering TB control in the Central Asia Republics. This Internet Access Project will build upon current TB diagnosis and treatment efforts currently being implemented by Project HOPE, the requesting organization, and strengthen capacity by improving exchange of information. The project will be initiated at the request and collaboration of the host
Studies 73
countries and is consistent with Project HOPE's vision and programming in the region. The projected plan for getting Internet access for the five TB institutes will begin with a consultant Internet specialist working with local Internet specialists and providing training of trainers specific to e-mail, the tuberculosis websites and provide the teaching methodologies to be Used in training at the TB institute sites. The consultant will assist with the preparation of an Internet Procedure Manual that outlines the use of Internet in a step-by-step format. Following the Training of Trainers (TOT), a two-page pamphlet in the local language will be written and printed by the local Internet specialist and may be given to each professional coming to the library/learning center to orient them how to use the Internet. The libraries/learning centers will be assisted by the Project HOPE office staff in each country to organize the connection of the phone line and modems and provide the training schedule for the staff. The local Internet specialist will go to each country to train the staff in the library learning center using the local language. Additionally, each site will be provided 750 pamphlets outlining procedure to use with medical staff requesting access to the Internet. Each library/learning center will keep a database of medical personnel accessing the Internet and report these statistics to the local HOPE office quarterly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INTRACELLULAR MACROPHAGES
INFECTION
OF
HUMAN
ALVEOLAR
Principal Investigator & Institution: Park, David R. Medicine; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 20-JUL-1997; Project End 30-JUN-2003 Summary: (Adapted from applicant's abstract) Legionella pneumophila and Mycobacterium tuberculosis, the etiologic agents of Legionnaires' disease and tuberculosis respectively, are facultative intra-cellular pathogens which parasitize human alveolar macrophages and blood monocytes recruited to the site of lung infection. An effective host response to these infections depends on cell-mediated immunity, and cytokine networks modulate this response. The overall hypothesis driving this proposal is that L. pneumophia and M. tuberculosis subvert the human alveolar macrophage cytokine response to facilitate their own survival by inducing permissive host cytokines which disarm the protective antimicrobial mechanisms of the phagocyte. The specific aims are: 1) to define the role of cytokine activation of human alveolar macrophages in determining the tolerance or elimination of intracellular infection by L. pneumophila and M. tuberculosis; 2) to determine whether apoptosis of infected alveolar macrophages diminishes the viability of intra-cellular L. pneumophila and M. tuberculosis; 3) to develop and use a virulent L. pneumophila strain transduced with the A victoria green fluorescent protein gene to co-localize intracellular bacteria and specific components of the human alveolar macrophage host response in infected cells. The experimental approach to the specific aims will use an established in vitro model in which human alveolar macrophages are infected with L. pneumophila or M. tuberculosis. Effects of cytokines on intracellular growth will be measured using selected combinations of recombinant cytokines and blocking antibodies. Specific interactions signaling cytokine induction by live bacteria and cell wall glycolipids will be assessed by blocking complement receptors, CD14, and LBP. Macrophage apoptosis will be assessed by cellular morphology, Annexin V binding, and by DNA fragmentation assays, and associated changes in bacterial viability will be quantitated. Individual cell response by infected cells will be assessed by flow cytometry and fluorescent microscopy co-localization of green fluorescent protein expressing bacterial
74 Tuberculosis
strains with selected markers of host defense. These studies will provide important insights into the human host responses to L. pneumophila and M. tuberculosis infections. A thorough understanding of these responses will be necessary for the development of rational immunotherapeutic approaches to the treatment of Legionnaires' disease and tuberculosis, which will be increasingly important for the treatment of immunocompromised patients and infections with drug-resistant strains. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IRON TUBERCULOSIS
REGULATION
&
VIRULENCE--MYCOBACTERIUM
Principal Investigator & Institution: Manabe, Yukari C. Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: The candidate is completing a three year infectious disease fellowship and has devoted the last 2 years to basic science research in tuberculosis. In particular, the candidate is interested in studying gene regulation in tuberculosis to elucidate virulence genes and protein antigens which may make important drug and vaccine targets. Through the research conducted under this grant, the candidate would like to establish herself as a junior faculty member at an academic medical institution and continue to pursue tuberculosis disease pathogenesis using molecular biologic techniques. In collaboration with Dr. John Murphy, a leader in iron-dependent regulons in diphtheria, and Dr. Richard Silver, who has developed a reproducible macrophage model of tuberculosis infection, the candidate will have the collaborative resources necessary for the successful completion of this project. The sponsor, Dr. William Bishai, has wellestablished expertise in mycobacterial gene regulation and tuberculosis disease pathogenesis. To complement her research, the candidate will attend approximately 3 hours per week of infectious disease and TB-related conferences. She also plans to take courses in molecular biology, tuberculosis, vaccine development, and immunology in the School of Medicine and the School of Public Health and Hygiene. Fueled by antibiotic resistance and HIV infection, the global burden of tuberculosis infection is staggering. The elucidation of virulence mechanisms and protein antigens for new antimicrobials and vaccines has moved to the forefront. Iron is an essential nutrient for the survival of most organisms and has played a central role in the virulence of multiple important infectious disease pathogens. Using the corynebacterial, iron- dependent DtxR regulon as a model, the candidate will study the mycobacterial homologue, ideR and its regulon. Preliminary results have shown that an iron-independent, corynebacterial DtxR mutant hyperrepressor attenuates Mycobacterium tuberculosis virulence in a murine model. A similar mutant of the mycobacterial ideR has been constructed and will be tested in vitro using a gel-shift assay, and in vivo in a murine and macrophage models. Taking advantage of the DtxR/IdeR "iron box", a palindromic DNA binding sequence present in all DtxR-regulated genes, other genes of interest have been identified in silico and will be examined. Elucidation of this iron-dependent IdeR regulon may lead to the identification of virulence determinants, and novel antigens for vaccines and therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
Studies 75
•
Project Title: RESISTANCE
KATG
PEROXIDASE
IN
ISONIAZID
ACTIVATION
AND
Principal Investigator & Institution: Owen, Whyte G.; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2006 Summary: (Adapted from the Applicant's Abstract): Tuberculosis is one of the leading causes of death worldwide from an infectious disease. Isoniazid is a front line antibiotic used in the treatment of tuberculosis. The Mycobacterium tuberculosis heme catalase/peroxidase KatG is responsible for activating isoniazid to a reactive biocidal species. Antibiotic resistance to isoniazid is a growing concern and can occur by deletions or point mutations in the katG gene. One of these, a serine-to-threonine substitution at position 315, KatG(S315T) is found in about 50 percent of clinical isolates resistant to isoniazid. Our research seeks to understand the mechanism of isoniazid activation and molecular basis for drug resistance caused by the S315T and other point mutations in KatG using biochemical, genetic, and spectroscopic techniques. KatG will be purified from recombinant and native sources and the activities and spectroscopic properties compared. Besides a catalase/peroxidase activity, KatG can also catalyze several other reactions including Mn2+ peroxidase, P450-like oxygenase, and peroxynitritase activities. Which of these or possibly other redox reactions are responsible for isoniazid oxidation and activation will be tested using wild-type and mutant KatG proteins to investigate the mechanism of activation. Genetic methods investigating the role of superoxide in isoniazid activation are proposed. Optical, EPR, NMR, and resonance Raman spectroscopies are revealing subtle differences in the heme active site of wild-type KatG and KatG(S315T). These spectroscopic techniques will be applied to various forms of wild-type and mutant enzymes in order to elucidate the molecular basis for reactivity toward isoniazid and the reduced rate of isoniazid oxidation by KatG(S315T). NMR relaxation measurements and x-ray crystallography will be used to map the isoniazid binding site on both enzymes to determine whether subtle differences in distance and/or orientation are responsible for the reduced turnover of drug by the mutant enzyme. Steady-state and rapid kinetic techniques will follow ligand-binding rates to the heme iron and the formation and decay of reactive intermediates in the catalytic cycle for both wild-type KatG and KatG(S3 1ST) to determine whether the S3 1ST mutation affects one of the steps in the catalytic cycle. EPR spectroscopy and spin-traps are being used to trap reactive intermediates. The stable products formed in this reaction are being characterized by mass spectrometry to reveal chemical information about the nature of intermediates in the reaction of isoniazid oxidation by KatG. Site directed mutagenesis of residues also implicated in isoniazid resistance other than S3 15 will be generated and the effects on enzyme activities and spectroscopic properties examined to determine structural information about the mutant enzymes. Analogs of isoniazid will be used as additional biochemical and spectroscopic probes of the reaction mechanism and molecular basis for drug resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LOSS OF OXYR IN M TUBERCULOSIS Principal Investigator & Institution: Deretic, Vojo P. Professor; Molecular Genetics & Microbiol; University of New Mexico Albuquerque Controller's Office Albuquerque, NM 87131 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2003
76 Tuberculosis
Summary: (Adapted from the applicant's abstract): M. tuberculosis is a natural mutant in the putative central regulator of oxidative stress response, oxyR. All M. tuberculosis strains investigated to date have nearly identical lesions in oxyR, and the elimination of oxyR function may have coincided with or directly participated in the evolution of M. tuberculosis into the potent contemporary human pathogen. The loss of oxyR has a dual significance for M. tuberculosis pathogenesis and treatment of tuberculosis. First, this surprising phenomenon reflects the complexity of host-parasite interactions and its continuing analyses are expected to reveal strategies used by M. tuberculosis for survival in the host. Second, the loss of oxyR and the associated dysfunction of oxidative stress responses most likely contribute to the exceptional sensitivity of M. tuberculosis to isonicotinic acid hydrazide (INH). The goals of this proposal are: (i) to delineate the effects of the loss of oxyR on M. tuberculosis response to reactive oxygen and nitrogen intermediates. This will be accomplished by identifying genes and functions affected by the loss of oxyR, analyzing alternative modes of their regulation, and characterizing M. tuberculosis response to reactive oxygen and nitrogen; (ii) to determine whether and how oxyR inactivation and the resulting dysfunction of oxidative stress responses contribute to the exceptional sensitivity of M. tuberculosis to INH. This will be examined by complementation of the defect in M. tuberculosis using a functional mycobacterial oxyR, by inactivation of oxyR in model mycobacteria, and by determination of the effects that such modifications have on INH sensitivity in vitro and in vivo; (iii) to investigate the role of the loss of oxyR in M. tuberculosis virulence and pathogenesis using mouse bone marrow derived macrophages and human monocytes, and models of tuberculosis in mice and guinea pigs. In addition to conventional analyses of M. tuberculosis survival and histopathology, GFP-based technologies developed in the PI's laboratory will be employed to monitor mycobacterial localization, and potential tissue- and infection stage-specific expression of oxidative stress response genes (e.g. ahpC). These experiments will delineate the effects that the loss of oxyR has on host-pathogen interactions in tuberculosis. The proposed studies are expected to improve understanding of the elusive virulence attributes of M. tuberculosis, and may help explain, at least in part, its high sensitivity to the front-line antituberculosis agent INH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: M TB SURVIVAL REGULATORY GENES Principal Investigator & Institution: Bishai, William R. Associate Professor; Molecular Microbiol and Immun; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-APR-1997; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract): This is a revised application in which the PI proposes to analyze an alternate sigma factor of Mycobacterium tuberculosis which may be involved in the intracellular survival of the tubercle bacilli. The PI points out that the ability of M. tuberculosis to adapt to a variety of environmental conditions is an important feature of its pathogenicity. Many bacteria use alternate sigma factors for RNA polymerase to upregulate response genes specific for a needed adaptation. Using degenerate PCR, the PI has identified an alternate sigma factor from M. tuberculosis which he has called SigF. M. tuberculosis SigF is homologous to the SigF and SigB proteins of Bacillus subtilis, which are involved in regulation of sporulation and general stress response gene expression, respectively. Not only does M. tuberculosis SigF have homology with B. subtilis SigF and SigB, but it is preceded by an antisigma and a possible anti-antisigma homologue, just as are the B. subtilis sigma
Studies 77
factors. In vitro (i.e., broth-grown cultures), the expression of the M. tuberculosis SigF is upregulated by stress conditions and entry into stationary phase. In vivo, its expression increases 10-fold upon entry into murine macrophages. Hence, the PI hypothesizes that the M. tuberculosis SigF may govern an intracellular survival regulon. In this application, the PI proposes to determine (i) the in vitro and in vivo phenotypes of an M. tuberculosis sigF mutant, (ii) how SigF is regulated (i.e., is an antisigma partner switching mechanism involved?), and (iii) the identities of SigF-dependent genes. The PI anticipates that understanding how M. tuberculosis adapts for intracellular survival may lead to novel drug and vaccine targets for tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: M DESIGN/EVALUATION
TUBERCULOSIS
CTL
EPITOPES:
VACCINE
Principal Investigator & Institution: Clayberger, Carol A. Associate Professor; Cardiovascular Surgery; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Tuberculosis (TB) is the leading cause of death from a single infectious agent (Mycobacterium tuberculosis (Mtb)), causing approximately 3,000,000 deaths each year. Although TB can be effectively treated with a combination of antibiotics, drug resistant Mtb strains have recently emerged which are classified as Category C biological agents. Thus, it is widely felt that the long term control of TB will require the development of a more effective vaccine. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the current anti-TB vaccine, is quite variable in its ability to protect against TB but is effective against tuberculosis meningitis, suggesting that for the foreseeable future, new TB vaccines will be given as an adjuvant or boost to BCG. Thus, understanding the immune response to both Mtb and BCG is critical for the development of an improved vaccine for TB. An increasing body of evidence indicates that both CD4+ and CD8+ T lymphocytes are critical to a protective immune response against Mtb. However, little is known about the antigens targeted by protective immune responses against Mtb in humans. Such information is required for the rational development and clinical evaluation of new, more effective TB vaccines. We propose here to characterize the human CD4+ and CD8+ T cell response to a panel of Mtb antigens in order to identify correlates with protective immunity. Antigens to be tested include proteins as well as peptide epitopes restricted by HLA-A2, an allele expressed by approximately 50% of the population. Some of these proteins and epitopes were selected from a subset of Mtb genes that are highly expressed under specified conditions and whose products are predicted to localize to the extracellular milieu, while the remainder represent previously identified HLA-A2 restricted epitopes. The T cell response to these antigens will be evaluated in peripheral blood leukocytes from three different groups of BCG immune and/or Mtb infected individuals: i. Neonates immunized a birth with one of 4 strains of BCG; ii. Individuals infected with Mtb but who do not progress to disease (latent TB infected individuals); and iii. PPD+ TB patients and PPD- "anergic" TB patients. Some of these peptide epitopes will be used to develop epitope oligomers which will be used to analyze anti-Mtb responses In vitro and in vivo. Lastly, the localization and function of Mtb peptide specific memory T cells will be studied in vivo. Correlates of protective immunity can be used to identify or prioritize protective antigens and vaccine candidates, to optimize vaccine dosing, schedules, adjuvants, etc., and to provide early evidence of efficacy. For TB, which takes years to decades to develop after infection with Mtb, immune correlates with protection are an attractive, and perhaps essential, supplement to efficacy trials.
78 Tuberculosis
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: M TUBERCULOSIS EVASION OF THE INNATE IMMUNE RESPONSE Principal Investigator & Institution: Fortune, Sarah M. Immunology/Infections Diseases; Harvard University (Sch of Public Hlth) Public Health Campus Boston, MA 02460 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-MAY-2006 Summary: (provided by applicant): This proposal describes a five year, twopart career development program in the study of Mycobacterium tuberculosis. This program will be carried out in the laboratory of Dr. Barry Bloom with the additional guidance of Dr. Eric Rubin, both in the Division of Immunology and Infectious Diseases at the Harvard School of Public Health. The candidate is trained in Infectious Diseases and has the long term goal of establishing an independent laboratory studying M. tuberculosis pathogenesis with a particular focus on mycobacterial interaction with the host immune response and vaccine development. The didactic component of this program involves courses in molecular biology and immunology through Harvard University. The research component of this program involves exploration of two putative mechanisms of immune evasion by M. tuberculosis, inhibition of IFN-gamma signaling and inhibition of inducible IL-12 production in infected macrophages. The specific aims of the research proposed will be: 1) to determine whether Toll-like receptor 2 (TLR-2) activation inhibits IFN-gamma signaling or inducible IL-12 production; 2) to identify the M. tuberculosis genes required for inhibition of IFN-gamma and IL-12 signaling by screening a transposon mutagenized library of M. tuberculosis; and 3) to characterize the genes identified in these screens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: M TUBERCULOSIS GENES INDUCED DURING MOUSE INFECTION Principal Investigator & Institution: Woolwine, Samuel C. International Health; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-JUL-2001 Summary: Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is responsible for the deaths of millions of individuals each year. One obstacle in the crusade against this pathogen is the ability of the organism to persist in an asymptomatic state, referred to as latency. Another rapidly increasing trend in tuberculosis is the emergence of multiply drug resistant strains of M. tuberculosis. In order to better understand the biology of M. tuberculosis during active or latent disease, and to identify new potential drug targets and candidate vaccine strains, a powerful technique known as differential fluorescence induction will be used to identify M. tuberculosis genes induced specifically during host infection. In this approach, a plasmid library of M. tuberculosis genomic DNA (gDNA) fragments fused to a promoterless gfp, encoding the green fluorescent protein, will be transferred into M. tuberculosis. The resulting clones will be used to infect Balb/c mice. At specific time points mice will be euthanized, and specific organs will be harvested and homogenized. The resulting homogenates will be analyzed in a fluorescence-activated cell sorter (FACS). In this way, fluorescent bacilli will be identified and collected.These bacilli harbor plasmids in which the M. tuberculosis gDNA fragments upstream of gfp contain promoters that are expressed in vivo. The collected bacilli will be cultured in vitro and then re-analyzed by FACS. During this round of analysis, those bacilli that exhibit low
Studies 79
levels of fluorescence will be collected and used to infect a second set of mice. By successive rounds of in vivo and in vitro propagation, a set of M. tuberculosis promoters will be identified that are specifically induced in the animal host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: M TUBERCULOSIS PHOP LIKE GENE IN MACROPHAGES Principal Investigator & Institution: Buchmeier, Nancy A. Associate Research Microbiologist; Pathology; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract): The regulated expression of specific Mtb genes is likely required for the establishment of tuberculosis infections. One family of gene regulators present in M. tuberculosis is the two component regulators. Two component regulatory systems sense and respond to environmental stimuli. tcrA (for two component regulator) is a two component regulatory gene found in M.tb. tcrA is present in M. tuberculosis isolates and in M. bovis isolates, but is absent in mycobacterial strains which belong to the four nontuberculosis groups of mycobacteria. tcrA has a regulatory effect on Mtb protein expression as evidenced by multiple changes in the synthesis of Mtb proteins in a tcrA mutant compared to Mtb Erdman. The objective of this proposal is to evaluate the role of the tcrA regulatory system in the production of tuberculosis infections. A tcrA mutant of Mtb Erdman will be used to assess the importance of the tcrA gene in Mtb growth in cultured macrophages. The sensitivity of the tcrA mutant to toxic macrophage compounds will be evaluated and the morphologic appearance of macrophages infected with the tcrA mutant analyzed. Mice will be infected with the tcrA mutant using aerosol inoculation and the resulting infection compared with Mtb Erdman infections. tcrA regulated genes will be cloned, mutants in each gene will be constructed and each mutant evaluated for growth in cultured macrophages. The environmental conditions which activate the tcrA regulon will also be identified. These studies will be valuable in identifying MTb genes which contribute to Mtb pathogenicity and which may serve as targets for anti-tuberculosis treatment either in vaccines or for anti-mycobacterial drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: M TUBERCULOSIS SURVIVAL AND GROWTH IN VIVO Principal Investigator & Institution: Smith, Issar; Member; Public Health Research Institute 225 Warren St Newark, NJ 07103 Timing: Fiscal Year 2001; Project Start 01-MAR-1999; Project End 29-FEB-2004 Summary: (Adapted from the Applicant's Abstract): Despite the use of a generally safe vaccine for 70 years and effective antibiotics for 40 years, tuberculosis still kills approximately 3 million people annually. To develop new methods of diagnosis and therapy, it is necessary to find new targets, i.e., genes and proteins, in the causative organism, Mycobacterium tuberculosis. An understanding of mycobacterial gene expression is expected to provide much assistance in achieving this goal. In recent years, the investigator's laboratory has studied general and specific mechanisms of gene regulation, i.e., the structure and function of the basic mycobacterial transcriptional apparatus and the control of iron acquisition. Much has been learned regarding these regulatory systems in pathogenic and non-pathogenic mycobacteria, both biochemically and in vitro. Information gained in these initial experiments is now being used to study the in vivo regulation of M. tuberculosis genes and their functions during the infectious
80 Tuberculosis
process. The aims of this new grant proposal are: 1) identification of M. tuberculosis genes that are specifically induced, in vivo. An IVET promoter trap system has been developed. Several genes have been isolated thus far, and the search for new candidate genes will be continued; 2) studying the expression of M. tuberculosis genes in vivo. A sensitive and accurate real time RT-PCR method has been developed to quantitate the in vivo expression of M. tuberculosis genes that have been and will be identified in the experiments described in first aim. In addition, they can also measure the expression of other M. tuberculosis genes that they believe may be induced (or repressed) upon infection of macrophages. Several genes showing differential regulation in macrophages have already been identified and they will study the mechanisms by which they are induced or repressed after infection. Since some of these genes are iron regulated, they will also manipulate iron levels in macrophages to measure the affects on their expression; 3) elucidating the role of in vivo-induced M. tuberculosis genes in virulence. In the course of these studies, they expect to identify many genes that are induced in vivo. To determine their role in virulence, they will inactivate these genes in M. tuberculosis and will measure the survival and growth of the mutants in various macrophages and in mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: M. TUBERCULOSIS CELL WALL BIOGENESIS; NEW DRUGS; TBHIV Principal Investigator & Institution: Brennan, Patrick J. Professor; Microbiology, Immunology & Pathology; Colorado State University Fort Collins, CO 80523 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): The incidence of HIV-associated tuberculosis has been increasing worldwide since the beginning of the AIDS epidemic, and is expected to rise even further in the future, especially in developing countries. The accelerating and amplifying influence of HIV infection is contributing to the increasing incidence of disease caused by multidrug-resistant strains of Mycobacterium tuberculosis. Development of new drugs against tuberculosis is thus important for control of both of the infections. Mycobacterial cell wall is an attractive target for rational drug design against tuberculosis, due to the fact that it forms a protective, almost impermeable barrier, on the surface of mycobacteria. Some of the most effective drugs currently used for the treatment of TB affect components of its backbone - mycolylarabinogalactanpeptidoglycan (mAGP) complex. Our long-term goal is to identify processes and enzymes involved in the mAGP assembly. Possible AG biosynthetic gene cluster has been recently identified in the genome of M. tuberculosis and thus the specific aims of this grant proposal are: 1. Identify the genes involved in mycobacterial galactan biosynthesis within AG biosynthetic cluster and determine their biological functions via cloning, overexpression and subsequent biochemical characterization. 2. Establish the function of the putative ABC transporter within the AG biosynthetic cluster by way of preparation and phenotypic characterization of the mutants/conditional mutants. The approach will help define one of the more complex pathways in microbial biochemistry and reveal reactions that should be exploitable for drug development. The research will be primarily carried out at Comenius University, Faculty of Natural Sciences in Bratislava, Slovakia in collaboration with Katarina Mikusova, as an extension of the NIH grant A1-18357. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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•
Project Title: M. TUBERCULOSIS SURVIVAL IN MACROPHAGES Principal Investigator & Institution: Friedman, Richard L. Professor; Microbiology and Immunology; University of Arizona P O Box 3308 Tucson, AZ 857223308 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (provided by the applicant): Central to the disease process in tuberculosis are the interactions of the bacilli with host macrophages. The infection of macrophages by Mycobacterium tuberculosis can be divided into four steps: adherence, entry, intracellular survival, and multiplication. This proposal will concentrate on one of these steps, survival. The role virulence factors of M. tuberculosis play in these complex interactions is virtually unknown. The aim of the proposed research is to identify, clone, and characterize genes and their protein products of M. tuberculosis which are required for intracellular survival within macrophages. Potential virulence factor genes of M. tuberculosis will be cloned by first constructing a recombinant library and incorporating it into the non-pathogenic Mycobacterium smegmatis. This rapidly growing mycobacterium is internalized and killed by macrophages. Clones with enhanced survival in macrophages will be identified and examined for the presence of M tuberculosis genes involved in survival. Using this system we have already isolated a M. tuberculosis gene, named eis (enhanced intracellular survival gene), which does enhance intracellular survival of M. smegmatis within macrophages. The primary focus of this grant application is the further characterization of the eis gene and its protein product Eis. The specific aims are: 1.Effect of eis Gene Inactivation on Survival and Multiplication of M tuberculosis in Macrophages and Mice. Mutations will be constructed in eis and introduced into the chromosome of both avirulent and virulent M tuberculosis (H37Ra and H37Rv) by allelic exchange. The ability of the eis knockout mutants to survive and replicate in the U-937 macrophage survival assay and in human mononuclear phagocytes will be tested and compared to the parental strain. Additionally, the ability of the eis mutants to persist and replicate in vivo in a mouse intravenous infection model will also be evaluated. 2.Mechanism(s) Whereby eis Enhances Survival and Multiplication of M tuberculosis in Unactivated and Interferongamma-Activated Macrophages. To learn how eis may enhance intracellular survival of mycobacteria in macrophages, survival in interferon-gamma-activated U-937 cells and human monocytes will be evaluated. The ability of M. smegmatis with and without eis, as well as wild-type M. tuberculosis and eis knock-out mutants, constructed in Specific Aim No.1, to survive/multiply in both unactivated and interferon-gamma-activated U937 cells and human monocytes will be determined. Studies will also be done to determine what role Eis may play in the ability of M. tuberculosis to resist known killing mechanisms operating in macrophages. 3.Properties of the Eis Protein and their Relationship to its Survival-Increasing Action. These studies will include: (I) intracellular localization of Eis in M. tuberculosis and M. smegmatis, (2) purification of the Eis protein, (3) screening of sera from tuberculosis patients for presence of antibody to Eis, and (4) measurement of eis gene expression in vitro and within macrophages using integrative reporter gene vectors. 4.Identification of Non-eis Survival Genes in a New M. tuberculosis DNA Library. In initial studies, eis-containing clones were the predominate clones isolated after the sixth passage in the U-937 macrophage survival assay. Such eis-containing clones are preferentially selected and appear to outcompete/dominate other M. tuberculosis genes which may also play a role in intracellular survival. Thus, in order to identify these other potential genes, a new M. tuberculosis plasmid library will be constructed with larger (10-12 kb) DNA inserts of genomic DNA from an H37Rv eis knockout mutant. This eis knockout library will then be screened for survival in the U-937 macrophage survival assay. Clones with enhanced survival will be isolated and further characterized.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: M.TUBERCULOSIS GENES REGULATING PERSISTENT INFECTION Principal Investigator & Institution: Zahrt, Thomas C,. Assistant Professor; Microbiol & Molecular Genetics; Medical College of Wisconsin Po Box26509 Milwaukee, WI 532264801 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-MAY-2006 Summary: (provided by applicant) Tuberculosis is the leading cause of death in the world from a single infectious agent, and is responsible for more than 3 million deaths annually. The high mortality rate in individuals infected with Mycobacterium tuberculosis is due in part to its ability to parasitize macrophages and establish longterm, persistent infection in the host despite cell-mediated immunity. Although the current anti-tubercular drug arsenal is effective in treating individuals suffering from active disease, these drugs are ineffective in treating the 2 billion people that currently suffer from latent tuberculosis, or that are infected with multi-drug resistant strains of M. tuberculosis. One group of transcriptional regulatory determinants that may play a critical role in processes associated with M. tuberculosis latency is the two-component signal transduction systems. These systems mediate adaptation processes and have been shown to contribute to virulence and disease elicitation in other organisms. The goals of this study are to characterize further a two-component system of M. tuberculosis (MprA-MprB) that is required for the establishment and maintenance of persistent infection. In this proposal, we plan to: (i) Identify and characterize the genes regulated by the MprA transcription factor. The genes regulated by MprA will be identified from the M. tuberculosis chromosome using biochemical enrichment and genetic selection techniques, and will be characterized by gene inactivation, promoter expression analysis, and evaluation in model systems for infection. (ii) Analyze the in vivo expression profile of the MprA response regulator, and the genes regulated by MprA. This will be accomplished by expression analysis of these genes using GFP reporter technology, primer extension analysis, molecular beacon technology, and DNA microarray based analysis under physiologically relevant conditions. (iii) Delineate the effects of MprA de-regulation on host-pathogen interactions. This will be accomplished by examining effects of MprA loss or overexpression on M. tuberculosis virulence. Virulence studies will include bacterial survival and cytokine expression analysis as assayed in in vitro tissue culture systems and animal model systems of infection. These studies will also address the effects of MprA de-regulation on Mycobacterium bovis BCG attenuation. The proposal outlined here is expected to improve our understanding of genes required by M. tuberculosis for pathogenesis, and help better define the conditions encountered and responses utilized by M. tuberculosis during the latent stage of infection. We hope that the analysis of two-component systems will aid in the identification of genetic determinants for which novel anti-tubercular drugs can be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MACAQUE MODEL OF AIDS VIRUS-RELATED PULMONARY TUBERCULOS Principal Investigator & Institution: Chen, Zheng W. Associate Professor; Beth Israel Deaconess Medical Center St 1005 Boston, MA 02215 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004
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Summary: Mycobacterium tuberculosis (M.tb) disease remains an important lifethreatening problem. While HIV infection clearly predisposes the infected patients to developing primary and reactivation tuberculosis, protective human immunity to M.tb is poorly understood. We have recently shown that the intravenous infection of macaques with Mycobacterium bovis Bacille Calmette-Guerin (BCG) induces potent CD4+ and CD8+ T cell responses, which are associated with the resolution of BCG infections. In contrast, the systemic BCG infection in SIV-infected monkeys results in the chronic co-infection and the development of disseminated BCG disease resembling tuberculosis. Based on the results showing the BCG-driven T cell responses, we hypothesize that MHC-restricted T cells exert anti-mycobacterial immunity against pulmonary mycobacterial infections in the infected individuals. The depletion or dysfunction of these T cell responses will, therefore, result in the increased susceptibility to primary mycobacterial infection or reactivation tuberculosis. To test this hypothesis, we have developed the macaque model of pulmonary BCG infection to characterize anti- mycobacterium T cells as well as to study BCG latency in the lungs. In addition, we have made use of systemic SIV/BCG co-infection to develop an in vivo system in which to test the role of antiretroviral therapy in restoring anti-mycobacterial immunity. Employing these model systems, we will: I. Identify anti-BCG T-cell responses in the lungs and determine the correlation between these responses and the resolution of active pulmonary BCG infection. II. Determine the impact of SIV-induced damage of anti-BCG T cell immunity on the reactivation of the latent pulmonary BCG infection. III. Determine the utility of antiretrovirals for restoring anti-BCG pulmonary T-cell immunity in SIV-infected monkeys. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MACROPHAGE TUBERCULOSIS
GENE
EXPRESSION:
IMPACT
OF
M.
Principal Investigator & Institution: Ehrt, Sabine; Microbiology and Immunology; Weill Medical College of Cornell Univ New York, NY 10021 Timing: Fiscal Year 2001; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) One third of the world's population is currently infected with Mycobacterium tuberculosis (Mtb) and every second, another person is newly infected with Mtb around the world. Each year an estimated 8 million people develop clinical disease and 1.87 million people die of TB. The primary host cell of Mtb is the macrophage and the Mtb-macrophage interaction is critical to every phase of Mtb's infectious cycle. Gene expression analysis (GEA) is the most effective technology currently available to record a quantitative picture of a cell's functional state, and therefore to compare cell states and types. The critical need for such a comparison in TB research is heightened when one takes into account the heterogeneity of macrophages by organ, species of origin and donor history. The goals of this study are to extend our understanding of macrophage biology relevant to tuberculosis (TB), and in so doing, to define the extent to which mouse macrophages can serve as surrogates for human macrophages. The latter question is key if functional genomics is used as a tool in TB research to test the course of infection by wild type and genetically modified Mtb in wild type and genetically modified mice. Specifically, we will extend our current use of high-density oligonucleotide microarrays, quantitative PCR and in situ hybridization (ISH) to analyze and compare the gene expression profiles of three distinct populations of primary cells: mouse bone marrow macrophages (BMM), mouse pulmonary alveolar macrophages (PAM), and human PAM. These relatively pure macrophage populations will be compared with the heterogeneous mixture of all cells in mouse lung. Both
84 Tuberculosis
human and mouse cells will come both from normal donors and individuals with active TB. Each cell population will be studied without further treatment, after infection in vitro with virulent Mtb, and/or after exposure to interferon gamma (IFNgamma), a cytokine critical for control of mycobacterial infection in both humans and mice. These comparisons will allow us to validate or qualify the use of mouse PAM, mouse BMM and human PAM as model systems for studying macrophage-Mtb interactions. The identification of genes regulated by Mtb in macrophages will generate hypotheses with respect to the role of these genes in pathogenesis. We will test at least one such hypothesis, that secretory leukocyte protease inhibitor (SLPI) plays a role in the pathogenesis of TB. Finally, we will share our GEA with others via the internet so that as many of the resulting hypotheses as possible can be rapidly and independently explored. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MCP-1 AND SUSCEPTIBILITY TO ACTIVE TUBERCULOSIS Principal Investigator & Institution: Flores-Villanueva, Pedro O.; Dana-Farber Cancer Institute 44 Binney St Boston, MA 02115 Timing: Fiscal Year 2002; Project Start 10-AUG-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Our long-term objective is to develop new approaches for the treatment of tuberculosis (TB) by studying the host genetic factors controlling the development of effective cellular immunity against M. tuberculosis (Mtb). We have preliminary data showing that the genotype GG in the promoter region of MCP-1 is present in 50% of individuals susceptible to TB. This genotype produces this trait by a mechanism that may involve increased production of MCP-l and MCP-l inhibition of IL-12 production through the down-modulation of Osteopontin (Opn) receptor alphaVbeta33 in macrophages. In specific aim 1, we seek to confirm the association of the genotype GG with susceptibility to TB in a two-step case/control and a family study with parental samples of affected individuals and a TDT (TransmissionDisequilibrium Test). The sample for the case/control studies will comprise a large and rigorously characterized group of unrelated individuals with active TB and controls. Plasma samples from these individuals will be used to determine the levels of MCP-l, IL-12, IL-10, IFN-gamma and Opn to uncover the effect of MCP-l on the levels of these factors. With the same purpose, PBMC from a limited number (20 of each genotype) of these fully typed TB cases and controls will be stimulated in vitro with Mtb antigens and the levels of factors mentioned above measured. In specific aim 2, we will extend our preliminary studies to characterize in vitro the effect of MCP-l in alphaVbeta33 and CD44 Opn receptors, CD14 and TLR-2, and CD40 and CD154 expression and its relevance in the modulation of IL-12, MCP-l, IL-10, and Opn production in response to Mtb antigens. We also seek to determine if alphaVbeta3/CD44, CD14/TLR-2, and CD40/CD154 have additive effects in the induction of IL-12, and how they interact to modulate each other, and how MCP-l affects these pathways and these pathways interaction. In specific aim 3, we will explore in vitro how mycobacterial infection affects the production of MCP-l, IL-12, IL-10, and Opn and the expression of alphaVbeta3, CD44, CD14, TLR-2, CD40 and CD154. To achieve our goals in specific aim 1, Dr. Julio Granados, Chairman Investigator, Dept. Immunology, Mexican Institute of Nutrition, will be our consultant and collaborator. He and Dr. Moises Selman, from the Mexican Institute of Respiratory Diseases will recruit the TB cases and controls, process blood samples to isolate DNA, plasma, and PBMC. The PBMC will be stimulated in vitro in Dr. Granados' laboratory. The DNA samples will be sent to Boston where they will be typed. The plasma samples and culture supernatants will be kept frozen until we pick
Studies 85
them up (twice a year) and bring them to Boston in vaporize-liquid nitrogen tanks for further analysis. For specific aims 2 and 3, we will use leukophoresis products from fully type- selected individuals of a panel of 200 healthy donors residents in Boston. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM BASED INHIBITION OF M TUBERCULOSIS ENZYMES Principal Investigator & Institution: Blanchard, John S. Professor; Biochemistry; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 31-AUG-2007 Summary: (provided by applicant): Bacterial resistance to antibiotics is a clinically significant problem that threatens current paradigms of antibacterial chemotherapy. This is particularly true for the treatment of tuberculosis, where singly- and multiplydrug resistant clinical strains of Mycobacterium tuberculosis have been identified with increasing frequency. Very few compounds are selective antimycobacterial agents, and mycobacteria are intrinsically resistant to many antibiotics either because of the constitutive expression of degrading enzymes (e.g., Beta-lactamases) or the inability of antibiotics to penetrate the uniquely hydrophobic outer cell wall. The principal investigator and his group have previously focused their attention on the DAP/L-lysine biosynthetic pathway, and will use similar approaches to explore the three-dimensional structures and chemical mechanisms of M. tuberculosis enzymes involved in the biosynthesis of pantothenate, a vitamin in mammals, and an essential pathway in M. tuberculosis. Specifically, they will clone, express and purify the M. tuberculosis ilvGM, ilvC and ilvD gene products involved in branched chain and pantothenate biosynthesis, and the panB gene product involved in pantothenate biosynthesis. They will clone, express and purify the M. tuberculosis dxs- and dxr-encoded deoxyxylulose5-phosphate synthase and isomeroreductase for mechanistic comparison to the ilvCand ilvGM-encoded enzymes. They will also determine the structures and chemical mechanisms of aminoglycoside N-acetyltransferases, enzymes that are primarily responsible for clinical resistance to aminoglycosides in both Gram-negative and Grampositive bacterial pathogens. These enzymes catalyze a rich variety of chemistries, and plausible chemical mechanisms suggest that mechanism-based, and bi- and tri-substrate analogue inhibitors might be found. They will continue to use an integrated approach involving kinetic and chemical mechanism studies, three-dimensional structural studies, and site-directed mutagenesis to identify active site residues important for substrate and inhibitor recognition, and fulfill their long term goal of characterizing unique bacterial multi-step biosynthetic pathways that are absent in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: METABOLOME OF NON-REPLICATING M. TUBERCULOSIS Principal Investigator & Institution: Pauli, Guido F. Inst for Tuberculosis Research; University of Illinois at Chicago 1737 West Polk Street Chicago, IL 60612 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): It is now generally accepted that new drugs are needed to make global tuberculosis control a reality. The completion of the sequence of the M. tuberculosis genome has laid the foundation for greatly accelerating new drug discovery. While a limited number of studies of the TB transcriptome and proteome have been reported, these global macromolecular analyses are still not able to contribute directly to drug discovery except where gene/protein function are known or protein
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crystal structures are available. Elucidating the full complement of low molecular weight compounds in an organism -the metabolome - is becoming recognized as a complementary and perhaps the most tractable approach to a comprehensive understanding of any pathogen including the insight necessary for rational drug discovery. This R-21 proposal seeks to define the metabolome of the tubercle bacillus in the stage of non-replicating persistence (NRP), the physiological state considered to be responsible for the required long treatment duration for TB. The metabolome will be elucidated by high-resolution chromatography (CCC, LC) and -spectroscopy (MS, NMR). Initial studies will utilize a high biomass of BCG to evaluate several separation schemes in optimizing the resolution of (secondary) metabolites. This protocol will then be used to define the metabolome of M. tuberculosis in NRP. Subsequent experiments will focus on understanding the growth-phase specificity of unique metabolites produced under NRP. The information obtained will not only complement the extensive knowledge of the chemistry of the cell wall but is also expected to I) identify novel secondary metabolites possibly related to those recently described for other mycobacteria, 2) help to clarify events and identify low MW markers during the metabolic shift to a low oxygen environment especially considering that >70% of genes up-regulated during this adaptation are of unknown function, 3) provide leads for drug development through analoging around TB-specific compounds not known to occur in mammalian cells and 4) assist in the understanding of the mechanism of action of newly discovered anti-TB agents. The operating hypothesis for this study is that elucidating the metabolome of Mycobacterium tuberculosis will overcome limitations inherent in global macromolecular analyses with respect to gaining key insights into dormancy and drug discovery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MHC TUBERCULOSIS
CLASS
1
MOLECULES
IN
IMMUNITY
AGAINST
Principal Investigator & Institution: Urdahl, Kevin B. Pediatrics; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-APR-2006 Summary: (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Pediatric Infectious Diseases. The principal investigator has completed residency training in Pediatrics at the University of Washington and is currently in his final year of fellowship training in Infectious Diseases at the same institution. This program will expand upon his current scientific skills, and promote new skills that will enhance his career development. Specifically, this program promotes the development of a career studying the immune response to tuberculosis. Dr. Michael Bevan will mentor the principal investigator's scientific development. Dr. Bevan is a Professor of Immunology, a Howard Hughes Medical Institute Investigator, and a world-renowned leader in the field of immunology. He has trained numerous postdoctoral fellows and graduate students who themselves have become recognized leaders in their fields. In recognition of this outstanding record, Dr. Bevan received the Excellence in Mentoring Award from The American Association of Immunologists in 2000. To enhance the training, the program will enlist the expertise of Dr. David Sherman, Assistant Professor of Pathobiology. Dr. Sherman is a molecular microbiologist with considerable experience with genetic manipulation of Mycobacterium tuberculosis (Mtb). In addition, an advisory committee of highly regarded scientists will provide scientific and career advice. Research will focus on understanding the roles of CD8+ T cells and MHC class I molecules in immune
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protection against tuberculosis. To approach these issues, a new system to monitor the activity of T cells specific for Mtb-derived antigens after aerosol infection of mice with M. tuberculosis will be established. This system will enable some of the most fundamental questions in the immunology of tuberculosis to be addressed with greater precision than is possible using currently available tools. The specific aims include: 1) Determining the locations, phenotypes, and functions of CD4+ and CD8+ T cells specific for an Mtb-derived antigen after aerosol infection of mice, 2) Determining the roles of CD4+ vs. CD8+ T cells specific for an Mtb-derived antigen in immunity against tuberculosis, and 3) determining the role of MHC class I molecules in regulating immune processes involved in protection against tuberculosis. In addition to providing important information about tuberculosis, these experiments will shed light on basic immune mechanisms that regulate host defense. The Division of Infectious Disease in the Department of Pediatrics at the University of Washington provides an ideal setting for training physician-scientists by advocating scientific exploration within any laboratory of the university. The training program described in this proposal, which draws on several interdepartmental collaborations, will establish a scientific niche for the principal investigator that will position him uniquely for a successful academic career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOGENS
MICROMACHINED
BIOSENSOR
FOR
MYCOBACTERIAL
Principal Investigator & Institution: Wavering, Thomas A.; Luna Innovations, Inc. 2851 Commerce St Blacksburg, VA 24060 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-JUL-2003 Summary: (Provided by applicant): Mycobacteria are slender, nonmotile, gram-positive rods and do not produce spores or capsules. Nineteen Mycobacterium species are associated with disease in humans. The most dangerous of these diseases is tuberculosis, caused by infection with M. tuberculosis. Tuberculosis kills about 2 million people annually and infects another 8 million people each year. Treatment and diagnosis of the disease is complicated by current laboratory methods that can take from four to six weeks to establish a definitive identification of infection. New diagnostic systems are needed for earlier detection of tuberculosis, to better monitor the treatment of tuberculosis, and to study the epidemiology of the disease. Luna Innovations has assembled a team of researchers to develop a micromachined biosensor array that combines technology from silicon micromachining, optical fiber sensors, and biochemistry for measurement of mycobacterial pathogens. The sensing element of the biosensor array will be a microcantilever beam coated on one side with receptors. As pathogens bind to the coated beam, a biochemical induced surface stress causes the beam to deflect proportionally to concentration. The Phase I program will focus on developing the microcantilever biosensor array, demonstrating detection of mycobacterial pathogens in neat solutions, and comparing performance to known standards. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODE OF ACTION OF PYRAZINAMIDE IN TUBERCLE BACILLUS Principal Investigator & Institution: Zhang, Ying E. Associate Professor; Molecular Microbiol and Immun; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218
88 Tuberculosis
Timing: Fiscal Year 2001; Project Start 01-DEC-1998; Project End 30-NOV-2003 Summary: (Adapted from the applicant's abstract): The long-term goal of this project is to improve our understanding of mechanisms of drug action and drug resistance in Mycobacterium tuberculosis and to provide knowledge important for designing new tuberculosis (TB) drugs. Two significant problems seriously compromise our ability to effectively control TB: the emergence of drug-resistant strains, and the lengthy 6 month TB chemotherapy. There is an urgent need to develop new TB drugs that are effective in both aspects. Pyrazinamide (PZA) is a paradoxical front-line TB drug, because while PZA has powerful in vivo sterilizing activity, through killing a population of semidormant organisms, and is thus involved in shortening the TB therapy to 6 month; PZA has no activity in vitro against M. tuberculosis under normal culture conditions except under acid pH (5.5). The mode of action of PZA in M. tuberculosis is unknown, and this project proposes to address this issue. The specific aims of the project are: (1) To determine the effect of pyrazinoic acid (POA), the active form of PZA, on membrane integrity and nutrient transport of M. tuberculosis. (2) To test the potential inhibition of POA on the NAD metabolism in M. tuberculosis. (3) To identify and characterize the efflux genes involved in pumping POA out of the mycobacteria. The health relatedness of this project lies in the possible design of new antituberculous drugs that may further shorten the current 6 month TB chemotherapy based on understanding the mode of action of PZA. The investigators hypothesize that POA as a lipophilic weak acid will partition into the lipid-rich membrane of M. tuberculosis and cause structural and functional damage to the membrane. This hypothesis will be tested in Aim I by EM analysis, by measuring the nutrient transport using radiolabeled amino acids, uracil and thymidine, and by measuring the possible effect of POA on the membrane potential. Because of structural similarity of POA to niacin, they hypothesize that POA may interfere with NAD metabolism in M. tuberculosis by feedback inhibition of NAD biosynthesis and by incorporation as a pseudo-NAD molecule without NAD function. This hypothesis will be tested in Aim 2 by using C 14-labeled precursors of NAD and by tracing C 14-POA in NAD molecule by mass spec and NMR analyses. Because they found the activity of efflux pumps extruding POA in various mycobacteria varies widely and correlates with their susceptibility to PZA, they propose to identify the POA efflux genes by testing putative efflux genes in the Sanger Centre M. tuberculosis genome database and by testing mycobacterial genomic DNA libraries for their ability to confer PZA resistance in M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR BEACONS FOR TUBERCULOSIS TESTING Principal Investigator & Institution: Meserol, Peter; Synectiq Corporation 66 Ford Rd, Ste 123 Denville, NJ 07834 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: Genome sequencing technologies have begun a revolution in the diagnosis of human diseases, and infections, and in the characterization of microbes. Specific mutations linked to cancer, metabolic disorders, as well as bacterial and viral drug resistance are often as small as a single nucleotide polymorphism (SNP). Unfortunately, DNA microarrays and the current generation of nucleic acid-amplification based techniques under development for the detection of SNPs and other genetic polymorphisms are technically complex and expensive. These factors are likely to limit the widespread availability of genetic testing. We have pioneered a simple, rapid, and robust method for DNA sequence identification and SNP analysis that uses new types of fluorescent probes called molecular beacons. Molecular beacons can be used to develop
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highly accurate and inexpensive polymerase chain reaction (PCR) assays, but these assays have been limited by the requirement for costly and complex detection instruments. Molecular beacons are ideally suited for use in assays that take maximum advantage of advances in polymer microfabrication technology, cooled CCD imaging systems, ink jet directed microprinting, and advanced image processing software modules. This proposal will develop inexpensive desktop systems and assays for genetic diagnosis and SNP detection. It will concentrate on developing urgently needed assays to simultaneously diagnose Mycobacterium tuberculosis, and detect drug resistance directly from clinical samples. The ultimate goal of this proposal is to design systems and applications that are sufficiently robust and inexpensive to be used virtually anywhere, to address a wide variety of diseases. PROPOSED COMMERCIAL APPLICATIONS: 2.1 Billion people harbor a TB infection. UNICEF reports that tuberculosis poses a serious risk to Asia's sustained socioeconomic development: In a recent National Intelligence Estimate, the Central Intelligence Agency singled out drugresistant TB - and especially its incidence among immigrants - as a potential threat to national security. Salomon and Murray report that world expenditure on TB therapy and diagnosis was $4.1 Billion (USD) in 1998. Diagnosis of TB worldwide is by sputum smear, with 50% accuracy. This new diagnostic is desperately needed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR BIOLOGY OF INFECTION WITH M TUBERCULOSIS Principal Investigator & Institution: Riley, Lee W. Professor of Infectious Diseases and Epi; Public Hlth Bio & Epidemiology; University of California Berkeley Berkeley, CA 94720 Timing: Fiscal Year 2001; Project Start 30-SEP-1993; Project End 30-JUN-2003 Summary: (Adapted from the Applicant's Abstract): Little is known about the bacterial Factors that contribute to pathogenesis of TB. However, during year 01-02 of AI-35266, the PI identified and characterized a recombinant protein encoded by M. tuberculosis that promoted uptake of latex microspheres coated with the protein into nonphagocytic cells. Subsequently (Year 03), this 27 kDa protein was discovered to be a truncated version of a native 45 kDa surface protein of M. tuberculosis encoded by a 1239-bp gene designated as mceA. The 45 kDa protein is referred to as mycobacterium cell entry protein or Mcep (the truncated protein is designated Mcep1). Reagents that affect cytoskeletal rearrangement (cytochalasin D, nocodazole, and onodansylcadaverine) inhibited the association with HeLa cells of microspheres coated with Mcep1. In addition, Mcep 1 inhibited Fc-receptor mediated oxidative burst in murine macrophage J774. A highly basic 22-amino region near the N-terminus of Mcep1 was found to be the cell uptake active domain. From the recently completed genome sequence of M. tuberculosis, the mceA locus was found to be part of a cluster of at least 15 open reading frames (ORF), 4 of which encoded a possible membrane-spanning lipoprotein, all located downstream of an ORF resembling the E. coli nta operon transcriptional regulator. The new proposal will have three specific aims. The first aim will continue the analysis of the structure and function of Mcep and its physiologic relevance to M. tuberculosis pathogenesis, focusing on characterizing the role of Mcep on inhibition of oxidative burst in macrophages and cytoskeletal rearrangement in nonphagocytic cells. The physiologic relevance of Mcep will be studied by the analysis of M. tuberculosis disrupted in mceA. The second aim will analyze the genes that cluster around the mceA locus. This aim will determine whether any of these genes constitutes part of a secretion system for the surface-expressed Mcep, and whether any of them regulates the expression of Mcep during and after entry into cells. The third aim will seek to
90 Tuberculosis
determine whether there is a specific receptor on mammalian cells for Mcep, and, if so, its function in relation to Mcep- mediated pathogenesis. It is hoped that these studies will determine whether Mcep constitutes a virulence factor of M. tuberculosis. At the same time, they may reveal new insight into how a possible effector molecule in mycobacteria is delivered to the surface through plasma membrane and the lipid-rich cell wall layer. In addition, these studies may identify several potential targets for new chemotherapeutic agents or vaccine candidates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR BIOLOGY OF MYCOBACTERIA AND THEIR PHAGES Principal Investigator & Institution: Hatfull, Graham F. Professor; Biological Sciences; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 01-DEC-1989; Project End 30-JUN-2005 Summary: (provided by the applicant): Mycobacterium tuberculosis, the causative agent of human tuberculosis, kills more people than any other single infectious agent. The prevalence of TB is greatest in the developing world but its control in the United States has become severely complicated by the appearance of multidrug resistant strains of M. tuberculosis. There has recently been a sharp increase in the incidence of these MDRTB strains in developing countries. Effective control of tuberculosis requires improved and more rapid diagnostic methods, more efficacious vaccines, and better antimycobacterial drugs, particularly for treatment of multidrug resistant infections. With the recent advances in mycobacterial genetics and the determination of the complete genome sequence of M. tuberculosis, there is now renewed hope that a more sophisticated understanding of the physiology, genetics, and metabolism of M. tuberculosis will lead to novel strategies for controlling mycobacterial infections. Unfortunately, in spite of these genetic tools and genomic information, we know little about the molecular basis of the fundamental aspects of mycobacterial physiology-such as slow growth, their unique cell wall, and DNA replication-let alone the molecular basis of mycobacterial pathogenesis. Viruses are powerful tools for genetic analysis of a broad range of organisms, and the viruses of mycobacteria (mycobacteriophages) are no exception. The use of mycobacteriophages was instrumental in the establishment of mycobacterial genetics and the creation of cloning vectors for the introduction of DNA into mycobacteria. More recently, recombinant reporter mycobacteriophages have been proposed as clinical tools for rapid determination of drug susceptibilities of clinical isolates of M. tuberculosis. This project aims at understanding the intimate interface between mycobacteriophages and their hosts. This interaction begins with the association of free phage particles with bacterial cells followed by injection of phage DNA into the cell. Phage DNA may then either integrate into the host genome and be genetically silenced, or reprogram the cell to direct it towards phage gene expression and subsequent cell lysis. By exploring these events we will gain insights into the regulation of gene expression, the structure of the mycobacterial envelope, and the process of phage-mediated cell lysis. We will also use proteomic approaches to understand the influence of phage gene expression on that of its host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: MOLECULAR TRANSMISSION
VS.
CONVENTIONAL
ASSESMENT
OF
TB
Principal Investigator & Institution: De Riemer, Kathy; Medicine; Stanford University Stanford, CA 94305
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Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: An estimated one third of the world's population is infected with Mycobacterium tuberculosis, and it is the leading cause of death among adults by an infectious disease worldwide. TB control using DOTS (Directly Observed Short Therapy, short course) to successfully diagnose, treat and follow sputum-smear positive TB cases is a priority of the World Health Organization (WHO), but there is growing recognition that DOTS alone will not be enough to control or eradicate TB given the extended duration of treatment and the emergence of drug-resistant forms of M. tuberculosis. New methods are needed to quantify the impact of ongoing TB transmission and the importance of preventive strategies. The focus of this research will be an evaluation of community- based TB transmission dynamics at a field site in Southern Mexico. Molecular epidemiology provides important insights into the transmission dynamics of tuberculosis, but because it relies upon mycobacterial cultures, it can only track active cases. The proposed research will integrate conventional tuberculin skin test survey methodology into an ongoing population-based research project so that we may track infection as well as disease and test hypotheses about alternative strategies for controlling TB infection. The specific aims are: 1) to describe the epidemiology of TB infection caused by culture-confirmed cases of M. tuberculosis; 2) to identify risk factors for TB infection, stratified by the biologic characteristics of the strains of M. tuberculosis and the gender, age group, and social setting of the index cases; 3) to determine the specificity and predictive value of contact tracing by comparing the RFLP patterns of cases and those arising among their contacts; and 4) to develop cost- effectiveness models of appropriate screening strategies and interventions to control TB infection. The research will also generate important baseline data for the future testing of new diagnostics and vaccines. This project will provide an ideal vehicle for additional, mentored training and research to develop the PI's long standing career interest in international infectious disease research. The grant award will build on previous work and provide training in areas new to the candidate, such as biomedical techniques and cost-effectiveness modeling. Her technical training in epidemiology and biostatistics, prior epidemiologic research studies, and extensive familiarity with Latin America fit perfectly with the strengths and needs of a well established field site in Veracruz, Southern Mexico. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR-GENETIC ANALYSIS OF TB PERSISTENCE AND LATENCY Principal Investigator & Institution: Mckinney, John D. Assistant Professor; Lab/Infection Biology; Rockefeller University New York, NY 100216399 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Tuberculosis (TB) is rivaled only by AIDS as a communicable cause of death. Infection is lifelong and may reactivate following an asymptomatic (latent) interval of variable duration. It is estimated that nearly two billion individuals worldwide have been exposed to Mycobacterium tuberculosis. Exposed (tuberculin-positive) individuals have a 5-10% lifetime risk of developing active TB. The risk rises to nearly 10% per year for individuals with HIV/AIDS, indicating a key role for the host immune response in maintaining TB latency. Chemoprophylaxis of latent TB to prevent reactivation requires months of drug therapy, a regimen that many individuals are unwilling or unable to complete. The development of better tools for TB control will hinge on the elucidation of the adaptive mechanisms that allow latent M. tuberculosis to persist in the face of host immunity and
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chemotherapy. Towards that goal, this application is focused on the identification of mycobacterial "persistence factors" and "defense factors" via signature-tagged mutagenesis (STM), a method for simultaneous screening of multiple mutants in mice. Two genetic screens are described. The persistence (per) screen will identify M. tuberculosis mutants that are specifically impaired in their ability to persist at later stages of infection in mice. The defense (def) screen will identify mutants whose attenuated phenotype in immune-competent mice is reversed in mice with specific immune deficiencies. These screens will identify mycobacterial genes involved in longterm persistence and defense against host immune mechanisms, respectively. The role of these genes in latent persistence will be assessed in the "Cornell model" of chemotherapy-induced latency and reactivation in mice. Our studies in the mouse will serve as a springboard for linked studies in humans. Relevance to human infection will be explored by analyzing the expression of per/def genes in the lungs of mice and humans via real-time RT-PCR with molecular beacons. Bacterial correlates of protection and pathogenesis will be identified by comparison of gene expression profiles in latent v. active human lesions, respectively. These studies will elucidate the host/pathogen interactions that determine the state of infection-latency or active disease-and may point the way to novel interventions against TB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MONOCYTE RECRUITMENT IN PLEUROPULMONARY TB IN AIDS Principal Investigator & Institution: Antony, Veena B. Professor; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2001; Project Start 01-FEB-1996; Project End 31-JAN-2006 Summary: Tuberculosis is endemic among patients with AIDS and follows an aggressive course with poor localization of mycobacteria into granuloma and widespread infection. Granulomas are monocyte rich collections of cells which derive from the circulating peripheral blood monocyte (PBMC). Monocytes are recruited to the site of tuberculous infection by the interaction of C-C chemokines, (mainly monocyte chemoattractant protein-1, MCP- 1) and monocyte expression of the CCR2 receptor. It is the hypothesis of this proposal that recruitment and retention of the monocyte at the site of tuberculous infection is predicated not only on local release of MCP-1 but on the expression of CCR2 receptor on PBMC. CD4 depletion alters monocyte recruitment and retention by altering the in vivo expression of CCR2 on PBMC and macrophages. This inhibitory effect of CD4 depletion is due to the relative imbalance between Thi and Th2 cytokines. We have developed a model of pleural tuberculosis in CD4 -1- and CD4 +/+ mice to evaluate the Th1/Th2 regulation of the CCR2 receptor on PBMC. We will evaluate our hypothesis in our model of pleural tuberculosis in vivo as well as in vitro in PBMC and elicited pleural macrophages (PM). Our specific aims are 1) To determine the in vivo moncyte influx, granulonia formation, mycobacterial clearance and mortality utilizing our model of pleural tuberculosis in a CD4 knockout mouse model, CD4 -/mice and control, wild type CD4 +1+/- mice. 2) To determine the in vivo effect of CD4 depletion on the compartmentalized and peripheral expression of CCR2 receptor on PBMC and PM and the regulatory role of Th1 (IL2, IL-12) and Th2 (11-10, JL-4) cytokines inCD4 -/- and CD 4 +/+ mice with pleural tuberculosis. 3) To determine the in vitro molecular and cellular regulation of CCR2 expression in PBMC and PM in the presence of Th1 and Th2 cytokines and 4) To determine the role of tubercie bacilli stimulated pleural mesothelial cell derived cytokines in the regulation of CCR2 receoptor on peripheral blood monocytes (PBMC) and pleural niacrophages (PM) in vivo and in
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vitro. Understanding the mechanism of regulation of CCR2 receptor by Th1 and Th2 cytokines may help us discern the pathophysiology of pleuro-pulmonary tuberculosis seen in patients with AIDS and may help develop therapeutic modalities that augment host-defense responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYCOBACTERIAL MACROPHAGES
CELL
WALL
RECOGNITION
BY
Principal Investigator & Institution: Smith, Kelly D. Pathology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2003 Summary: Mycobacterium tuberculosis is a leading cause of death by infectious disease in the world. Mycobacterial cell wall components are potent stimulators of the immune system, and have long been as adjuvants. The host systems that recognize these components are poorly defined, but several studies implicate CD14, a component of LPS recognition pathway that utilizes Toll- like receptor-4 (TLR4). TLRs appear to be early and important inducers of tumor necrosis factor-alpha (TNFalpha). TNFalpha is a critical factor for protective immunity to tuberculosis. We hypothesize that innate recognition of mycobacterial cell wall components by TLRs is important for host defense. TLRs have a signaling pathway that has similarities to the IL-1 receptor pathway, and include MyD88 as a proximal component. Using murine macrophage cell line RAW 264.7, we have identified three cell wall fractions that stimulate MyD88dependent TNFalpha production. This implies TLR-dependent recognition of mycobacterial cell wall components. The mechanism of stimulatory ligand recognition by TLRs is unknown and may require direct or indirect involvement of CD14. Phagocytosis of mycobacterium involves another set of receptors including the complement and mannose receptors. Complement opsonization increases the infectivity of mycobacteria in vitro. In addition, phagocytic receptors recognize mycobacterium and potentially activate an overlapping set of signaling pathways. This suggests that cross- talk may exist between phagocytic and inflammatory signaling pathways. The aims of this proposal are to 1) identify the specific mycobacterial cell wall components recognized by TLRs, 2) identify the corresponding receptors that are responsible for MyD88-dependent recognition of mycobacteria, 3) characterize mycobacterial cell wall ligand-recognition by TLRs, and 4) characterize the consequences of complement opsonization and TLR- dependent recognition on phagocytosis of mycobacteria. Understanding the innate recognition of mycobacteria will greatly advance our understanding of tuberculosis, point to possible sites of host genetic variation that alter responses to M. tuberculosis, and disclose fundamental principles of innate immunity in infectious and inflammatory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYCOBACTERIAL TRANSMISSION
DETERMINANTS
OF
CAVITATION
&
Principal Investigator & Institution: De Jong, Bouke C. Medicine; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2002; Project Start 18-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Dr. de Jong has prior international research experience and recently completed her clinical training in infectious diseases at Stanford University. In order to foster her transition into an international research scientist, she
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now proposes to combine didactic training in epidemiology with a hypothesis driven project designed to better understand the determinants of tuberculosis transmission. This work will be conducted in a well-established research setting in the Gambia and mentored by faculty with complementary expertise. Over three consecutive summers she will obtain a Masters degree in epidemiology at the Netherlands Institute for Health Sciences. This curriculum provides a comprehensive survey of the principles and practices of epidemiologic research and is specifically structured to be spread over this period and integrated with an independent research project. The research project that she will pursue tests the hypothesis that genetic differences between mycobacterial strains contribute to variable rates of pulmonary cavitation and person- to- person transmission. It is well established that host and environmental factors greatly impact the clinical manifestations and consequences of infection with M. tuberculosis. However, little is known about the consequences of differences between mycobacterial strains. The combination of expertise the candidate has gained to date working in a molecular epidemiology laboratory and the clinical epidemiologic lessons that she will learn in the classroom will provide her the opportunity to formally address this issue in the field. Specifically, she will spend at least two years in The Gambia quantifying the propensity of clinical isolates of M. tuberculosis to cause cavitation and be transmitted to household contacts. Subsequently, at Stanford University, she will use a DNA microarray based comparative genomic approach to seek genetic correlates of these bacterial propensities. While it would be presumptuous to promise that these activities will have a major impact on the global burden of tuberculosis, it is likely that the proposed project will serve as a vehicle for her transition into an independent physician scientist focused on international translational clinical investigation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYCOBACTERIAL GENES THAT ENHANCE INTRACELLULAR GROWTH Principal Investigator & Institution: Lakey, David L. Nursing; University of Texas Hlth Ctr at Tyler 11937 Us Highway 271 Tyler, TX 75708 Timing: Fiscal Year 2001; Project Start 18-APR-2000; Project End 30-JUN-2001 Summary: Dr. David Lakey completed a Pediatric and Adult Infectious Diseases fellowship at Vanderbilt University Medical Center. He spent 2 years in Dr. Douglas Kernodle's laboratory, studying expression of mycobacterial genes in E. coli. Dr. Lakey received 1 of only 3 fellowships awarded by the Pediatric Infectious Disease Society and was the 1998 Grant Liddle Scholar, given to the best research fellow in the Vanderbilt University Department of Medicine. Dr. Lakey has a superb grasp of molecular microbiology. His ability to think independently, use novel approaches to solve problems, and interact with other scientists make him an excellent candidate for a career in biomedical research. The UT Health Center at Tyler has a long-term commitment to excellence in tuberculosis research, and 5 NIH-funded investigators there are currently engaged in research in mycobacterial disease. The institution is committed to Dr. Lakey's career development and has provided him with a fully equipped laboratory and support staff. Dr. Peter Barnes, an accomplished investigator in tuberculosis, will serve as Dr. Lakey's mentor, and an Advisory Committee of 6 other experienced scientists will provide guidance to Dr. Lakey. Dr. Lakey will devote 90 percent effort to this proposal. The research project is to identify genes of M. tuberculosis that contribute to enhanced mycobacterial growth in macrophages. This information will facilitate development of attenuated M. tuberculosis strains as vaccines, as well as design of drugs for treatment and prevention of tuberculosis. Our specific aims are: 1) To establish methods to
Studies 95
quantitate mRNA expression of intracellular mycobacteria, using competitive RT-PCR; 2) To evaluate differential gene expression of laboratory and clinical M. tuberculosis strains during intracellular growth, using competitive RT-PCR, differential display-PCR and mycobacterial microarrays. We will identify genes that are differentially expressed by M. tuberculosis strains that grow at different rates in macrophages; 3) To determine the functional effects of differentially expressed genes identified in aim 2 on intracellular mycobacterial growth. Candidate mycobacterial genes associated with rapid intracellular growth will be expressed by E. coli and by M. tuberculosis H37Ra to assess their effects on intracellular growth. In addition to this research project, Dr. Lakey will take didactic courses offered by the Master's Program in Biotechnology, and participate in other educational activities within and outside of the institution. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYCOBACTERIAL GENES, ANTIGENS, AND VACCINES Principal Investigator & Institution: Bloom, Barry R. Dean; Immunology/Infections Diseases; Harvard University (Sch of Public Hlth) Public Health Campus Boston, MA 02460 Timing: Fiscal Year 2001; Project Start 01-APR-1986; Project End 31-MAY-2006 Summary: (provided by the applicant): Tuberculosis and HIV/AIDS represent the major infectious causes of death in the world, and tuberculosis (TB) is the attributable cause of death in a third of AIDS patients in Africa. Drug resistance to TB is emerging in Europe and Asia, drug treatment regimens are long and expensive and compliance is limited. For these reasons, we propose to bring a multidisciplinary approach, joining molecular genetics and immunology, to developing safe and effective live attenuated vaccines against TB. Since peak age of disease is 15-25y, we believe a live attenuated vaccine that induces long enduring immunological memory will provide the most useful protection against disease. In previous work we have developed tools to genetically manipulate slow growing mycobacteria, including the capability of creating specific deletion mutants to attenuate virulent M tuberculosis. One aim is to test the hypothesis that M tuberculosis represents a better vaccine candidate than BCG, to create and test auxotrophic mutants, growth mutants and persistence mutants of M. tuberculosis for safety and immunogenicity in mice. A second is to determine the optimal duration of growth of vaccine strains in vivo for the development of immunological memory responses, particularly through the use of regulated promoters. This will also allow us to elucidate similar requirements for producing tissue damage. Our final aim remains to understand the immunological mechanisms of protection against experimental tuberculosis, particularly exploring the role of innate responses mediated by the Toll-like receptor family, the minimum epitope and antigen requirements for protection, and the possible role of cytotoxic T-lymphocytes (CTL) in protection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: MYCOBACTERIAL SULFATION PATHWAYS Principal Investigator & Institution: Bertozzi, Carolyn R. Professor; Chemistry; University of California Berkeley Berkeley, CA 94720 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 30-MAR-2006 Summary: (provided by applicant): Sulfated are central mediators of extracellular traffic and cell-cell communication in humans. The enzymes that install and remove sulfate esters, sulfotransferases and sulfatases, respectively, are now appreciated as major
96 Tuberculosis
contributors to human health and disease. By contrast, the roles of sulfated sugars and the associated enzymes in bacteria remain relatively unexplored. Mycobacterial pathogens have been declared a global emergency by the World Health Organization, particularly in regard to the deadly synergy of Mycobacterium tuberculosis with AIDS, but also due to the emergence of drug-resistant strains. In Mycobacteria, several sulfated molecules have been identified. These include a sulfated glycolipid, SL- 1 that has been implicated as a virulence factor for M. tuberculosis. Another sulfated carbohydrate, part of a glycopeptidolipid, has been detected in a drug resistant strain of M. aviurn isolated from an AIDS patient. Recently, the complete genome sequences of M. tuberculosis, M. avium, and M. smegmatis have become available, enabling the search for genes that participate in sulfation pathways. We have identified an extensive family of sulfotransferases and sulfatases from the completed genomes of these three Mycobacteria. The enzymes may be critical determinants of Mycobacterial virulence and potential targets for anti-Mycobacterial therapy. Through a collaborative effort, our laboratories (Prof. Carolyn Bertozzi and Prof. Lee Riley, UC Berkeley) have initiated a program aimed at the genetic and biochemical characterization, and small molecule inhibition of the sulfotransferases from M. tuberculosis and M. smegmatis. In addition, we have identified several sulfatases that have considerable similarity to mammalian carbohydrate sulfatases, suggesting a role for these enzymes in host/pathogen interactions. Finally, in order to define the sulfur incorporation pathways of Mycobacteria, we have begun the characterization of enzymes involved in the early stages of cysteine biosynthesis. The aims of this proposal are threefold: (1) to determine the functions of the carbohydrate sulfotransferases in M. tuberculosis and M. smegmatis using genetic, biochemical and chemical approaches; (2) to investigate the involvement of bacterial sulfatases in host/pathogen interactions; and (3) to define the sulfur assimilation pathway of M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TUBERCULOSIS
MYCOBACTERIOPHANGE
INTERACTION
WITH
M
Principal Investigator & Institution: Riska, Paul F. Medicine; Suny Downstate Medical Center 450 Clarkson Ave New York, NY 11203 Timing: Fiscal Year 2001; Project Start 15-JUL-1998; Project End 30-JUN-2003 Summary: This training program is designed so that the investigator-candidate can develop the necessary skills to become an independent physician- scientist. The program builds on the skills and interests attained in the previous three years of a postdoctoral training position, during which the candidate adapted a novel molecular genetic tool for application in the clinical realm. Specifically, mycobaceriophages, viruses which infect Mycobacterium spp. including M. tuberculosis, were designed to express a reporter gene encoding the firefly light-emitting enzyme luciferase upon infection of a viable mycobacterium. This technology, which can be used to rapidly detect M. tuberculosis as well as determine its drug susceptibilities, is much needed to combat the resurgence of tuberculosis associated with the AIDS epidemic. The current application aims to investigate the genetic mechanisms underlying this technology in order to facilitate rational improvements in the systems's performance, while solidifying the candidates facility in the techniques of molecular genetics. The specific aims are to identify phage and host factors which influence the efficiency of the detection scheme. Specifically, the virus has certain features--its lytic phenotype and its shutdown of host protein synthesis which are unfavorable in its adopted role as a producer of receptor genes, yet are required for its effective propagation as a reagent. Cloning the
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determinants of these two processes will allow their rational regulation. The mycobacterial receptor for phage is an important parameter for both sensitivity and specificity of phage infection; its expression should correlate with the spectrum and degree of infectability of related mycobacteria, some of which are nonpathogens. Knowledge of receptor regulation will help optimize the conditions for performing phage infections, and perhaps allow selective detection of pathogens. The results of this work will produce a superior diagnostic reagent with an extended range of applications, and will likely provide valuable information in the biology of mycobacteriophage and mycobacteria. At the conclusion of the training period, the candidate investigator will have had extensive exposure to the methods of microbiology and molecular biology, and the experience to establish an independent research program in an academic setting, with a close connection to clinical medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INITIATION
MYCOBACTERIUM
TUBERCULOSIS
AND
REPLICATION
Principal Investigator & Institution: Madiraju, Murty V. Associate Professor; Biochemistry; University of Texas Hlth Ctr at Tyler 11937 Us Highway 271 Tyler, TX 75708 Timing: Fiscal Year 2003; Project Start 01-AUG-1997; Project End 31-JAN-2008 Summary: (provided by applicant): Human tuberculosis caused by Mycobacterium tuberculosis is the most prevalent and deadly bacterial infectious disease worldwide. This problem is compounded by the emergence of strains of M. tuberculosis that are resistant to one or more anti-tuberculous drugs. Following initial infections, M. tuberculosis frequently enters a latent or dormant state for extended periods and subsequently, under appropriate conditions or following immune suppression, revives, multiplies and causes a secondary infection. DNA replication constitutes an important step in the exit from latency. The development of novel therapeutic agents to control M. tuberculosis infections in HIV infected patients as well as other individuals is severely hindered by our limited understanding of the initiation and regulation of M. tuberculosis DNA replication and its coordination with other events in cell cycle. Initiation of DNA replication is believed to be triggered when DnaA, the putative initiator protein, interacts with oriC or origin of replication. Although oriC is essential for survival, some clinical strains of M. tuberculosis appear to tolerate major deletions and IS6110 insertions in their oriC, thereby raising questions as to how these clinical strains replicate their genome. Our research proposal focuses on understanding the replication initiation process in M. tuberculosis. Specifically, we propose to inactivate oriC, dnaA individually and together by homologous recombination in an attempt to determine whether replication in M. tuberculosis can proceed from alternate origins, and if so whether dnaA function is required for such replication. The interactions of DnaA with replication origins and consequences of these interactions will be investigated using biochemical and genetic approaches. To begin identifying the factors that could potentially affect DnaA activity, a proteomic approach combining twodimensional gel electrophoretic separations of proteins with subsequent identification of protein spots by matrix-assisted laser ionization desorption/ionization mass spectrometry, will be used. Defining the molecular events involved in the initiation and regulation of replication is an essential prerequisite for developing defined systems for identifying novel antimycobacterial compounds, and thereby preventing the development of potentially lethal infections of M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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•
Project Title: MYCOBACTERIUM TUBERCULOSIS CELL WALL VIRULENCE FACTORS Principal Investigator & Institution: Dorman, Susan E. Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Tuberculosis (TB) kills approximately 3 million people per year. An important characteristic of M. tuberculosis is its ability to survive within human macrophages, and mycobacterial cell wall components are plausible mediators of this effect. However, little is known about the role of specific cell wall components in either mycobacterial survival within host macrophages or modulation of macrophage responses to mycobacterial infection. In our laboratory, the recent generation of a M. tuberculosis transposon-mediated mutant library provides a unique opportunity to systematically investigate these issues. Our overall objective is to understand the role of M. tuberculosis cell wall components in the pathogenesis of TB. Our hypothesis is that M. tuberculosis cell wall components modulate macrophage immune responses, and that alteration of the cell wall will affect macrophage responses to mycobacteria. The specific aim of this R03 proposal is to characterize human macrophage responses to a) infection with M. tuberculosis transposon-mediated mutants predicted to have alterations in the cell wall, and b)stimulation with cell wall fractions from those mutants. Mutants with disruptions in genes known or predicted to be involved in biosynthesis of sulfolipids, lipoarabinomannan, mycolic acids, and phthiocerol dimycocerosate will be used. Host cell cytokine production, chemokine production, apoptosis, IFN gamma-mediated responses, and toll-like receptor-mediated responses will be characterized, and mycobacterial survival and growth within macrophages will be determined. This research will lead to a better understanding of how mycobacterial cell wall components affect bacteria-host cell interactions, and will facilitate identification of new anti-tuberculosis drug targets and vaccine strategies. If cell wall components contribute to M. tuberculosis-induced immune suppression, then evaluation of appropriate mutant strains as vaccines would be warranted. These studies will also serve as a foundation for development of rapid in vitro screening systems to evaluate the effects of other M. tuberculosis genes or cellular components on targeted host immune responses. Finally, new information from the proposed self-contained pilot studies will serve as the foundation for future comprehensive dissection of macrophage response pathways affected by specific cell wall components. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MYCOBACTERIUM TUBERCULOSIS IN VIVO GENE EXPRESSION Principal Investigator & Institution: Graham, James E. Medicine; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001; Project Start 17-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) Mycobacterium tuberculosis is a pathogen that is able to adapt to a variety of different environments encountered during the progressive course of human infection. An ability to inhibit maturation of the macrophage phagosome initially created an ideal environment for bacterial growth, allowing colonization of the body. when deprived of this favorable environment by the hosts's own tissue-damaging immune response, infection often fails to progress, and bacilli enter an nonreplicating latent state, having reached a degree of equilibrium with the host. Changes in the host over time may then allow bacteria to resume replication, leading to further tissue destruction and extracellular growth to high titers. This project
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will identify bacterial genes that are specifically expressed by M. tuberculosis during adaptation to these in vivo environments. A new method developed specifically for examination of mycobacterial mRNAs expressed in infected host cells and tissues (SCOTS) has so far identified 9 M. tuberculosis genes which are expressed in response to growth within cultured human macrophage phagosomes. The first aim of the proposed work is to make bacterial strains specifically inhibited in expression of these genes and evaluate their ability to survive and grow in cultured human macrophages. The second aim is to identify additional M. tuberculosis genes that are differently expressed by tubercle bacilli in another environment that bacilli normally encounter during the natural course of human infection. Bacterial genomic array hybridization with cDNAs obtained by SCOTS will be used to analyze global mRNA expression patterns in bacilli recovered from patient sputum samples, providing insight into the physiology and metabolism of the microbe during active growth in the human lung. Our third aim is to extend analysis of differential bacterial gene expression to a C57BL/6 mouse model of host interaction, facilitating studies of both active and latent types of infection in a genetically defined host. Bacterial cDNA already obtained by SCOTS from tubercle bacilli growing in cultured mouse macrophages and from infected mouse lung tissues will be compared by array hybridization to cDNA from tubercle bacilla growing in human macrophages and lung tissues. A limited number of M. tuberculosis genes commonly expressed in response to these mammalian host interactions will then be evaluated for their contributions to virulence in this animal model. Understanding the roles of such differentially expressed genes will further define host-pathogen interactions in human disease, and allow development of new tools to reduce the enormous global impact of tuberculosis on mankind. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYCOBACTERIUM TUBERCULOSIS;INDUCED MACROPHAGE SIGNALLING Principal Investigator & Institution: Imboden, John B. Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 30-SEP-1993; Project End 31-AUG-2003 Summary: Adapted from the applicant's abstract): Tuberculosis (TB) is the most common fatal infectious disease in the world, and remains a threat to health in the United States. While improved case finding and access to treatment have reduced the incidence of TB in the United States, further improvements in TB control and therapy depend on better understanding of the pathogenesis of TB. Macrophages are essential for defense against infections, and are central to the pathogenesis of TB. When macrophages encounter most bacteria, they phagocytose and kill them. In contrast, macrophages phagocytose, but do not kill M. tuberculosis, even when they are stimulated with IFN gamma. Recent experiments in the PI's laboratory reveal that one means that M. tuberculosis uses to evade killing by macrophages is to block the signal transduction pathway initiated by interferon gamma. The PI has found that infection of macrophages with M. tuberculosis blocks several macrophage responses to IFN gamma, and has found that this disruption of signalling reduces transcriptional activation of IFN gamma-responsive genes at a distal step in the signalling pathway. M. tuberculosis infection of macrophages causes release of one or more soluble factors that inhibit IFN gamma signaling in uninfected macrophages. TGF-beta, IL-4, IL-6, IL-10, and prostaglandin E2 cannot account for this phenomenon. The PI proposes to identify the component of M. tuberculosis that initiates the inhibition of IFN gamma signaling. One hypothesis to be tested is that infection of macrophages by M. tuberculosis induces
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a repressor that binds specific DNA elements in the promoter region of interferon gamma-responsive genes. Finally, the PI will purify the soluble factor present in the conditioned medium from infected cells that inhibits interferon gamma signaling in uninfected macrophages. The proposed experiments will enhance the understanding of the pathogenesis of tuberculosis, and will provide insight essential for developing effective approaches to enhancing the protective immune response to M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYCOBACTOCID, A NOVEL ANTITUBERCULOSIS DRUG Principal Investigator & Institution: Cynamon, Michael H. Consultant; Natural Drug Science, Llc 48 S Franklin Turnpike Ramsey, NJ 07446 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 30-JUN-2002 Summary: (provided by applicant):Tuberculosis (TB) poses significant risk to mankind with nearly 8 million people contracting TB and 3 million people dying from it each year. A TB epidemic is becoming more dangerous because of the emergence of multidrug resistant tuberculosis and the lack of effective new drugs. The main goal of Natural Drug Services is to develop and commercialize a new anti-tuberculosis compound, Mycobactocid (MCB). MCB belongs to a new class of chemical compounds, has low toxicity in mice and is effective against strains of tuberculosis resistant to the known anti-tuberculosis agents. The specific aims of this project include:1) evaluation of the anti-tuberculosis activity of MCB in standard, well-characterized in vitro and in vivo models and, 2) compare it to other regimens of treatment. Previous studies indicate that MCB has potent specific activity against M. tuberculosis, low toxicity, and is effective against multi-drug resistant strains. Further study of MCB will facilitate commercialization of this novel class of compounds for treatment of tuberculosis. PROPOSED COMMERCIAL APPLICATION: Tuberculosis claims three million lives a year world-wide and reached epidemic proportions in the US, with outbreaks of drugresistent strains in several cities. The compound under investigation. Mycobactocid, has high specific activity against M. tuberculosis, low toxicity and is active against the resistant strains of M. tuberculosis. The specific goal of this project is to develop preclinical data to facilitate evaluation in human clinical trials and ultimately lead to a commercial product. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MYCOTHIOL BIOSYNTHESIS AND METABOLISM AS TB DRUG TARGETS Principal Investigator & Institution: Fahey, Robert C. Chemistry and Biochemistry; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2003; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: (provided by applicant): Tuberculosis is now second behind AIDS, as the World's most deadly microbial infection. However, a major fraction of AIDS patients die of mycobacterial infections, including TB. The TB problem is aggravated by the growing prevalence of drug-resistant TB, and especially multi-drug resistant (MDR) TB which cannot be treated with the front-line antibiotics for Mycobacterium tuberculosis. It is therefore important that targets be identified for development of new drugs for treatment of MDR TB. Suitable target enzymes should have biochemical functions essential for mycobacteria but with no similar function in mammals making it likely that drugs can be developed that will not lead to adverse reactions in humans. They should have well-defined assays suitable for screening of potential drugs. The proposed
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research elucidates the biochemistry associated with the production and utilization of the antioxidant thiol known as mycothiol. Mycothiol is produced only by mycobacteria, and other actinomycetes, and is not found in animals. The key genes for mycothiol biosynthesis have recently been identified and provide important potential new drug targets. Studies of MSH-deficient mutants indicate that mycothiol metabolism is involved in protecting against oxidative damage and in the detoxification of antibiotics, including one first-line TB drug. Although not essential for the laboratory culture of the model organism Mycobacterium smegmatis, current evidence suggests that mycothiol may be required for survival of M. tuberculosis in an oxygen rich environment. The present studies will determine the extent to which mycothiol is essential for survival of M. tuberculosis, will define the biochemistry involved in the first key step of mycothiol biosynthesis, and will determine how the biosynthesis of mycothiol is regulated. Methods used include new analytical and enzyme assays developed in these laboratories as well as established protocols in biochemistry and molecular biology. The results obtained will provide a key test of the suitability of mycothiol biosynthesis as a target for new TB drugs and will elaborate the biochemistry of a novel class of thiol important to a broad class of soil microorganisms, including most antibiotic producing bacteria. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NANOPARTICLE DELIVERY SYSTEM FOR ANTITURBERCULOSIS DRUG Principal Investigator & Institution: Heifets, Leonid B. Director; National Jewish Medical & Res Ctr and Research Center Denver, CO 80206 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2005 Summary: (provided by applicant): The U.S. Department of State recently invited us to collaborate with Russian Research Center of Molecular Diagnostics and Therapy (RDCMDT) in the evaluation of nanoparticles as drug delivery vehicles for antituberculosis drugs. While the project by RDCMDT is funded through the International Science and Technology Center (ISTC), funding for the portions of the project to be performed at National Jewish must be funded from U.S. domestic sources. Nanoparticles are small (Submicron) colloidal particles in which different drugs can be entrapped or adsorbed, and their usefulness as an advanced drug delivery system has been demonstrated in many areas. They can be stored without refrigeration for extended periods, and may enable targeting of anti-tuberculosis drugs to macrophages, and the intracellular compartments of macrophages in which Mycobacterium tuberculosis resides. We hypothesize that formulations of existing antituberculosis drugs within nanoparticles modified to traffic to intracellular compartments bearing M. tuberculosis will result in a reduction of the minimal inhibitory concentrations (MIC) relative to the free drugs. Our preliminary data, the only data on anti-TB drugs, suggest that the MICs for streptomycin and isoniazid were reduced by 4.5-7 fold. Dr. Geuelperina at RDCMDT has already begun encapsulation of ethambutol, pyrazinamide, capreomycin, amikacin, kanamycin, ethionamide, levofloxacin, cycloserine, moxifloxacin, vancomycin, and cefoxitin. These drugs, if efficiently encapsulated, will be tested in a macrophage model of M. tuberculosis infection at National Jewish Medical and Research Center in Denver. We will test the hypothesis that increasing the intracellular accumulation, particularly in phagosomes harboring M. tuberculosis will result in enhanced efficacy, as measured by reduced growth and viability of intracellular organisms. We will characterize the accumulation of each formulation by labelling the drugs and following their routes of uptake when the particles are opsonized by serum proteins, when opsonization is
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inhibited by coating the particles with polyethylene glycol, and when the nanoparticles are targeted to specific cell surface receptors via modification with transferrin or mannoside clusters. Distribution of the drugs within the cells over time will also be monitored by immunostaining of the drug molecules within the cells at increasing intervals following uptake. The immunostaining will be made quantitative by creating standard curves for each drug concentration, such that concentrations within particular cellular compartments can be estimated. Finally, we will correlate viability of intracellular M. tuberculosis with drug exposure at the sub cellular level, and determine which formulations are most effective at directing drug accumulation in the cellular compartments harboring M. tuberculosis. Successful completion of this project will provide us with the most promising formulations of encapsulated anti-TB drugs which will create a basis for further collaboration with RDCMDT in preclinical development, including animal models of efficacy, pharmacokinetics, and toxicology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NATAL-COLUMBIA CLINICAL AIDS/TB TRAINING PROGRAM Principal Investigator & Institution: Abdool Karim, Salim S. Deputy Vice-Chancellor of Research; University of Natal Durban 4041, South Africa Durban, Timing: Fiscal Year 2002; Project Start 22-SEP-2002; Project End 21-SEP-2003 Summary: (provided by applicant): South Africa is currently experiencing one of the worst H IV epidemics in the world and tuberculosis is the most common opportunistic infection associated with advancing HIV disease and AIDS. The recent, substantial increase in numbers of people co-infected with HIV and tuberculosis is exacerbating the existing tuberculosis crisis in South Africa. Building on the longstanding collaborative relationships between the University of Natal and Columbia University with respect to research and training in HIV and tuberculosis through the existing Fogarty AITRP, HVTN and HPTN, we propose to develop a collaborative program in clinical, operational and health services research and training to fill an important training gap in the local response to the HIV and tuberculosis epidemics in South Africa. In order to expand the existing collaboration between the two institutions and the South African Medical Research Council we propose to: i. develop a common vision and understanding of the training program between the US and South African partners; ii. identify the specific research training opportunities and required infectious diseases resources in both the US and South Africa; iii. establish the structure, policies and procedures for the comprehensive ICOHRTA-AIDS/TB co-operative agreement; iv. develop integrated links with other training programs such as the CU-SA Fogarty AITRP; and v. prepare an institutional development plan for the next 10 years demonstrating how ICOHRTA resources will enable the University of Natal to achieve its long-term goals in infectious diseases. The continuum of training concept that has evolved through the CU-SA Fogarty AITRP for HIV and tuberculosis basic science, public health, behavioral and ethics research training where Fellows do coursework in the US and conduct their research in South Africa will be applied to this proposed training program for building clinical, operational and health services research capacity. Training opportunities at Columbia University through the Division of Infectious Diseases in the context of providing clinical care include: consultation rounds for patients on the HIV/TB inpatient care, a unit dedicated to the management of HIV infection and the diagnosis and management of tuberculosis, and augmented by a core conference schedule. The following collaborative projects will provide research opportunities for Fellows in South Africa: HPTN 046, HPTN 035, HPTN 043, HVTN 040, numerous operational tuberculosis projects and new initiatives such as the proposed
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CIPRA which includes an acute infection and natural history study in a clade C population and strategies to integrate antiretroviral therapy with the tuberculosis directly observed short course therapy program. This planning grant will facilitate the development of an ICOHRTA training program which addresses South Africa's priority needs and the institutional development plan of the University of Natal. It optimally utilizes the Columbia University training resources and strong linkages with existing NIH funded clinical research and other Fogarty training programs through building on a well-established, vibrant collaboration involving Columbia University, the University of Natal, the South African Medical Research Council and potentially the NIH Clinical Center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL COMPOUNDS FOR IMPROVED TREATMENT OF TUBERCULOSIS Principal Investigator & Institution: Owens, Albert H. Member; Fasgen, Inc. 5210 Eastern Ave Baltimore, MD 21224 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): In 2000, the U.S. had over 16,000 cases of infectious tuberculosis and an estimated 10-15 million latent cases. Despite prolonged treatment regimens with significant side effects, reports of drug resistant TB in 43 states, and an estimated $345 million market opportunity, few new drugs to treat TB are in development. FASgen's SBIR Phase I goal is to choose a lead anti-tuberculosis candidate from 6 molecules active in vitro against Mycobacterium tuberculosis. Phase I specific aims are: 1) resupply candidate compounds and determine purity and chemical and biological stability; 2) determine minimum inhibitory concentrations (MICs) against a panel of mycobacteria in vitro; 3) determine in vitro cytotoxicities (lC50s) against Vero cells; 4) determine maximum tolerated dose (MTD) and dose limiting toxicity in mice for compounds with selectivity index (MTD/IC50) >10; 5) test the best compound in a murine inhalation model of TB; 6) verify that the MTD is not substantially different in immunocompromised (beige) mice; 7) test whether the best anti-tuberculosis compound is also active against M. avium in an immunocompromised mouse model; 8) repeat/confirm efficacy in animal models. In SBIR phase II, the lead compound will undergo safety/toxicology testing in animals and Phase I/Il safety and Phase II efficacy testing in man, most likely against multidrug resistant TB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL DELIVERY OF A NEW VACCINE FOR TUBERCULOSIS Principal Investigator & Institution: Pereira, Diane; Mycos Research, Llc 217 Racquette Dr, #6 Ft. Collins, CO 80524 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 30-NOV-2003 Summary: (provided by applicant): Tuberculosis is responsible for the death of over 3.3 million people each year, which is more than any other infectious agent. The current vaccine for tuberculosis is the BCG vaccine. BCG has been proven safe and effective at protecting young children, it is relatively inexpensive to produce, and it requires only a single immunization. Unfortunately, protecting adults from pulmonary disease with the BCG vaccine has been variably efficacious. As a result, the effort to produce a novel and efficacious vaccine for tuberculosis has intensified over the last decade. In the mouse model, the combination of a TH1 stimulating adjuvant and a M. tuberculosis derived recombinant fusion construct (Corixa Corporation) has resulted in a approximately 2 log
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decrease in bacterial burden following an aerogenic challenge with M. tuberculosis (approaching the level seen with the BCG vaccine). This vaccine formulation has also been effective in the guinea pig and cynomolgus monkey models of tuberculosis. This application proposes to investigate the ability of a transcutaneous immunization (TCI) to deliver this vaccine formulation to mice. The effectiveness of TCI has been demonstrated in pre-clinical and clinical trials and has been shown to induce both serum and mucosal humoral responses as well as cellular immune responses. The success of this novel delivery method will be evaluated by its ability to induce the development of a TH1 immune response and to provide a significant level of protection following a low dose aerosol challenge with M. tuberculosis. If successful, the advantages of transcutaneously delivering a vaccine for tuberculosis would be the lack of a needle injection, the simplicity of administration (especially in developing countries where tuberculosis is endemic), and the potential for using a lower dose of specific antigen, which would decrease the cost of vaccination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL INHIBITORS OF M. TUBERCULOSIS RNA POLYMERASE Principal Investigator & Institution: Lynch, Anthony S.; Cumbre, Inc. 1502 Viceroy Dr Dallas, TX 75235 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 14-APR-2004 Summary: (provided by applicant): Previous efforts at Cumbre Inc. have resulted in the discovery, characterization and optimization of a novel class of inhibitors of bacterial RNA polymerase The overall objective of this project is to establish the SAR of the Cumbre series as inhibitors of the RNA polymerase derived from M. tuberculosis, the causative agent of TB. These studies will involve the preparation and reconstitution of recombinant core and holoenzyme forms of M. tuberculosis RNA polymerase and the adaptation of current plate and gel format assays for the characterization of the mechanism of action of inhibitors of the M. tuberculosis enzyme. In addition, the Cumbre Inc. inhibitor series will be assessed for antibacterial activity against a panel of Mycobacterium species with the goal of establishing a strategy wherein future synthetic chemistry efforts may be directed toward the optimization of the series for activity against M. tuberculosis. Finally, additional studies will be focused toward establishing whether there may be any therapeutically relevant benefits of combining the Cumbre inhibitor series with rifampicin, a known inhibitor of bacterial RNA polymerase, which is clinically approved and currently used for the treatment of TB. Preliminary data obtained in Escherichia coli suggests that some mutations conferring resistance to rifampicin cannot be combined with mutations conferring resistance to the Cumbre series, and vice versa. Hence, the frequency of resistance to either agent may be reduced when the two classes of inhibitors are administered together in a single regimen. The results of the combined Phase I studies should provide a platform of data by which an informed decision can be made as to whether the Cumbre series has potential for future development as a novel antitubercular agent. Phase II studies would thereafter be addressed toward systematic optimization of the series as an antitubercular agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL MECHANISM OF INNATE DEFENSE IN MURINE TB Principal Investigator & Institution: Kornfeld, Hardy; Professor; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, MA 02118 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-JUL-2004
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Summary: We discovered that M. tuberculosis (Mtb) infection causes apoptosis of primary human alveolar macrophages (AMphi) in vitro by a tumor necrosis factor-alpha death signaling pathway. Apoptotic AMphi are present in bronchoalveolar lavage of tuberculosis (TB) patients and in TB lung biopsies. We found that virulent Mtb strains downregulate apoptosis of host AMphi, and we have shown that apoptosis is linked to microbicidal processing. Based on these observations, we hypothesize that lung Mphi apoptosis constitutes a newly recognized mechanism of innate immunity in TB. TB is a major co-infection in AIDS, contributing to increased morbidity and mortality. With declining adaptive immunity in AIDS, the relative importance of innate immunity may be augmented. Our research plan proposes novel use of the murine aerosol TB model to define the role of lung Mphi apoptosis in disease susceptibility and resistance in vivo. The specific aims address three key issues: 1, we will characterize the kinetics and distribution of lung Mphi apoptosis following aerosol Mtb infection; 2, we will examine the relationship between lung Mphi apoptosis and host resistance in experiments comparing Mtb strains of high and low virulence, common inbred mouse strains that are innately susceptible or resistant to TB, wildtype and knockout mice with targeted deletion of genes regulating apoptosis, and Mtb transduced to express apoptosis regulating genes; 3, we will evaluate the impact of lung Mphi apoptosis on cytokine expression and the pattern of leukocyte recruitment to the lung in TB, and it's contribution to the development of delayed type hypersensitivity. These studies will provide a detailed analysis of early events in murine TB, and will be the first to fully characterize lung Mphi apoptosis in vivo and to define it's contribution to the integrated host response to infection. Our model may reflect a mechanism broadly involved in the defense against a variety of other intracellular pathogens (such as Legionella) of immediate relevance to the HIV-infected host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NUTRIENT TRANSPORT MECHANISMS IN MYCOBACTERIA Principal Investigator & Institution: Connell, Nancy D. Associate Professor and ViceChair for r; Microbiol & Molecular Genetics; Univ of Med/Dent Nj Newark Newark, NJ 07103 Timing: Fiscal Year 2001; Project Start 01-JUL-1993; Project End 31-MAY-2005 Summary: (Adapted from the Applicant's Abstract): Mycobacteria are extremely important human pathogens. Their unusual cell wall structure and slow growth rate make them difficult to study from the standpoint of basic bacterial physiology. Mycobacteria have evolved into facultative intracellular parasites, capable of surviving with the phagocytic vacuole of the macrophage. It is likely that the ability of mycobacteria to acquire nutrients within the macrophage vacuole is tightly linked to intracellular survival and, therefore, to virulence. Knowledge of nutrient transport mechanisms for virulent mycobacteria will contribute directly to the design of novel therapeutic strategies and the development of new vaccines. The PI has isolated several mutants of Mycobacterium bovis BCG and M. tuberculosis which are deficient in transport of amino acids and peptides. In this competing continuation proposal, the PI will use classical and molecular genetic techniques and macrophage infection technology to address four specific aims: (1) to isolate and/or construct mutants of BCG and M. tuberculosis defective in transport and metabolism of arginine and oligopeptides; (2) to characterize transport of substrates by mutant and wild type BCG and M. tuberculosis; (3) to isolate and characterize transport regulatory mutants of BCG and M. tuberculosis; and (4) to examine the survival and growth characteristics, and nutrient transport activities, of mutant mycobacteria within mouse and human
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macrophages. These experiments will lead to a more complete understanding of the vacuolar environment which is the preferred ecological niche for mycobacteria within a mammalian host, and the nutrient uptake strategies employed by virulent mycobacteria to survive and grow in that intracellular environment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOKINETICS OF ISONIAZID/RIFABUTIN--HIV RELATED TB Principal Investigator & Institution: Sterling, Timothy R.; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: The treatment of tuberculosis in persons co-infected with HIV using standard rifampin-based regimens is generally successful. However, rifampin activates the hepatic cytochrome p450 enzyme system, resulting in a 40-90% decrease in serum concentrations of the HIV-1 protease inhibitors, a key component of highly active antiretroviral therapy. Rifabutin ishighly active against M. tuberculosis, yet is a lesspotent inducer of the cytochrome p450 enzyme system than rifampin. The CDC Tuberculosis Trials Consortium study, "Treatment of HIV-related tuberculosis using a rifabutin-based regimen" (USPHS Study 23--JCCI RPN 99-01-26-01), is evaluating the efficacy of an intermittent TB treatment regimen that includes rifabutin. Although the pharmacokinetics of isoniazid and rifabutin in immunocompetent individuals are sufficient to result in effective therapy without drug toxicity, there are concerns that malabsorption and diarrhea in HIV-infected persons will affect the pharmacokinetics of both drugs. The purpose of this study is to determine the proportion of patients with HIV-related tuberculosis who have abnormal pharmacokinetics of isoniazid and rifabutin. This study will also determine risk factors for abnormal pharmacokinetics of isoniazid and rifabutin, and evaluate the correlation between the pharmacokinetic parameters of isoniazid and rifabutin and the therapeutic efficacy and toxicity attributed to these medications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHOSPHOLIPASES IN THE PATHOGENESIS OF M. TUBERCULOSIS Principal Investigator & Institution: Parker, Sarah K. Microbiology; University of Colorado Hlth Sciences Ctr Uchsc at Fitzsimons Aurora, CO 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 30-APR-2007 Summary: (provided by applicant): The applicant, Dr. Sarah Parker, will conduct research on phospholipases in the pathogenesis of Mycobacterium tuberculosis. Though M. tuberculosis kills three million people per year, 450,000 of whom are children, the mechanisms of its success are not well understood. Evidence suggests that phospholipase A2 (PLA2), which is described here for the first time in M. tuberculosis, and phospholipase C (PLC) are surface exposed components of the mycobacterial cell wall. These phospholipases degrade phospholipids to fatty acids and other inflammatory mediators, and Dr. Parker hypothesizes that they contribute to the intracellularsurvival or extracellular pathogenesis of M. tuberculosis. She postulates that the degradation of hostsurfactant and membranes by M. tuberculosis PLC and PLA2 contributes to virulence by a number of possible mechanisms: facilitation of bacillary entry into host cells, production of inflammatory mediators, alteration of the phagosomal environment, and/or acquisition of nutrition in the form of fatty acids. Dr. Parker has designed her specific aims to address each of these possible contributions of
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PLAand PLC to M. tuberculosis pathogenesis. Currently she has a partial PLC deletion mutant in M. tuberculosis. Once she has purified PLA2 from M. tuberculosis, she will use the partial amino acid sequence to identify the pla2 gene. She will construct phospholipase C, A2 and C + A2 deletion mutants, and they will be bacteriologically and biochemically characterized. Phospholipid degradation and utilization by these strains will be investigated in varied nutritional environments, including using pulmonary surfactant as a carbon source. In a human macrophage model of infection, she will analyze PLC and PLA2 contributions to bacillary macrophage entry, trafficking and survival. The research project is designed to result in Dr. Parker becoming a successful and independent M. tuberculosis investigator. Not only will she learn many basic and state-of-the-art techniques, she will receive didactic training to compliment her research. She will spend 15% of her time honing her clinical skills as an assistant professor in Pediatric Infectious Diseases. Dr. Parker is committed to research in M. tuberculosis, and it holds a special significance to her because of her life experiences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PLANNING GRANT FOR ICOHRTA AIDS/TB PROGRAM IN INDIA Principal Investigator & Institution: Pande, Jitendra N.; All-India Institute of Medical Sciences Ansari Nagar New Delhi, Timing: Fiscal Year 2002; Project Start 22-SEP-2002; Project End 21-SEP-2003 Summary: (provided by applicant): Both AIDS and TB are very large health problems in India, The objective of this project is to develop a plan for the coming ten years to strengthen integrated and multidisciplinary research and training at the All India Institute of Medical Sciences (AIIMS), New Delhi, India in the fields of HIV/AIDS and tuberculosis. The University of California in Los Angeles (UCLA) will be the partner institution in the U.S, in this collaboration. Research, training and capacity building needs are truly multidisciplinary and will encompass clinical medicine, drug and vaccine trials, behavioral and social sciences, operational research and health services research. This will include cost-effective strategies for prevention, diagnosis and management of tuberculosis and HIV/AIDS and associated complications, including opportunistic infections. The project envisages training of several categories of health professionals including clinicians, laboratory scientists, research nurses, social scientists, psychologists, biostatisticians, and health care administrators. It will consolidate partnership with other stakeholders in India including Ministry of Health, Directorates of National Programs for Tuberculosis and AIDS, research organizations such as Indian Council of Medical Research (ICMR) and its institutions (Tuberculosis Research Center, Chennai, National AIDS Research Institute, Pune), Department of Biotechnology of the Ministry of Science and Technology, etc. Leadership in key Departments at AIIMS have been identified and agree to participate. Similar steps have been taken at UCLA. Multiple linkages already exist between faculty at AIIMS and UCLA. Administrative support has been obtained at the highest levels. Preliminary meetings took place in New Delhi, February 2002. Key Faculty from AIIMS will visit UCLA, the FIC and other NIH institutes and attend major relevant research meetings in the U.S. between June 2002 and February 2003. Several UCLA Faculty will visit AIIMS. Planning will proceed from June 2002 with repeated opportunities for input and critique by involved faculty at both institutions. This will complement existing or planned U.S, programs including FIC, CIPRA, ICTTRI and international CFAR activities, Current plans for training at UCLA and courses, workshops and cooperative projects at AIIMS in 2002 and 2003 will continue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: POPULATION BASED INVESTIGATIONS OF TUBERCULOSIS Principal Investigator & Institution: Alland, David; Associate Professor of Medicine; Montefiore Medical Center (Bronx, Ny) Bronx, NY 104672490 Timing: Fiscal Year 2001; Project Start 01-MAY-2000; Project End 04-JAN-2002 Summary: (adapted from applicant's abstract): The rational design and implementation of the next generation of therapies and vaccines against Mycobacterium tuberculosis will require a thorough understanding of the mechanisms of antibiotic resistance and bacterial pathogenesis as they apply to human infections. In this proposal, populationbased genetic studies of human specimens will be used to determine the clinical consequences of mutations in genes associated with bacterial antibiotic resistance and virulence. Previous population based genetic studies of M. tuberculosis have been limited in scope due to the difficulty and expense of large scale DNA sequencing or DNA chip analysis. The applicants have developed molecular beacon PCR assays which are expected to allow them to rapidly and accurately screen large numbers of samples for specific genetic mutations with the accuracy of a single base pair. They will screen for the presence of larger insertions and deletions in DNA sequence using a modified slot blot cross- hybridization approach. They propose to use novel transducing phage techniques to induce homologous recombination and gene substitution in M. tuberculosis. These techniques and more established methods will be used to study clinical M. tuberculosis isolates acquired by three large scale epidemiological studies underway in Arkansas, San Francisco, and Orizaba, Mexico. DNA sequence analysis will be combined with classical and molecular epidemiology to study the mutational events that lead to resistance to isoniazid (INH), to determine the distribution of specific mutations in susceptible and resistant isolates, and to discover other mechanisms of isoniazid resistance that develop in clinical strains. Transducing phage assays will be used to uncover and characterize additional resistance mutations. A similar approach will be applied to investigate infectivity and virulence in clinical M. tuberculosis strains. The complete genomic sequence differences between the laboratory strain H37Rv, and a highly virulent clinical strain CSU093, have recently become known. Studies of these sequence variations in clinical strains will be used to determine the associations between specific mutations and the phenotypes of infectivity and virulence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: POPULATION BASED MOLECULAR EPIDEMIOLOGY OF TB Principal Investigator & Institution: Hopewell, Philip C. Professor of Medicine; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-APR-1993; Project End 31-JUL-2006 Summary: (provided by applicant): Since January 1991 we have been using genotyping ot Mycobacterium tuberculosis together with conventional epidemiological approaches to elucidate the distribution and dynamics of tuberculosis in San Francisco. During this time we have refined and validated molecular epidemiological methods and applied these methods in a systematic series of studies that have been used to guide interventions tailored to the prevailing epidemiological circumstances. This study will extend our previous population-based, molecular epidemiologic studies of tuberculosis in support of the broad objective of eliminating tuberculosis in San Francisco that is caused by the transmission of Mycobacterium tuberculosis in San Francisco. This objective can be measured only by long-term application of molecular epidemiological methods. In addition, we propose to contribute to this objective by utilizing our detailed
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understanding of the dynamics of tuberculosis in San Francisco to examine genetic factors in both host and microbe that are associated with transmission of M. tuberculosis and progression of tuberculosis infection to clinical tuberculosis. In the proposed studies we will be combining state-of-the-art molecular epidemiology with recent advances in molecular biology, genomics, and computational biology in the setting of an effective tuberculosis control program to address some of the major current impediments to the elimination of the disease. The specific aims have been divided into four closely related components, intended to examine the interrelationships between clinical and epidemiological features of tuberculosis and human host and microbial genetic events in a setting wherein findings can be translated quickly to tuberculosis control efforts. The specific aims are divided as follows: 1) Identification and evaluation of tuberculosis control strategies; 2) Quantification of exposure and transmission; 3) Identification of host gene expression responses that distinguish susceptible and resistant persons; 4) Identification of mycobacterial factors associated with various outcomes following exposure to infectious tuberculosis. The components of these aims are all related to elucidating the factors related to transmission of M. tuberculosis and directed toward providing the scientific basis for measures designed to prevent transmission. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PRO-APOPTOTIC TUBERCULOSIS VACCINE Principal Investigator & Institution: Kernodle, Douglas S. Associate Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): A major hurdle in the development of effective vaccines against pathogens that reside within macrophages, including Mycobacterium tuberculosis, is how to deliver antigens in a manner that stimulates a protective cellular immune response. Recent investigations involving antisense mutants of M. tuberculosis that have diminished production of iron-cofactored superoxide dismutase (SOD) show that they are attenuated, induce strong CD4+ and CD8+ T-cell responses in mice, and exhibit promising activity as a vaccine prototype. These effects appear to be related to an unmasking of the innate immune responses normally inhibited by SOD, which is a prominent extracellular enzyme of M. tuberculosis and other pathogenic mycobacteria. The enhanced innate host immune responses presumably permit apoptosis-associated cross-presentation of microbial antigens via MHC Class I pathways to induce strong adaptive CD4+ and CD8+ T-cell responses, in contrast to the current vaccine for tuberculosis, BCG, which exhibits a predominant CD4+ T-cell response and minimal CD8+ T-cell responses. The goals of the current proposal are first, to characterize the cellular and cytokine responses in the lung observed early after infection with SODdiminished M. tuberculosis, as rapid pulmonary interstitial infiltration with mononuclear cells undergoing apoptosis appears to be a process unique to the SODdiminished strains that is not observed during infection with either virulent M. tuberculosis or BCG. This should define the conditions under which antigen crosspresentation occurs in vivo, yielding information that may be useful for a variety of vaccines. The second goal is to construct non-reverting SOD-diminished mutants of H37Rv and BCG by replacing the wild-type SOD allele with mutant alleles, some of which encode enzymatically less efficient mutants of SOD. This should yield a SODdiminished vaccine candidate that is stable and safe enough for administration to man. The third goal is to determine the optimal level of SOD production for maximal vaccine efficacy and the immune correlates of protection. Diminishing the production of factors
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produced by intracellular pathogens that inhibit macrophage apoptosis is a strategy for making new vaccines that achieve MHC Class I antigen presentation. This should have implications not only for tuberculosis but also for other infectious diseases in which CD8+ T-cell responses are a critical component of a protective immune response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PULMONARY IMMUNE DEFENCES AGAINST M. BOVIS-BCG INFECTION Principal Investigator & Institution: Fulton, Scott A. Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-JUL-2005 Summary: Dr. Fulton is an Instructor at Case Western Reserve University School of Medicine in the Division of Infectious Diseases. As a fellow, Dr. Fulton was supported by an institutional training grant supported by the NIAID and a training grant from the American Lung Association. He has been responsible for setting up a new animal model to study the immune response to tuberculosis and chosen to continue studying tuberculosis at CWRU because of its long and productive interest in in immunity to tuberculosis. The scholarly environment was initiated by Dr. J. Ellner who is the current PI for a multi-center collaborative Tuberculosis Research Unit. Dr. Fulton's mentors, Drs. W. H. Boom and F. P. Heinzel are interested in cellular immune responses to complex intracellular pathogens and have had significant success in training physician scientists. Other members include Dr. Z. Toossi, Dr. R. Wallis, Dr. C. Hirsch and Dr. R. Silver who contribute to the intellectual environment. Additional formal and informal interactions with scientists in Geographic Medicine (Dr. J. Kazura, Dr. C. King, Dr. E. Pearlman) will foster Dr. Fulton's training environment. Dr. Fulton now proposes addditional specialized training with the goal of becoming an independent physician scientist. He has set up a mouse model of aerogenic M. bovis-BCG infection as a model of human disease since M. bovis-BCG grows in the lung and elicits protective T cell responses that eradicate 99 percent of the bacteria. 1 percent of bacteria persist in a steady state infection characterized by granuloma formation and immune surveillance. In contrast, viulent M. tuberculosis leads to progressive infection. Since human pulmonary immune responses can be only partially and indirectly studied, animal models have provided a means for studying the unique susceptibilty of the lung. To analyze immune responses that characterize the susceptibility of the lung to mycobacteria, three aims are proposed: Aim 1. To characterize the expression of chemokines and cytokines within the bronchoalveolar and lung microenvironments during early, maximal, and late immune activation phases of aerogenic M. bovis-BCG and M. tuberculosis infection. Aim 2. To characterize mycobacterial antigen presentation and T cell activation within the bronchoalveolar and lung microenvironments during early, maximal and late immune activation phases of aerogenic M. bovis-BCG and M. tuberculosis infection. Aim 3. To characterize the early pulmonary immune responses to aerogenic M. bovis-BCG and M. tuberculosis during local and systemic immunomodulation of cytokine and chemokine expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PUTATIVE MYCOBACTERIAL REGULATORY FACTOR Principal Investigator & Institution: Godfrey, Henry P. Professor; Pathology; New York Medical College Valhalla, NY 10595 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2002
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Summary: (Adapted from the Applicant's Abstract): The recent increase in the incidence of tuberculosis (TB) in the United States (due at least in part to the HIV epidemic) has focused renewed interest on this disease and the physiology of its causative organism. Regulation of gene expression in pathogenic mycobacteria such as M. tuberculosis is incompletely characterized. The investigators have identified a 36 nucleotide sequence, rpt-1, occurring both as single units and as 2-, 3- or 4-unit tandem repeats in 30 M. tuberculosis sequences. Sequences similar to rpt-1 were also found to occur in M. bovis BCG and M. leprae, suggesting a broader role of repetitive DNA elements in regulating mycobacterial gene expression. rpt-1 sequences occurred upstream and in the same orientation to annotated ORFs in 27 of 30 cases; in the remaining cases, rpt-1 was located between two ORFs read in opposite directions. Among the genes preceded by rpt-1 sequences were a putative DNA helicase, a putative transcriptional regulator and several putative response regulators. Tandem repeats of rpt-1 units were separated by 20-23 intervening nucleotides, close to the number of nucleotides comprising two turns of the DNA helix so that tandem rpt-1 sequences lie on the same side of the DNA helix. The regulatory role of rpt-1 or its ability to interact with mycobacterial proteins is completely unknown. The investigators' preliminary studies using electrophoretic mobility shift assays and radiolabeled rpt-1 probes indicated that rpt-1 bound specifically to distinct protein(s) in cleared BCG cytosolic lysates. Unexpectedly, specific DNA-binding activity for rpt-1 was also present in nuclear extracts from eukaryotic HeLa and MCF-7 human breast cancer cell lines. The existence of mycobacterial DNA recognition sites in eukaryotic transcription factors could have important implications for pathogenesis of TB and other chronic intracellular infections. The long-term goal of this project is to characterize the role of regulators of mycobacterial gene expression in the pathogenesis of TB. The present project will test the hypothesis that rpt-1 is important for regulating mycobacterial gene expression. The Specific Aims of the project are: 1) characterize nucleotide motifs involved in binding of rpt-1 to mycobacterial cytosolic proteins; 2) characterize the protein(s) binding to rpt-1 biochemically using microsequencing and cloning and immunochemically; and 3) examine the role of rpt-1 as a regulatory element in M. tuberculosis gene expression under various environmental conditions and in reporter gene fusions preceded by rpt-1 sequences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RAPID DIAGNOSTICS FOR TB Principal Investigator & Institution: Kritski, Afranio; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: Rapid and accurate diagnosis of tuberculosis (TB) is the essential first step in the successful treatment and control of the disease in the individual and the community. In addition, rapid identification of drug- resistant TB is critical for tailoring effective regimens, particularly in areas with emerging drug-resistant TB. Current diagnostic tests for TB are cumbersome, expensive, slow and may lack sensitivity. Novel tests that provide an accurate result and that are affordable and feasible for studies of innovative diagnostic methods for detecting Mycobacterium tuberculosis in clinical specimens from clinical settings in a developing country, and to evaluate novel assays for the rapid diagnosis of drug- resistant TB. The purpose of this project is to develop and evaluate novel, rapid methods for the identification of M. tuberculosis and drug resistance from clinical specimens in a developing country setting. We will utilize the patient population of the University Hospital in Rio de Janeiro to perform pilot studies of candidate tests in patients suspected of having TB. Candidate tests will be evaluated in well-characterized
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patients for sensitivity, specificity, predictive value, and time required to provide results in comparison with conventional techniques. Candidate tests that show promise in the hospital setting will then be field tested in patients suspected of having TB at community clinics at the sites of our other trials (Project 1 and 2 of this proposal). Candidate tests to be developed and evaluated include: 1) C18-Carboxypropylbetaine (CB-18) specimen processing for enhancement of identification of M. tuberculosis by smear and in standard solid and radiometric media assays, as well as in nucleic acid amplification tests; 2) multiantigen serologic assays using lipid antigens of M. tuberculosis to distinguish active diseases from latent or absent infection; 3) solid phase amplification assays (e.g., Lineprobe (LIPA]) for rapid identification of both M. tuberculosis and specific resistance mutations; 4) use of immunocapture of BrdUlabeled mycobacterial DNA with PCR amplification to diagnose TB and identify phenotypic resistance after in vitro exposure to anti-mycobacterial drugs; and 5) use of redox dyes such as Alamar blue and triphenol tetrazolium to determine rapidly MICs of M. tuberculosis to first line anti-mycobacterial drugs. Identification of novel diagnostic tests that can provide a reliable and rapid diagnosis of TB and of drug resistance will contribute substantially to improving TB control globally. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RATIONAL INHIBITION OF INHA, A TUBERCULOSIS DRUG TARGET Principal Investigator & Institution: Tonge, Peter J. Associate Professor; Chemistry; State University New York Stony Brook Stony Brook, NY 11794 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 30-APR-2003 Summary: (Adapted from Applicant's Abstract) The development of multidrug-resistant strains of Mycobacterium tuberculosis and the emergence of tuberculosis as a major opportunistic infection in HIV- infected people are linked to the worldwide increase in tuberculosis. InhA, the NADH-dependent enoyl-ACP reductase from M. tuberculosis, is the target for the antitubercular drug isoniazid. The enzyme is involved in the biosynthesis of fatty acids and enzyme inhibition interferes with the synthesis of mycolic acid, a critical component of the mycobacterial cell wall. Currently 20% of M. tuberculosis strains are resistant to isoniazid due primarily to mutations in the InhA protein or mutations in the metabolic pathway for isoniazid activation. Consequently, InhA is a bona fide target for the development of novel antitubercular agents. The objective of this proposal is to provide detailed information on the mechanism of InhA with the knowledge that this information will be critical to the design and development of drugs that are effective against both sensitive and drug-resistant strains of M. tuberculosis. Initial efforts are focused on using conjugated substrate analogs to probe the mechanism of InhA. Raman and infrared spectroscopy will provide precise information concerning the geometry and electronic structure of substrates, substrate analogs and cofactors bound to InhA. The vibrational studies will elucidate whether the enzyme promotes catalysis by activating the ground state of the substrate or cofactor to hydride transfer. Site-directed mutagenesis, in concert with the spectroscopic studies, will be used to identify and quantitate the role of specific amino acid residues in substrate activation and transition state stabilization. Structural information on the enzyme- bound ligands will also be provided by NMR spectroscopy using transferred NOE methods and X-ray crystallography. This information will be combined with studies into the molecular basis for isoniazid action to drive the development of novel InhA inhibitors that are effective against both sensitive and drug-resistant strains of M.
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tuberculosis. Finally, the antimycobacterial activity of InhA inhibitors will be tested directly against cultures of M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REACTIVATION TUBERCULOSIS IN A/J MICE Principal Investigator & Institution: Jagannath, Chinnaswamy; Associate Professor; Pathology and Lab Medicine; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, TX 77225 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) One quarter of the world's population is infected with M. tuberculosis resulting in approximately 2.9 million deaths each year. Reactivation tuberculosis is the major cause of adult tuberculosis today although the mechanisms that predispose to reactivation are complex and enigmatic. Since animal models are useful for understanding pathogenesis of tuberculosis, we performed a series of studies to standardize murine models of acute, chronic and reactivation tuberculosis by varying the mouse strain, route and dose of infection. We then found that A/J mice were highly susceptible while C57Bl/6 mice were relatively resistant to progressive disease when infected either i.v. or via aerosol routes. A/J mice were unable to form granulomas in lungs and their macrophages were defective in killing MTB. Unlike C57Bl/6 mice, A/J mice also underwent an early and near uniform reactivation of tuberculosis following the Cornell model. A/J mice have a deletion in the gene encoding for Complement C5 which in intact mice yields the C5a anaphylatoxin, a known regulator of cytokine and chemokine synthesis of macrophages. Therefore, in this investigation, we will examine the hypothesis that the lack of C5a compromises the immune responses in mice allowing the reactivation of tuberculosis through the following aims. Specific Aim I will investigate whether the deletion in C5 gene affects the synthesis of cytokines (TNF alpha, IL1-beta and IL-6), prevents macrophage activation and thereby macrophage mediated killing of MTB in A/J mice. Specific Aim II will investigate the effects of the deletion in C5 gene to the secretion of chemokines by MTB infected A/J macrophages and evaluate whether they are important in causing influx of immune cells into the lungs and formation of granulomas. Specific Aim III will characterize histological, cytokine and chemokine responses of lungs in A/J mice to determine the type of immune response (Th1 vs Th2) that dominates during the reactivation of tuberculosis. These studies are anticipated to enhance our understanding on putative mechanisms that precede the reactivation of tuberculosis in the lungs of mice and ultimately help us to develop better strategies to prevent tuberculosis in man. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF HOST RESPONSE GENES IN PATHOGENESIS OF TB Principal Investigator & Institution: Roman, Jesse R. Division Director; Medicine; Emory University 1784 North Decatur Road Atlanta, GA 30322 Timing: Fiscal Year 2001; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death worldwide. Our inability to control the spread of this disease and the absence of new effective chemotherapeutic agents are due in part to the limited knowledge about host genes that control granuloma formation and other aspects of the host's response to this pathogen in lung. One host response considered important in tuberculosis is that of tissue remodeling which is characterized by alterations in
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extracellular matrix expression and degradation. Tissue remodeling is responsible for the development of Mtb- mediated fibrosis, bronchiectasis, and cavitation. Although these processes are often considered late manifestations of pulmonary tuberculosis, mounting evidence suggests that the genes involved in the control of tissue remodeling (TR genes) are expressed very early in lung after Mtb infection, and are involved in other key processes including leukocyte recruitment and granuloma formation. Consistent with this, we have demonstrated that: 1) Mtb Erdman bacilli and isolated cell wall components of Mtb induce the expression of TR genes encoding for extracellular matrices, matrix-degrading proteases, and pro-fibrotic growth factors in vitro (i.e., human monocyte/macrophages) and in vivo (C57BL/6 mice). In mice, the induction of TR genes correlated both spatially and temporally with the inflammatory response. 2) The induction of TR genes in monocyte/macrophages by Mtb occurs via receptormediated protein kinase pathways and requires the induction of specific transcription factors (e.g., AP-1). 3) The injection of trehalose-6,6'-dimycolate (previously called mycobacterial cord factor) or live Mtb Erdman strain into mice with knockout mutations in a TR gene (Matrix Metalloproteinase-9) resulted in increased inflammation and granuloma formation. Together, this information suggests that the interaction between Mtb and host cells triggers TR gene expression; in turn, the products of TR genes play important roles in the host response to Mtb. The overall goal of this application is to identify the TR genes that are differentially expressed in pulmonary tuberculosis and study their function. This will be accomplished in 3 specific aims designed to: 1) Identify host TR genes differentially expressed in vitro in human monocyte/macrophages after infection with Mtb using High Density Oligonucleotide Array or HDOA. 2) Identify the TR genes differentially expressed in the lungs of infected mice and in the lungs of humans with pulmonary tuberculosis using HDOA. 3) Determine the function of specific TR genes identified in Specific Aims I and II by infection of mice with gene knockout mutations. We propose to study the function of 3 (at the most 4) TR genes. We will begin exploring the function of 2 TR genes encoding for matrix metalloproteinases which we have demonstrated to be differentially expressed in Mtb-infected lungs and for which knockout animals are already available in our laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF HTRA-LIKE SERINE PROTEASES IN TB PATHOGENICITY Principal Investigator & Institution: Morin, Paul M. Microbiology and Immunology; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001; Project Start 01-APR-2001 Summary: (provided by the applicant): Two billion people are currently infected with the infectious organism, M tuberculosis, which causes tuberculosis. Understanding TB pathogenicity is critical for the development of more effective treatment and vaccines that could change the global emergency. This research proposal will use novel genetic tools to create specific TB mutants that will be used to elucidate the role of HtrA-like serine proteases in M tuberculosis pathogenicity. HtrA serine proteases have been shown to be associated with virulence in many organisms including Salmonella, Yersinia, and Brucella, and are induced by exposure to heat shock and oxidative and osmotic stresses. By using a novel phage delivery system, allelic exchange will be performed in TB to create mutants with deletions in the HtrA-like serine protease genes: htrA, pepA, and Rv0983. These 3 TB mutants will be characterized in vitro for their growth characteristics, thermosensitivity, and ability to survive in cultured macrophages. TB serine protease mutants will also be characterized in vivo by infecting C57BL/6 mice and BALB/c SCID mice to determine if mutants are attenuated in the
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murine model. HtrA mutants in other organisms have been shown to act as vaccines by protecting mice against a lethal challenge with the wildtype organism. BALB/c mice will be vaccinated with TB serine protease mutants and challenged with a virulent wildtype strain of TB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF MMPL TRANSPORTERS IN M. TUBERCULOSIS VIRULENCE Principal Investigator & Institution: Cox, Jeffery S. George Williams Hooper Foundation; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 15-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) Tuberculosis (TB) is a persistent lung infection that has plagued mankind for centuries and ranks as one of the most serious threats to world health today. The 2-3 million deaths attributed yearly to the disease, as well as the emergence of strains resistant to all of the available chemotherapeutic agents, urgently call for the development of new therapies to treat TB. For years, the identification of new drug targets has been hampered by the intractability of the bacillus to genetic analysis. Now with the advent of powerful genetic tools, combined with well-established mouse infection models, we have isolated novel M. tuberculosis mutants with lesions in individual genes that are required for normal growth during acute infection. Our initial results have led us to the hypothesis that M. tuberculosis influences host- pathogen contacts by utilizing the MmpL family of transporters to secrete biologically active lipids to the surface of the mycobacterial cell and ultimately into infected host cells. The studies proposed here give us the opportunity to test this model and thus understand the molecular details host- pathogen interactions critical during this stage of M.tuberculosis infection. Specifically, we will study a subset of Mmpls that are required for disease and identify the host-pathogen interactions mediated by these virulence molecules. We will determine the mechanism of transport of the cell wall lipid phthiocerol dimycocerosate (PDIM) by MmpL7 and seek to understand why this molecule is important for lung specificity of M. tuberculosis. Furthermore, we will identify the molecules transported by the other MmpL proteins identified by our genetic screens and determine their role in pathogenesis. Finally, we will determine if these molecules serve distinct roles in modifying the host for the benefit of the bacterium. Because members of the MmpL family of transporters are highly homologous to one another and to MmpL proteins of other mycobacterial pathogens, understanding the common mechanisms of their function may lead to the development of inhibitors that could be useful for treating a broad range of infectious diseases. The results from these studies will direct our long-term plans to understand the role secreted lipids play in the struggle between M. tuberculosis and the host. Ultimately, by understanding tuberculosis pathogenesis at the molecular level, we hope to aid in the discovery of new therapies to combat and eradicate this persistent infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF MMPL4 IN MYCOBACTERIUM TUBERCULOSIS PATHOGENESIS Principal Investigator & Institution: Skoble, Justin; George Williams Hooper Foundation; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-JUL-2001
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Summary: (provided by the applicant): Mycobacterium tuberculosis infects nearly one third of the world?s population and is a resurgent health hazard. In order to identify new targets for antimicrobial chemotherapies, it is critical to understand the molecular mechanisms of M tuberculosis pathogenesis. Cox et al. have recently performed a signature tagged mutagenesis to identify genes required for M. tuberculosis virulence in mice. One of the genes identified in this screen is mmpL4, which is predicted to encode a member of a family of large membrane proteins that act as lipid transporters. We have demonstrated that disruption of mmpL4 results in M. tuberculosis strains that are attenuated for growth in mice and that this growth defect is rescued in IFN-g -/mice. Thus, we hypothesize that MmpL4 secretes a lipidic virulence factor into host cells that either inhibits IFN-g signaling or an IFN-g-regulated effector function. We propose to use biochemical methods to identify the molecule(s) secreted by MmpL4 and study the effects of this molecule on the immune response of the host. In order to understand the role of MmpL4 and its secretion substrate, we will compare the host-parasite interaction of wild-type and mmpL4 mutant bacteria using macrophage and mouse models of infection. We will determine whether MmpL4 is required for survival in activated macrophages or whether MmpL4 is required for proper IFN-g signaling. Finally, to identify other components of the MmpL4 pathway, we will disrupt genes in the putative mmpL4 operon and determine whether they are required for virulence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SCREEN FOR ISOPRENOID PRODUCTION IN M. TUBERCULOSIS Principal Investigator & Institution: Brown, Mark J.; Echelon Biosciences, Inc. 675 Arapeen Dr, Ste 302 Salt Lake City, UT 84108 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 14-NOV-2003 Summary: (provided by applicant): Isoprenoid compounds form a large ubiquitous class of natural products that fulfill a wide variety of essential cellular functions in all living organisms. In eukaryotes, isoprenoid compounds are synthesized by a mevalonate (MVA) dependent pathway. However, in many bacteria, these compounds are synthesized by an alternative, MVA-independent route whose first committed intermediate is 2-methylerythritol 4-phosphate (MEP). Both pathways converge at isopentenyl diphosphate (IPP) and subsequent steps are similar in all organisms. Since the MEP pathway is absent in mammals, it is considered an attractive target for the development of novel antibiotics. The pathogen, M. tuberculosis belongs to the MEP pathway class of organisms. The applicants will prepare a transgenic bacterial E. coli host cell whose genome contains disruptions in a first endogenous gene in the MEP pathway and a second endogenous gene which is located downstream of the first gene in the MEP pathway. A transgene from M. tuberculosis that functionally replaces the disrupted downstream gene will be cloned into the cell. The growth of the host cell in the presence of test agent is then compared to a control culture to determine the activity of the test agent. Where the test agent renders the bacterial host cell nonviable on media containing a chemical supplement to relieve the 1-deoxy-D-xylulose-5-phosphate (DXP) block and viable on the media containing MVA indicates that the test agent has the potential to be an effective antibacterial against M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STEROL/HOPANOID BIOSYNTHESIS: AN ANTI-TB DRUG TARGET Principal Investigator & Institution: Crick, Dean C. Microbiology, Immunology & Pathology; Colorado State University Fort Collins, CO 80523
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Timing: Fiscal Year 2001; Project Start 15-JUN-2001; Project End 31-MAY-2005 Summary: (provided by applicant): Multi-drug resistant tuberculosis is increasing in prevalence worldwide; therefore, a greater understanding of the basic biochemistry of Mycobacterium tuberculosis is of utmost importance. Analysis of the M. tuberculosis genome suggests that there may be a biosynthetic pathway analogous to eukaryotic sterol synthesis in this organism. Preliminary evidence indicates that the M. tuberculosis genome encodes enzymes with structural homology to several eukaryotic sterol synthesis enzymes including farnesyl diphosphate synthase, squalene synthase, squalene epoxidase, oxidosqualene cyclase and lanosterol 14a-demethylase. It has been shown that both the M. tuberculosis farnesyl diphosphate synthase and lanosterol 14ademethylase are functional as well as structural homologs of the eukaryotic enzymes. More importantly, commercial anti-fungal drugs that are known inhibitors of sterol synthesis (specifically oxidosqualene cyclase and lanosterol 14a-demethylase) effectively inhibit the growth of M. tuberculosis in culture. It is hypothesized that M. tuberculosis synthesizes cyclic isoprenoid compounds, perhaps sterols or hopanoids, which are essential to the viability of the organism. Therefore, the specific aims of this proposal are to: 1) identify and characterize cyclic isoprenoid compounds in M. tuberculosis. 2) isolate, enzymatically characterize and determine the essentiality of the sterol synthesis homologs expressed by M. tuberculosis. 3) identify and characterize the active site of the oxidosqualene cyclase homolog. The identification of a sterol/hopanoid biosynthetic pathway in M. tuberculosis and characterization of relevant enzymes represents a novel approach to the identification of previously unsuspected antituberculosis drug targets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STIGMA AND TUBERCULOSIS IN HAITIAN POPULATIONS Principal Investigator & Institution: Coreil, Jeannine; Community and Family Health; University of South Florida 4202 E Fowler Ave Tampa, FL 33620 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Tuberculosis is a public health problem of global magnitude. In the U.S. its victims are primarily the poor, foreign immigrants and persons with AIDS. Efforts to control the disease are severely handicapped by the effects of social stigma, and further compounded by issues of race, social class, ethnic stereotypes, immigrant status and HIV co-infection. We will investigate the social dynamics of stigma in relation to TB in two populations particularly affected by all of these issues, Haitians in the U.S. and in Haiti. The study design will enable important comparisons across national settings that highlight the differential effects of politicaleconomic context, as well as comparisons of stigma in a traditional public health clinic and an innovative culturally competent clinic. It will identify differences in stigma dynamics for active disease compared to latent infection, and will measure the impact of stigma on adherence to preventive therapy. Results of the study will enlarge our understanding of the role of social context on stigma enactment, and will help improve illness management strategies. An innovative study design applies the methodology of cultural epidemiology in an interactive quantitative-qualitative approach to developing locally valid measures of illness concepts and behavior. The approach combines the strengths of ethnography with traditional epidemiologic research. We will conduct an ethnography of TB stigma, a cross-cultural epidemiologic study, and a community trial of adherence to preventive therapy. Study sites are Broward County, Florida, and Leogane, Haiti. The methodology has been tested and refined in a broad range of geographic settings and illness problems, including tuberculosis. The research team brings ample qualifications to implement the proposed study, including preliminary
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studies of stigma and TB among Haitians in South Florida that led to the development of a culturally competent Haitian community clinic. The project has strong support from the Florida Bureau of Tuberculosis Control and Immigrant Health, the Broward County Health Department, Haitian Physicians Abroad and St. Croix Hospital in Haiti. Parallel cultural epidemiologic studies of illness-related stigma are being planned for several other countries. This will provide an opportunity to integrate the Haitian study with a larger, multi-country collaboration. However, this application is designed as a standalone project with independent research aims. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURE/FUNCTION RELATIONSHIP FOR ANTIBODIES TO M. TUB Principal Investigator & Institution: Glatman-Freedman, Aharona; Pediatrics; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Our overall aim is to develop a novel approach to the prevention and therapy of Mycobacterium tuberculosis infections. We have generated murine monoclonal antibodies that recognize surface antigens of M. tuberculosis and identified one of them as protective in a mouse model. The aims of this project are: 1) to define the relationship between antibody isotype and biological efficacy; 2) to establish the mechanism(s) of antibody-mediated protection (or enhancement) in M. tuberculosis infection; 3) to study the interaction of monoclonal antibodies with cell-mediated immunity. The experimental approach will be: to generate switch variants of the protective monoclonal antibody; test the ability of these reagents to prolong survival and decrease organ mycobacterial burden in a mouse model; study the mechanisms by which they exert their biological functions using in-vivo and in-vitro studies; and study their interaction with cell-mediated immunity using in-vivo and in-vitro studies. This study will help us understand the structural characteristics required for useful antibodies to M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SURFACTANT AND TUBERCULOSIS PATHOGENESIS Principal Investigator & Institution: Ferguson, J Scott. Internal Medicine; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: (Adapted from applicant's abstract) Tuberculosis is the leading cause of death due to an infectious disease in the world. As a pulmonary pathogen, the initial interaction between the causative bacterium Mycobacterium tuberculosis (M.tb) and the human host is in the lung where surfactant, epithelial cells, and alveolar macrophages are located. This initial interaction between these components of the alveolus and M.tb dictate the outcome of infection. The understanding of this process is limited, but critical in this disease. This five year award will provide insight into the pathogenesis of tuberculosis, specifically in the role that surfactant components play in the early host response to this host-adapted microorganism. The specific aims are to: characterize the binding of surfactant protein D (SP-D) to virulent and attenuated M.tb strains, and their major surface components, and to determine the impact of this binding on bacterial agglutination; determine if SP-D alone or in conjunction with surfactant protein A (SPA), and the major surfactant phospholipid, dipalmitoyl phosphatidylcholine (DPPC), influences the phagocytosis of M.tb by macrophages; determine if SP-D, SP-A, and
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DPPC influence the intracellular survival of M.tb in the macrophage, and to examine whether this is the result of altered cellular responses such as phagosome-lysosome fusion or the oxidative burst; and, determine if SP-D, SP-A, and DPPC influence the M.tb-pulmonary epithelial cell interaction. These specific aims will be accomplished using in vitro techniques available at the primary laboratory and through collaborative efforts. The candidate is a fellow in the Division of Pulmonary, Critical Care, and Occupational Medicine. Through an intense course of didactic and laboratory study, he will define the essential role that surfactant components play in the host defense response to M.tb using methods of microbiology, immunology, biochemistry, molecular biology, and cell physiology. He will determine the role that SP-A, SP-D, and DPPC, have in regulating the immune response of macrophages and epithelial cells to this intracellular pathogen. The proposed work will be performed at the University of Iowa, a well-known leader in biomedical research. The work to be performed encompasses the Division of Infectious Diseases and the Division of Pulmonary, Critical Care, and Occupational Medicine, as well as various departments from the College of Medicine. Laboratory facilities are at the Iowa City Veterans Administration Center, and the University of Iowa. The candidate, mentors, advisory committee, and collaborators will work closely to achieve the goals of this proposed award: to define critical interactions between the human pathogen M.tb and the host, and for the principal investigator to become an accomplished independent biomedical investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: T TUBERCULOSIS
CELL
RESPONSE
TO
CDI-RESTRICTED
LIPIDS
IN
Principal Investigator & Institution: Moody, David B.; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2006 Summary: (provided by the applicant): Mycobacterium tuberculosis has infected one third of all humans, resulting in 2-3 million deaths annually and increasing rates of coinfection with the human immunodeficiency virus (HIV). The main impediment to eradication of tuberculosis relates to the ability of M. tuberculosis to persist long term intracellularly within host tissues. Cellular immune responses, particularly activation of Th1 T cells, are crucial for killing intracellular mycobacteria and successfully resolving tuberculosis infections. Although most studies have evaluated mycobacterial protein antigen for activation of T cells, it is now known that group 1 CD1 molecules (CD1a, CD1b, CD1c) mediate T cell activation by mycobacterial glycolipids, including two classes of glycolipid antigen discovered by the applicant's group, glucose monomycolate (GMM) and mannosyl phosphodolichol (MPD). Preliminary studies indicate that CD1restricted T cells that recognize MPD and GMM are detectable in the peripheral blood of human subjects infected with M. tuberculosis, but not naive controls, indicating that M tuberculosis infection generates glycolipid-specific T cell responses in vivo. T cells use clonally variable T cell receptors to specifically recognize several mycobacterial glycolipids without crossreactivity. T cell recognition of mycobacterial glycolipids is generally specific for the carbohydrate structure of the antigens, including a product of glycosylation reactions that is produced during intracellular growth within host tissues. Now the applicant proposes to measure polyclonal T cell responses from naive and M tuberculosis infected humans to the major classes of purified mycobacterial glycolipids typical of extracellular and intracellular growth. We will use purified CD1-presented antigens as well as mycobacterial glycolipids that are specifically upregulated during intracellular growth to measure human lymphocyte responses during the first year after
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infection. Antigen-specific lymphocytes will be detected using proliferation assays, antibody-capture cytokine ELISA (elispot) and glycolipid-loaded CD1 -tetramers. Glycolipid-specific T cells will be characterized with regard to restriction by CD1 isoforms, dependence on prior infection and expression of cell surface markers of immunological memory. These studies will determine whether human infection by M tuberculosis generally results in acquired T cell responses that are specific for mycobacterial glycolipids expressed during intracellular growth. Determination of the immunodominant glycolipid targets of the human T cell response during natural tuberculosis infection will provide crucial information for development of CD1presented glycolipids as immunomodulatory agents, including vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGET FOR MEFLOQUINE IN MYCOBACTERIA Principal Investigator & Institution: Bermudez, Luiz E. Associate Professor; California Pacific Med Ctr-Pacific Camp Pacific Campus San Francisco, CA 94115 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2003 Summary: (provided by applicant): Infections caused by mycobacteria are responsible for severe morbidity and mortality. Mycobacterium tuberculosis and Mycobacterium avium are intracellular pathogens that infect both healthy individuals and immunocompromised patients. M. avium are usually resistant to conventional antituberculosis therapy, and with the few drugs shown to have anti-M. avium activity in humans, such as the new macrolides, treatment or prolonged prophylaxis of disseminated disease selects resistant mutants after a course of monotherapy. In addition, multiple outbreaks of multi-drug resistant M. tuberculosis have created clinical challenges for hospital and community management of patients. The goal of this proposal is to be focused and apply new strategies to identify and characterize the targets of mefloquine, a drug just recognized to have activity against mycobacteria. We have found that mefloquine has in vitro activity against both M. avium and M. tuberculosis and is borderline bactericidal against M. avium organisms in mice (we have not tested the activity in vivo against M. tuberculosis). Because mefloquine can achieve tissue concentrations 80-fold greater than serum levels, and mycobacteria survive intracellularly and have a long half-life, this class of compound has potential to become part of anti-mycobacterial regimen. Furthermore, mefloquine is active against M. avium strain resistant to macrolides, quinolones, isoniazid, ethambutol and rifampin, suggesting a novel mechanism of action. Therefore, we believe that determining the biochemical target of mefloquine in mycobacteria can lead the way to developing compounds with even more potent activity. The results thus far obtained with mefloquine suggest that it is the first very active drug identified against mycobacteria in years. Specifically, we plan to: (1) clone the mefloquine resistant-determinant using resistant mutants. In addition, by using a M. avium promoter library cloned in a reporter construct (green fluorescent protein), we plan to determine the pathways in the bacterium that are inhibited or stimulated when M. avium is exposed to mefloquine. This work, focused on an active anti-mycobacterial compound, has the potential to unveil new target(s) in both M. avium and M. tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETING M. TUBERCULOSIS ALANINE LIGASE FOR DRUG DESIGN Principal Investigator & Institution: Barletta, Raul G. Veterinary & Biomedical Scis; University of Nebraska Lincoln 14Th and R Sts Lincoln, NE 68588
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Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (Provided by the applicant): Mycobacterium tuberculosis causes a serious chronic infection in human beings. M. tuberculosis, along with Mycobacterium avium, is a major opportunistic pathogen of AIDS patients. Although generally susceptible to antimycobacterial agents, multi-drug resistant strains of M. tuberculosis have emerged, underlying the need for new therapeutic agents. Peptidoglycan is the backbone of the mycobacterial cell wall, and drugs that inhibit its biosynthesis cause a bactericidal effect due to cell lysis. D-alanine is a required component of the mycobacteriai peptidoglycan. Thus, those biosynthetic enzymes involved in the synthesis and incorporation of Dalanine are attractive targets for new drug development, especially because these enzymes are not found in mammalian hosts. The terminal D-alanyl-D-alanine dipeptide of the peptidoglycan side chain is an essential component for this process and its synthesis is catalyzed by the enzyme D-alanyl-D- alanine synthetase, usually denominated D-alanine ligase (Ddl). Unfortunately, the specific characteristics of the M. tuberculosis enzyme have not been fully characterized, nor the essentiality of the gene has been elucidated. In this context, our hypothesis for the proposed project is that Dalanine ligase plays an essential role in M. tuberculosis physiology and is a useful target for drug design. To test this hypothesis, we plan to: 1) Overexpress, purify, and characterize biochemically the M. tuberculosis Ddl enzyme; and 2) Test the essential role of Ddl enzyme in M. tuberculosis physiology. These studies are expected to provide basic knowledge on key enzymes involved in the pathway of peptidoglycan biosynthesis in mycobacteria. Most importantly, we will obtain information on the physiological essentiality and biochemical parameters of the Ddl enzyme necessary to develop assays for the screening and testing of candidate compounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TB LAM AND AG--STRUCTURES CORRELATED WITH BIOLOGY Principal Investigator & Institution: Chatterjee, Delphi; Associate Professor; Microbiology, Immunology & Pathology; Colorado State University Fort Collins, CO 80523 Timing: Fiscal Year 2001; Project Start 01-JUN-1996; Project End 30-JUN-2003 Summary: (Adapted from the Applicant's Abstract): Important physiological and immunopathogenic features of mycobacteria including slow growth, acid fastness, resistance to drug permeation, and immunological persistence have been attributed to the presence of lipoarabinomannan (LAM) and arabinogalactan (AG) in the cell wall. This competitive renewal of Al 37139 is built on success in the initial funding period of determining structural characteristics of truncated LAM from laboratory induced ethambutol (Emb) resistant M. smegmatis and LAM and AG from clinical isolates of M. tuberculosis resistant to Emb. To take the next step in fully understanding the cell surface of M. tuberculosis and its manifestation in bacterial physiology and pathology, it is proposed to determine the entire structures of LAM and AG, to characterize LAM and AG in a panel of Emb resistant M. tuberculosis isolates, and, in collaboration, to determine and precise structures of LAM needed for CD1 T-cell and macrophage mannose receptor recognition. Although some structural features of LAM and AG have been delineated, key issues, including the structure of the arabinan regions of both polymers, and the site of the arabinan attachments to the hexose backbones of each polymer remain unknown. To obtain the complete primary structure of these two 100 glycosyl residues glycans, novel cell wall degrading enzymes will be used to prepare fragments whose structures will be determined by state-of-the-art nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. The enzymes include seven
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novel arabinanases and galactofuranases secreted by a Cellulomonas species and an endo alpha-1,6 mannosidase from Bacillus circulans. NMR will focus on the analysis of fully 1 3C labeled polysaccharides and polysaccharide fragments by 2-D and 3-D techniques. Mass Spectrometry will feature a novel Q-TOF-tandem electrospray mass spectrometer to obtain sequence information. Techniques based on SDS-PAGE, endoarabinanase cleavage, 1-D-NMR, and MS will be used to efficiently characterize LAM and AG from our panel of Emb resistant M. tuberculosis. The structural studies will directly aid the immunological studies by providing a wealth of LAM related molecules needed to decipher the structural characteristics necessary for recognition by T-cells and macrophages. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TECHNOLOGY FOR NEW TUBERCULOSIS ANTI-INFECTIVES Principal Investigator & Institution: Cunningham, Philip R. Associate Professor; Biological Sciences; Wayne State University 656 W. Kirby Detroit, MI 48202 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): A genetic system was developed in Escherichia coil that uses combinatorial genetics to identify mutations in ribosomal RNA (rRNA) drug targets that might lead to antibiotic resistance. Recently, the 16S RNA from Mycobacterium tuberculosis was substituted for E. coil 16S RNA in this system but the construct produced inactive ribosomes when expressed in E. coll. Hybrid 16S rRNAs containing the 5' and central domains from E. coil and the 3' major and minor domains from M. tuberculosis, however, produce active ribosomes in E. coil This suggests that nucleotide differences in the 5' and/or central domain of M. tuberculosis 16S RNA are responsible for loss of function when expressed in E. coll. Absence of function in 30S subunits composed entirely of M. tuberculosis 16S rRNA is probably due to the inability of a nucleotide(s) in M. tuberculosis 16S RNA to interact with an E. coil 30S ligand(s). The goal of this project is to develop genetic technology for the isolation of new anti-infectives that address the issue of drug resistance in M. tuberculosis. Two aims are proposed: (1) The nucleotides in M. tuberculosis rRNA responsible for loss of function in E. coil will be identified and (2) the M. tuberculosis 30S ligand(s) required for expression of M. tuberculosis 16S RNA in E. coil will be identified and cloned. Coexpression of M. tuberculosis 16S RNA and the ligands should produce functional ribosomes containing M. tuberculosis 16S RNA in E. coil Drug resistance in M. tuberculosis is due primarily to chromosomal mutations in the drug targets. Multi-drug resistance appears to occur through sequential accumulation of such mutations. For target-site mutations to be clinically significant, the mutated target must retain most of its biological activity since loss of function decreases the fitness and virulence of the pathogen. This is especially so for functional regions of rRNA, which are critical for protein synthesis. Successful completion of this project will provide a technology to develop novel anti-infectives that recognize all possible functional forms of the target, even if not yet found in nature, and are therefore unlikely to be susceptible to the development of resistance through target modification. Once developed, this technology will allow the use of rRNA genes from other microbial pathogens in designing new antiinfectives. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE COMPLETE GENOME SEQUENCE AND ANALYSIS OF M SMEGMATIS Principal Investigator & Institution: Fleischmann, Robert D. Investigator; Institute for Genomic Research Rockville, MD 20850 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2003 Summary: The completion and annotation of the DNA sequence from two strains of M. tuberculosis, the laboratory strain H37Rv and the virulent clinical isolate CDC1551 will provide the mycobacteria and tuberculosis research communities with an unprecedented resource for investigating the infectivity, virulence, colonization, pathogenicity, and the mechanisms of drug- sensitivity and resistance of M. tuberculosis. Despite the abundance of information provided by the genomic sequence, the exceedingly slow growth rate and highly virulent nature of the organism make working with M. tuberculosis and its genetic manipulation formidable tasks. A great deal of effort has gone into developing M. smegmatis, a fast-growing non-pathogen, as a genetic surrogate for M. tuberculosis. Through these efforts, it is possible for the mycobacterial researcher to utilize M. smegmatis in much the same manner as E. coli is used in the greater microbiological community. Obtaining the complete genome sequence of M. smegmatis will represent a milestone in mycobacterial research. In addition to providing invaluable information for continuing its development as a genetic system for recombinant methodologies, the organism provides a valuable model for studying unique aspects of mycobacterial biology, including cell wall biosynthesis, regulation of growth-rate, drug-sensitivity, protein secretion, gene regulation, etc. The Institute for Genomic Research has developed a cost effective and efficient approach to microbial genome sequencing that has been used to sequence and assemble seven microbial genomes. The genome of M. smegmatis strain mc2155 will be sequenced using this whole genome shotgun strategy. Small and large insert random libraries will be prepared and a sufficient number of random shotgun sequences to reach 8-fold coverage will be obtained. Assembly of the genome will be done using the version 2.0 of the TIGR Assembly software and closure will be obtained with a variety of PCR based techniques developed at The Institute. Annotation of the genome will employ a variety of computer techniques for identifying open reading frames and identifying proteins of known function through similarity searches against curated databases. Additional analyses will identify features such as exported proteins, tRNA and rRNA genes, repeated sequences, promoter sequences and ribosome binding sites. The data will be made available to the research community through the TIGR Microbial Database on the World Wide Web (www.tigr.org). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE TUBERCULOSIS
DYNAMICS
OF
GRANULOMA
FORMATION
IN
Principal Investigator & Institution: Kirschner, Denise E. Associate Professor; Microbiology and Immunology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The goal of this proposal is to explain the formation of granuloma in infection with Mycobacterium tuberculosis. Understanding granuloma formation and function will elucidate the primary immune mechanism for controlling tuberculosis infection. Our goal is to simulate the process of granuloma formation on a spatio-temporal scale and present the results in a time-lapse movie format. This will
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yield an interactive tool to study the role of specific immune elements in granuloma formation and function. Development of a virtual model of human infection will allow for integration of the plethora of chemokine, cytokine, cellular influx information and other relevant immunological factors, as generated by experimental systems. To this end, powerful techniques (e.g., microarrays) are available for obtaining comprehensive gene expression data. Using these methods to survey expression within the granulomas of non-human primates and mice will enable us to determine which immunological mediators are involved in granuloma formation, what the timing of their expression is in the formation, and their location within the granuloma. Further studies will indicate which cell-types are expressing which mediators. Our specific aims are to: (1) Identify the temporal and spatial expression of host immune elements participating in granuloma formation using gene expression tools in murine models of tuberculosis (2) Identify the temporal and spatial expression of host immune elements participating in granuloma formation using gene expression tools in murine models of tuberculosis (3) Determine the dynamics of granuloma formation and function in humans using mathematical models of the granuloma response in tuberculosis. Through this unique approach, the interaction of multiple factors that control the formation of the granuloma will be defined. Key parameters governing these interactions will be identified. The ability to synthesize the data generated by the experiments in the models allows for an understanding of the dynamics of granuloma formation as more than the sum of its parts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE EFFECT OF ART ON RATES AND TRANSMISSION OF TB Principal Investigator & Institution: Bekker, Linda-Gail; Univ of Witwaterstrand Johannesburg, Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: Mycobacterium tuberculosis is the commonest pathogen leading to fatal opportunistic disease in sub-Saharan Africa. South Africa is one of 5 countries with HIVpositive TB > 300 cases/100,000This proposal aims at demonstrating the benefits of antiretroviral therapy on TB in the community of Masiphumelele. Because the major cause of morbidity and mortality in HIV-1 infected adults and children is TB, safeguarding the household from the disease is a public health priority Project hypothesis: The introduction of ART in HIV-positive members of a community will have an impact on the TB morbidity and mortality in both HIV negative and positive members. Masiphumelele, a well circumscribed community of 10,000 in Cape Town where 600 adults, 100 children and 60 neonates will be treated with ART (Project 1 and 2 of this CIPRA). In addition it is our hypothesis that ART will change transmission patterns of tuberculosis in this community. Specific Aims: 1. To measure the impact of community-based antiretroviral therapy (ART) on active tuberculosis case rates, TB hospitalization rates and tuberculosis death rates, of the community residents, both HIV infected and un-infected. 2. To measure the impact of ART on the proportion of active TB in HIV infected individuals due to reactivation of latent infection versus reinfection. 3. To measure the impact of ART on transmission patterns of TB within the community. Is there a reduction of cluster sizes of M. tuberculosis? 4. To measure the contribution of HIV infected individuals to the transmission of TB. 5. To type the strains of M. tuberculosis cultured from the community using restriction length polymorphism (RFLP) to determine if the introduction of ART will change the transmission patterns of tuberculosis qualitatively as well as quantitatively in this community. 6. To use a geographic information system (GIS) and RFLP database for the Masiphumelele village,
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identifying TB transmission locations. 7. To measure the ongoing transmission of TB using annual tuberculin skin tests (TST) in cohorts of local school children and correlate it with the successful use of ART by. the reduction in AIDS related deaths, opportunistic infections and hospitalizations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF THE GRANULOMA IN M. TUBERCULOSIS INFECTIONS Principal Investigator & Institution: Russell, David G. Professor and Chairman; Microbiology and Immunology; Cornell University Ithaca Office of Sponsored Programs Ithaca, NY 14853 Timing: Fiscal Year 2001; Project Start 30-SEP-1995; Project End 31-MAR-2006 Summary: M. tuberculosis demonstrates an extraordinary penetrance of the human population. Much of its success is liked to its ability to persist within the host, which is dependent on the formation of granulomas, or localized infections that support bacterial persistence without overt disease. The granuloma fulfills functions ambivalent to the host because although it limits spread of the infection it also provides a haven for the bacterium from the more extreme rigors of the host immune response. Dr. Russell proposes to extend his existing studies into the life cycle stages of M. tuberculosis by studying how both the host and the bacterium initiate and maintain the granuloma in both the murine and human infections. The specific aims of the proposal are: 1. Characterization of the bacterial factors that induce and modulate granuloma development. M. tuberculosis synthesize and release 7 major lipids these lipids induce granuloma-like structures in mice and stimulate a pro-inflammatory response in macrophages in culture. These lipids will be identified structurally and their biological activities delineated. 2. Elucidation of the roles of host cytokines, chemokines and their receptors in the biology of the granuloma. The ability of the cell wall lipids to induce granuloma in non-immune and immune mice will be determined and compared with bacterial granulomas. Bacterial lipid granulomas will be dissected in an in vivo model that mixes labeled macrophages from relevant knock-out mice with the lipid-bearing particles and the data compared to immunohistological analysis of murine tuberculosis granulomas. The PI will also develop an in vitro cell migration model to determine the cytokines and chemokines responsible for recruitment of macrophages to the infection foci. 3. Examination of human alveolar macrophages from BAL cells from tuberculosis patients. These studies will encompass functional characterization of BAL macrophages for phagocytosis, vacuolar acidification and cellular responsiveness. The PI will also examine the cytokine/chemokine profiles of these cells as well as whether or not they contain mycobacterial cell wall constituents. The BAL cells will also be examined in cell migration assays based on the result from the murine granuloma model described in aim # 2. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRAINING AND RESEARCH IN HIV PREVENTION IN RUSSIA Principal Investigator & Institution: Merson, Michael H. Dean of Public Health; Epidemiology and Public Health; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-MAY-2003 Summary: This proposal is an "Administrative Supplemental Budget Request" to the Fogarty International Center (FIC) for expanded training within the Yale AITRP to
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further build in-country research and public health capacity in Transitional Case Management (TCM) of cases of active Mycobacterium tuberculosis infection in Russian prisoners at the time of their release. The training and research program that we propose has the following objectives: 1) To identify two psychologists or sociologists from the Departments of Psychology and/or Sociology at St. Petersburg State University and one junior physician currently working at the Tuberculosis Institute I St. Petersburg, Russia who will receive targeted training in; infectious disease epidemiology at Yale University School of Public Health; Transitional Case Management of prisoners at the time of their release from prison; direct observed therapy (DOTS). To provide these junior physician/scientists with re-entry grants for conducting research in St. Petersburg concerning identifying cost-effective practical methods for assuring that these recently discharged prisoners will be properly placed in an after-care situation providing adequate treatment for their Mycobacterium tuberculosis infection. This proposal links five institutions; Yale University School of Public Health; the CT Prison Association; the Tuberculosis Institute in St. Petersburg; the Departments of Psychology and Sociology at St. Petersburg State University; and the Center for Sociology, Psychology and Law Research, an NGO in St. Petersburg with experience in aftercare for individuals recently released from prison. These five institutions will collaborate in a training and research program to introduce a system of Transitional Case Management (TCM) of active cases of tuberculosis in prisoners immediately upon release from a prison in St. Petersburg, Russia. This three-year program will conduct an open search in the Departments of Psychology at St. Petersburg State University (SPSU) for two psychologists and/or sociologists and in the Tuberculosis Institute for one junior physician who will each spend 12 months in the United States; 7 months at Yale for graduate training in infectious disease epidemiology; 4 months in the Translational Linkage to the Community (TLC) Program at the Connecticut Prison Association for on-the job training in translational use management of prisoners with anti-tuberculosis treatment. Following this 12 month stay in the United States; each Fogarty Transitional Case Management Scholar will return to St. Petersburg to begin research work on a subject related to transitional case management of prisoners released with active TB. This work will be supported by his/her Re-entry Grant. A senior scientist(s) at SPSU or the TI and a senior scientist(s) at Yale will provide appropriate mentorship. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSDERMAL TEST FOR ACTIVE TUBERCULOSIS Principal Investigator & Institution: Nacy, Carol A. Chief Executive Officer; Sequella, Inc. 9610 Medical Center Dr, Ste 200 Rockville, MD 20850 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 29-SEP-2002 Summary: (provided by applicant):This proposal seeks to establish a development program to transition an experimental Transdermal Tuberculosis Skin Test into a commercial product. This technology has already demonstrated a remarkable ability to specifically identify AFB+ TB patients by adminstering a small amount of a TB protein (MPB64) to the skin and monitoring for an erythemic skin response. PPD+ symptomless individuals are non-reactive to the protein. The MPB-64 Transdermal Patch was applied to sixty-two patients, 49 with sputum-positive active disease and 13 who had completed TB chemotherapy, and 28 non-TB but tuberculin-positive controls. The results were read at 72h. The sensitivity of the Transdermal Patch was 87.8 percent, efficacy 92.9 percent, and specificity 100 percent. The thirteen TB patients who had each completed 6 months of TB chemotherapy showed different reactions to MPB64 patch test: those who had completed chemotherapy less than 4 months before testing were positive; 50 percent of
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patients who completed chemotherapy 5 months prior were positive; and those who had completed chemotherapy 7 and 8 months before were negative. All the non-TB controls with positive tuberculin tests were negative to the MPB-64 Transdermal Patch, even at the highest protein dose tested. This test may be a useful method to distinguish active TB patients from TB-infected but asymptomatic individuals. The current version of the technology is a research grade patch. This proposal will outline a development pathway to improve product packaging, ease of use and product stability. Initial efforts will be to characterize a unique animal model for use in examining component materials and technologies. Our specific aims are 1. Validate an animal model to test variables in the formulation and transdermal delivery of the skin test antigen, 2. Establish the most cost effective source of MPB64, 3. Establish the best packaging / delivery technology for the patch, 4. Establish animal test procedures for toxicity, product release and to test product stability. Phase II aims include optimizing protein production and manufacturing scale up, and performance of clinical trials for product registration. PROPOSED COMMERCIAL APPLICATION: The proposed commercial application would be to develop a patch test for diagnostic screening of active cases of tuberculosis by using transdermal delivery of MPB64 protein. The patch test could be used in place of other screening tests, such as the PPD skin test or the AFB smear, as a means of diagnosing patients with active tuberculosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSMISSION OF PAUCIBACILLARY AND DRUG RESISTANT TB Principal Investigator & Institution: Schoolnik, Gary K. Professor; Medicine; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2003; Project Start 01-JUN-1994; Project End 31-JUL-2004 Summary: Considerable efforts are being expended to implement "Directly Observed Therapy, Short course" (DOTS) globally. However, several key assumptions about the basic biology of tuberculosis transmission, upon which this strategy is based, remain unresolved. Results obtained from our current ICIDR project and other work in which we are engaged have lead us to hypothesize that, in the context of a well functioning DOTS based program, 1) relying solely on sputum microscopy (AFB smear) for diagnosis provides a biased underestimate of TB epidemiology, 2) that patients who are AFB smear negative, but culture positive (termed "paucibacillary") contribute significantly to disease transmission 3) that there are concerning rates of ongoing transmission of drug resistant M. tuberculosis, and 4) insight gained from the availability of the complete genomic sequence of M. tuberculosis can be exploited to provide clinically and epidemiologically relevant understanding of M. tuberculosis population genetics. We now propose to use "state of the art" molecular epidemiologic techniques to test these hypotheses. These results will have immediate implications for tuberculosis control programs in many tropical countries. In addition, the availability of fully characterized strains from this study will allow us to examine the nature and consequence of genetic diversity within populations of M. tuberculosis and begin to exploit this information for improved genotyping and diagnostic systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TUBERCLE BACILLI BINDING TO HOST CELLS: VACCINE DESIGN Principal Investigator & Institution: Hall-Stoodley, Luanne; Ligocyte Pharmaceuticals, Inc. 920 Technology Blvd, Ste C Bozeman, MT 59715
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Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-MAR-2004 Summary: (Provided by Applicant) Three million people die each year from tuberculosis (TB) in spite of the use of the existing anti-mycobacterial antibiotics and the BCG vaccine. Clearly, a better vaccine and better ways to treat TB are needed. The purpose of this STTR Phase I feasibility study is to evaluate Mycobacterium tuberculosis-binding interactions with several human cell types and pathogen recognition molecules. Pathogens typically gain entry to a host tissue by using cell-tocell recognition and attachment mechanisms. Conversely, the innate immune system recognizes many common motifs in microbial cell walls. These motifs are present in M. tuberculosis and bacilli-host binding interactions are increasingly being identified for M. tuberculosis. The experimental aim of the proposed study is to functionally evaluate M. tuberculosis binding interactions with human host molecules and cells under shear conditions that more accurately simulate physiological conditions in the lung. By exploring adhesion events we anticipate the discovery of novel molecular targets that could be used to develop better therapies or an improved vaccine. Blocking these targets may prevent infection by abrogating initial attachment by M. tuberculosis to permissive host cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TUBERCULOSIS EDUCATION AND CONTROL PROGRAM Principal Investigator & Institution: Blumberg, Henry M. Medicine; Emory University 1784 North Decatur Road Atlanta, GA 30322 Timing: Fiscal Year 2000; Project Start 30-SEP-1993; Project End 31-AUG-2004 Summary: The resurgence of tuberculosis has had a marked impact upon the Emory University School of Medicine community and Grady Memorial Hospital (GMH), a major teaching affiliate. GMH provides care to a large number of indigent minority patients with and at risk for tuberculosis. Currently, Atlanta has the highest rate of TB in the U.S. We propose to establish the Emory Tuberculosis Education and Control Program which will take advantage of a number of unique resources in our area (Emory University School of Medicine (EUSM) and School of Public Health, the Emory AIDS Training Network (EATN), GMH, the Centers for Disease Control and Prevention (CDC), Georgia Institute of Technology) in developing a model program for education, applied research, and TB control to help reduce the rate of TB in metropolitan Atlanta and the state of Georgia. Our first objective is to implement a coordinated competency based program of instruction for medical students and house staff in the principles and practice of preventing, managing, and controlling TB. Our curriculum expansion will be based on Knowles' principles of androgogy. Design, implementation, and evaluation will follow Green and Kreuter's PRECEDE-PROCEED analysis for health educational activities. Included in our model program will be a computer based learning component; the introduction of a problem based learning module on TB; summer research projects for medical students in the control of TB, applied research, or basic research. A second major aim of our program is to increase awareness and improve the knowledge base of community physicians. This effort will be done in collaboration with other groups such as the EATN and the American Lung Association through conferences, symposia, and a mini-residency program. We also plan to develop A Clinician's Guide to Tuberculosis in Georgia that can serve as a primary reference for practicing physicians. Applied research in the control and prevention of TB, both in the hospital and community is the third major objective of our program. Study of the efficacy of control measures to prevent nosocomial transmission of TB will be an important focus. We also plan a major expansion of screening and prevention efforts.
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Our fourth objective is to reduce the incidence of tuberculosis in Atlanta. This will require efforts to enhance communication and coordination of TB control activities with local and state health departments; EUSM and GMH; Morehouse School of Medicine; and the Division of TB Elimination at CDC. This will be accomplished in part by the establishment of a computerized network between these different groups that have responsibility for the management and care of TB patients. The establishment of a computerized network/TB database which will allow sharing of information between medical providers and the ability to track patients through the health care system should lead to improved surveillance and control of TB in our community and state. Implementation and evaluation of an intensive education program for TB patients at GMH, including one-to-one counseling and low-literacy teaching aids will also be a component of this objective. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TUBERCULOSIS IMMUNITY IN YOUNG CHILDREN Principal Investigator & Institution: Lewinsohn, Deborah A.; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality worldwide. Young children are more likely to contract infection with and develop severe disease from the causative agent Mycobacterium tuberculosis (Mtb). These clinical observations likely reflect fundamental differences in the immune systems of young children and adults. Critical differences relevant to TB immunity include the propensity for infants and young children to develop TH2-type CD4+ T cells in response to immunogens, deficiencies in the development of TH1-type T cells in response to pathogens, and deficiencies in macrophage and dendritic cell (DC) function. We propose to systematically define, in young children (less than or equal to 10 years of age), these important differences relevant to the successful containment of Mtb infection. The specific aims are: 1) To determine if severity of disease following Mtb infection in young children is associated with TH2-type Mtb-specific immunity, and conversely, if absence of disease following Mtb infection is associated with TH 1-type Mtb-specific immunity. 2) To determine if immunologic immaturity is associated with the development of TH2-type Mtb-specific immunity following Mtb infection, and conversely if immunologic maturity is associated with the development of TH 1-type Mtb-specific immunity following Mtb infection. 3) To evaluate aspects of innate immunity relevant to Mtb infection by characterizing the phenotype and function of macrophages and DC from cord blood derived from healthy neonates in comparison to macrophage and DC function in healthy adults. These studies may contribute to a more complete understanding of TB immunity in young children, and hence 'facilitate the development of an improved TB vaccine for this vulnerable population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TUBERCULOSIS POLICY IN LOS ANGELES, 1870-1940 Principal Investigator & Institution: Abel, Emily K. Health Services; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): This project seeks to make three important contributions to the history of tuberculosis in the United States during the late
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nineteenth and early twentieth centuries. First, it examines tuberculosis in a major metropolitan area, which has received little attention from medical historians. Although several historians have shown how the medical, social, and cultural context of tuberculosis changed over time, most restrict their purview to the East Coast. The disease had a very different meaning in a region that promoted itself as uniquely healthy. Second, the project broadens the understanding of the relationship between tuberculosis and immigrant groups. The association with tuberculosis had an even more devastating impact on Mexicans in Los Angeles than on the European immigrants in the East Coast, whom medical historians previously have examined. Reports of high rates of tuberculosis among Mexicans hardened the perception that they were "illegal aliens" and contributed not only to the campaign to restrict their immigration in the 1920s but also to their expulsion in the 1930s. Third, the study focuses on tuberculosis as a communicable as well as a chronic disease. Recent historical studies have demonstrated how the discovery of the tubercle bacillus and gradual acceptance of the germ theory transformed the medical treatment, social situation, and cultural representation of people with tuberculosis during the late nineteenth and early twentieth centuries. Major changes in the understanding of disability also profoundly affected tubercular people. This project thus seeks to apply some of the insights of the new disability history to the study of tuberculosis. This historical study relies primarily on in-depth analysis of extensive archival sources. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TUBERCULOSIS VACCINE STRATEGY USING SALMONELLA VECTORS Principal Investigator & Institution: Groger, Richard K. Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2004 Summary: The candidate is applying for a Career Development Award in order to gain additional training in vaccine research. He will work in Dr. Josephine Clark-Curtiss' lab, with Dr. Roy Curtiss serving as a co- mentor. The collaborative research environment of these laboratories should provide an ideal setting for the candidate to extend his previous research experience toward tuberculosis vaccine development. Several investigators in these laboratories are working on mycobacterial genetics and on the development of vaccines for other bacterial pathogens. During the award period the candidate will use a Salmonella live vaccine system to deliver specific mycobacterial polypeptide epitopes to the cytoplasm of antigen presenting cells, in order to stimulate an MHC class I-restricted CD8+ T cell response to these antigens. Growing evidence suggests a role for CD8+ T cells in natural immunity to tuberculosis. This hypothesis suggests that vaccine strategies designed to stimulate a CD8+ T cell response system may yield advances in tuberculosis vaccine technology. In addition, such advances may have implications for vaccines against other intracellular pathogens. The goals of this proposal are to: (1) test the ability of recombinant proteins based on SptP, or other proteins secreted and translocated by Salmonella, to stimulate a CD8+ T cell response to ESAT-6, (Z) test the ability of the elicited ESAT-6- specific T cells to kill intracellular mycobacteria, (3) test the ability of the recombinant SptP/ESAT-6-expressing, attenuated Salmonella typhimurium vaccine strain to protect mice from an aerosol challenge with a virulent Mycohac(erium (ttherculosis strain and (4) screen for additional mycobacterial antigens that could serve as alternative vaccine candidates in this antigen presentation system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TUBERCULOSIS, HIV AND SURFACTANT APOPROTEINS Principal Investigator & Institution: Martin, William J. Dean; Medicine; Indiana UnivPurdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2001; Project Start 10-JUL-1998; Project End 31-JUL-2002 Summary: (Adapted from the Applicant's Abstract): Pulmonary tuberculosis remains a serious world-wide problem. Mycobacterium tuberculosis (MTB) causes pulmonary infection by first being inhaled into the alveolar spaces where it attaches and enters alveolar macrophages (AM) to survive and replicate. The ability of MTB to use AM as a "safe habitat" is central to its survival during the earliest stages of infection. Studies from this laboratory indicate that bronchoalveolar lavage (BAL) fluid from HIV subjects contains a factor that promotes attachment of MTB to AM. This factor was shown to be surfactant protein A (SP-A). Preliminary data indicate that SP-D is also elevated in the HIV BAL fluid and can also promote MTB attachment to AM. Interestingly, two conditions associated with a marked elevation of SP-A and SP-D include HIV disease and silicosis; both conditions are associated with an increased risk for tuberculosis. Thus, the hypothesis is: SP-A/SP-D mediates attachment of MTB to AM in HIV-infected subjects facilitating MTB growth and survival in the alveolar spaces. The Specific Aims of this proposal include: 1 Determine molecular site(s) and characteristics of SP-A/SP-D binding to MTB; 2. Determine if: a)SP-A/SP-D mediated attachment of MTB to AM in vivo impairs AM immune response and/or facilitates MTB growth and b) prevention of SP-A/SP-D mediated attachment of MTB to AM in vivo blocks these effects suggesting a cause-effect mechanism; 3.) Determine if: a) SP-A/SP-D mediated attachment of MTB to AM in vivo impairs AM immune response and/or facilitates MTB growth and b) prevention of SP-A/SP-D- mediated attachment of MTB to AM in vivo blocks these effects suggesting a cause-effect mechanism; 4) Determine how human BAL fluid from normal and HIV-infected individuals influences MTB attachment to AM, the AM cytotoxic response and growth of MTB inside AM. If successful, these studies will result in the development of fundamentally new approaches to the study of pulmonary tuberculosis in HIV subjects. The opportunity to determine the specific site of SP-A or SP-D binding to MTB may provide insights that suggest novel therapeutic strategies in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: VIRULENCE FACTORS IN MYCOBACTERIA Principal Investigator & Institution: Rubin, Eric J. Immunology/Infections Diseases; Harvard University (Sch of Public Hlth) Public Health Campus Boston, MA 02460 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: (provided by the applicant): Tuberculosis infects much of the world's population and is responsible for millions of deaths annually. The causative organism, Mycobacterium tuberculosis, has been recognized for over a century, but little is known about the molecular mechanisms used by this bacterium to cause disease. I propose to use three methods we have recently developed in conjunction with the M tuberculosis genomic sequence to determine which genes are required by M tuberculosis to survive both in vitro and in vivo. First, we have developed a new transposon to perform saturating mutagenesis in M tuberculosis. Second, we have made a DNA microarray with which we can measure hybridization to each M tuberculosis open reading frame. Third, we have developed transposon junction hybridization (TJH), a method for mapping the sites of transposon insertions in large pools of mutants using a DNA microarray. We propose to use TJH to compare the genes required for M tuberculosis in
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vitro growth with those needed to survive in an animal. We will use a variation of TJH, differential length hybridization, to identify the complete set of genes that are essential for growth in defined media. We will also sequence several thousand clones from an insertion mutant library to produce a bank of defined mutants. This will allow us to test individual strains that contain mutations in candidate virulence genes identified by TJH. Since pathogens coordinately regulate expression of virulence genes, we will focus on regulatory genes required for infection and determine which downstream genes they control. This will enable us to identify both genes required for survival and for causing disease. Identification of genes important in infection should lead to the development of new strategies of tuberculosis treatment and prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VIRULENCE RELATED GENETIC VARIATION OF M TB STRAINS Principal Investigator & Institution: Yang, Zhenhua; Epidemiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Tuberculosis (TB) remains the leading infectious cause of global mortality. The emergence of drug resistant TB and a deadly synergy with HIV seen in recent years highlight the need for a better understanding of TB transmission and pathogenesis. The long term objectives of our project are: 1) to identify underlying genetic factors of Mycobacterium tuberculosis important to the pathogenesis and the epidemiology of TB and 2) to provide targets for the development of more efficient vaccine and therapeutical agents for TB prevention and control. Our hypothesis for the present project is that survival of successful bacterial pathogens not only depends on their ability to alter global patterns of gene expression in response to the changing environments during infection, but also depends on the presence or absence of certain genes in the bacteria that play an important role in virulence, and that loss or gain of such genes in clinical strains of M. tuberculosis is associated with their infectivity and pathogenicity. Our specific aims and the related experimental strategies are: 1) to determine genomic variation among M. tuberculosis strains associated with different epidemiological and clinical characteristics by genomic subtraction and to identify DNA unique to epidemiologically and clinically successful strains of M. tuberculosis in comparison with epidemiologically and clinically less successful strains, and with already sequenced strains of M. tuberculosis, H37Rv and CDC 1551; 2) to assess the potential importance of the fragments identified by DNA subtraction to TB transmission and pathogenesis by screening for the presence or absence of the fragments in approximately 700 clinical isolates collected during a five year population-based molecular epidemiological study conducted in Arkansas; and the relative distribution of these subtraction products will be determined by epidemiological and clinical covariates; and 3) to identify and to characterize genes contained in the subtraction products which are associated with TB transmission and pathogenesis, the flanking regions of the fragments identified by subtraction will be cloned for sequencing. By combining epidemiological information with molecular genetics, we are conducting a focused search for genes associated with transmission and pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: VOLATILE MARKERS OF PULMONARY TUBERCULOSIS IN THE BREATH Principal Investigator & Institution: Phillips, Michael; Director; Menssana Research, Inc. 1 Horizon Rd, Ste 1415 Fort Lee, NJ 07024
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Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2003 Summary: (provided by applicant): Background: Pulmonary tuberculosis (TB) is a growing public health problem, and detection is often costly and time-consuming. A breath test for volatile markers of Mycobacteria could provide a new test for the disease. An advanced new breath test routinely detects volatile organic compounds (VOCs) in breath in picomolar (10-12 mol/l) concentrations. M. tuberculosis manufactures volatile fatty acids and other volatile metabolites; detection of these VOCs in breath could provide an accurate, rapid, inexpensive and non-invasive new marker of infection in patients with active pulmonary TB. Experimental plan: In vitro study: Volatile metabolites in cultures of M. tuberculosis will be identified by gas chromatography and mass spectroscopy. Human study: In patients evaluated for suspected pulmonary TB, breath VOCs will be compared in those with and without disease. The sensitivity, specificity, and positive and negative predictive values of the breath test will be determined. Long term aims: a. Scientific: To determine the diagnostic accuracy of breath markers of M. tuberculosis. b. Technical: to develop a comparatively inexpensive miniaturized and rapid breath test suitable for clinical use and in less developed countries. c. Commercial: To obtain Food and Drug Administration (FDA) approval of the device and market it. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “tuberculosis” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for tuberculosis in the PubMed Central database: •
A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. by Nau GJ, Guilfoile P, Chupp GL, Berman JS, Kim SJ, Kornfeld H, Young RA. 1997 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21064
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A Combination of Two Genetic Markers Is Sufficient for Restriction Fragment Length Polymorphism Typing of Mycobacterium tuberculosis Complex in Areas with a High Incidence of Tuberculosis. by Rasolofo-Razanamparany V, Ramarokoto H, Auregan G, Gicquel B, Chanteau S. 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87965
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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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A Comparison of Seven Tests for Serological Diagnosis of Tuberculosis. by Pottumarthy S, Wells VC, Morris AJ. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86769
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A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival. by Teitelbaum R, Glatman-Freedman A, Chen B, Robbins JB, Unanue E, Casadevall A, Bloom BR. 1998 Dec 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28105
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A Multidrug-Resistant Tuberculosis Microepidemic Caused by Genetically Closely Related Mycobacterium tuberculosis Strains. by Kubin M, Havelkova M, Hyncicova I, Svecova Z, Kaustova J, Kremer K, van Soolingen D. 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85324
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A new evolutionary scenario for the Mycobacterium tuberculosis complex. by Brosch R, Gordon SV, Marmiesse M, Brodin P, Buchrieser C, Eiglmeier K, Garnier T, Gutierrez C, Hewinson G, Kremer K, Parsons LM, Pym AS, Samper S, van Soolingen D, Cole ST. 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122584
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A New Vaccine against Tuberculosis Affords Greater Survival after Challenge than the Current Vaccine in the Guinea Pig Model of Pulmonary Tuberculosis. by Horwitz MA, Harth G. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=152073
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A rare site for tuberculosis. by Monga A. 2002 Nov 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=134299
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Activities of poloxamer CRL8131 against Mycobacterium tuberculosis in vitro and in vivo. by Jagannath C, Allaudeen HS, Hunter RL. 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=162740
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Activity of pyrazinamide in a murine model against Mycobacterium tuberculosis isolates with various levels of in vitro susceptibility. by Klemens SP, Sharpe CA, Cynamon MH. 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163048
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AhpC, AhpD, and a Secreted 14-Kilodalton Antigen from Mycobacterium avium subsp. paratuberculosis Distinguish between Paratuberculosis and Bovine Tuberculosis in an Enzyme-Linked Immunosorbent Assay. by Olsen I, Tryland M, Wiker HG, Reitan LJ. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96145
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An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon. by Sousa AO, Salem JI, Lee FK, Vercosa MC, Cruaud P, Bloom BR, Lagrange PH, David HL. 1997 Nov 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24291
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An Ex Vivo Study of T Lymphocytes Recovered from the Lungs of I/St Mice Infected with and Susceptible to Mycobacterium tuberculosis. by Lyadova I, Yeremeev V, Majorov K, Nikonenko B, Khaidukov S, Kondratieva T, Kobets N, Apt A. 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108618
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Analysis for a Limited Number of Gene Codons Can Predict Drug Resistance of Mycobacterium tuberculosis in a High-Incidence Community. by Van Rie A, Warren R, Mshanga I, Jordaan AM, van der Spuy GD, Richardson M, Simpson J, Gie RP, Enarson DA, Beyers N, van Helden PD, Victor TC. 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87790
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Analysis of Rifapentine for Preventive Therapy in the Cornell Mouse Model of Latent Tuberculosis. by Miyazaki E, Chaisson RE, Bishai WR. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89434
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Analysis of the oxyR-ahpC region in isoniazid-resistant and -susceptible Mycobacterium tuberculosis complex organisms recovered from diseased humans and animals in diverse localities. by Sreevatsan S, Pan X, Zhang Y, Deretic V, Musser JM. 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163758
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Antigen Specificity in Experimental Bovine Tuberculosis. by Rhodes SG, GavierWiden D, Buddle BM, Whelan AO, Singh M, Hewinson RG, Vordermeier HM. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97461
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Antigenic Equivalence of Human T-Cell Responses to Mycobacterium tuberculosisSpecific RD1-Encoded Protein Antigens ESAT-6 and Culture Filtrate Protein 10 and to Mixtures of Synthetic Peptides. by Arend SM, Geluk A, van Meijgaarden KE, van Dissel JT, Theisen M, Andersen P, Ottenhoff TH. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97589
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Antigens of Mycobacterium tuberculosis Expressed during Preclinical Tuberculosis: Serological Immunodominance of Proteins with Repetitive Amino Acid Sequences. by Singh KK, Zhang X, Patibandla AS, Chien P Jr, Laal S. 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98491
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Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. by Delgado JC, Tsai EY, Thim S, Baena A, Boussiotis VA, Reynes JM, Sath S, Grosjean P, Yunis EJ, Goldfeld AE. 2002 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124289
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Antiretroviral Agents Restore Mycobacterium-Specific T-Cell Immune Responses and Facilitate Controlling a Fatal Tuberculosis-Like Disease in Macaques Coinfected with Simian Immunodeficiency Virus and Mycobacterium bovis BCG. by Shen Y, Shen L, Sehgal P, Zhou D, Simon M, Miller M, Enimi EA, Henckler B, Chalifoux L, Sehgal N, Gastron M, Letvin NL, Chen ZW. 2001 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=115114
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Antituberculosis activities of clofazimine and its new analogs B4154 and B4157. by Reddy VM, Nadadhur G, Daneluzzi D, O'Sullivan JF, Gangadharam PR. 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163171
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Antituberculosis activity of clarithromycin. by Luna-Herrera J, Reddy VM, Daneluzzi D, Gangadharam PR. 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163014
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Antituberculosis Treatment: Increasing Evidence for Drug Effects on Innate Cellular Immunity. by Tiemessen CT, Shalekoff S, Meddows-Taylor S, Martin DJ. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96127
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Application of the C18-Carboxypropylbetaine Specimen Processing Method to Recovery of Mycobacterium avium subsp. paratuberculosis from Ruminant Tissue Specimens. by Thornton CG, MacLellan KM, Stabel JR, Carothers C, Whitlock RH, Passen S. 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130914
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Are Three Sputum Acid-Fast Bacillus Smears Necessary for Discontinuing Tuberculosis Isolation? by Mathew P, Kuo YH, Vazirani B, Eng RH, Weinstein MP. 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130719
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Assessment of Morphology for Rapid Presumptive Identification of Mycobacterium tuberculosis and Mycobacterium kansasii. by Attorri S, Dunbar S, Clarridge JE III. 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86457
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Association of Interleukin-10 Cytokine Expression Status with HLA Non-DRB1*02 and Mycobacterium bovis BCG Scar-Negative Status in South Indian Pulmonary Tuberculosis Patients. by Dheenadhayalan V, Shanmugalakshmi S, Vani S, Muthuveeralakshmi P, Arivarignan G, Nageswari AD, Pitchappan RM. 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98679
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Attenuation of and Protection Induced by a Leucine Auxotroph of Mycobacterium tuberculosis. by Hondalus MK, Bardarov S, Russell R, Chan J, Jacobs WR Jr, Bloom BR. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97501
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Automated High-Throughput Genotyping for Study of Global Epidemiology of Mycobacterium tuberculosis Based on Mycobacterial Interspersed Repetitive Units. by Supply P, Lesjean S, Savine E, Kremer K, van Soolingen D, Locht C. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88389
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Automated Tuberculosis Detection. by Hripcsak G, Knirsch CA, Jain NL, PablosMendez A. 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61255
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Bactericidal Activity in Whole Blood as a Potential Surrogate Marker of Immunity after Vaccination against Tuberculosis. by Cheon SH, Kampmann B, Hise AG, Phillips M, Song HY, Landen K, Li Q, Larkin R, Ellner JJ, Silver RF, Hoft DF, Wallis RS. 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120034
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Bactericidal Activity of Increasing Daily and Weekly Doses of Moxifloxacin in Murine Tuberculosis. by Yoshimatsu T, Nuermberger E, Tyagi S, Chaisson R, Bishai W, Grosset J. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127203
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Bacteriological and Molecular Analysis of Rifampin-Resistant Mycobacterium tuberculosis Strains Isolated in Australia. by Yuen LK, Leslie D, Coloe PJ. 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85826
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Blood Agar and Mycobacterium tuberculosis: the End of a Dogma. by Drancourt M, Carrieri P, Gevaudan MJ, Raoult D. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153881
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Can you get tuberculosis twice? by Hoey J. 2002 Feb 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=99361
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Cavitary tuberculosis produced in rabbits by aerosolized virulent tubercle bacilli. by Converse PJ, Dannenberg AM Jr, Estep JE, Sugisaki K, Abe Y, Schofield BH, Pitt ML. 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=174445
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CD4 + T-Cell Subsets That Mediate Immunological Memory to Mycobacterium tuberculosis Infection in Mice. by Andersen P, Smedegaard B. 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97184
•
CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis. by Leemans JC, Florquin S, Heikens M, Pals ST, Neut RV, van der Poll T. 2003 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151898
•
CD8 + T Cells Participate in the Memory Immune Response to Mycobacterium tuberculosis. by Serbina NV, Flynn JL. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98502
•
Cell-Mediated Immune Response to Tuberculosis Antigens: Comparison of Skin Testing and Measurement of In Vitro Gamma Interferon Production in Whole-Blood Culture. by Katial RK, Hershey J, Purohit-Seth T, Belisle JT, Brennan PJ, Spencer JS, Engler RJ. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96059
•
Cellular Immune Responses to ESAT-6 Discriminate between Patients with Pulmonary Disease Due to Mycobacterium avium Complex and Those with
138 Tuberculosis
Pulmonary Disease Due to Mycobacterium tuberculosis. by Lein AD, von Reyn CF, Ravn P, Horsburgh CR Jr, Alexander LN, Andersen P. 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95736 •
Characterization of Finnish Mycobacterium tuberculosis Isolates by Spoligotyping. by Puustinen K, Marjamaki M, Rastogi N, Sola C, Filliol I, Ruutu P, Holmstrom P, Viljanen MK, Soini H. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153930
•
Characterization of IS6110 Restriction Fragment Length Polymorphism Patterns and Mechanisms of Antimicrobial Resistance for Multidrug-Resistant Isolates of Mycobacterium tuberculosis from a Major Reference Hospital in Assiut, Egypt. by Abbadi S, Rashed HG, Morlock GP, Woodley CL, El Shanawy O, Cooksey RC. 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88138
•
Characterization of Mycobacterium tuberculosis Isolates from Patients in Houston, Texas, by Spoligotyping. by Soini H, Pan X, Amin A, Graviss EA, Siddiqui A, Musser JM. 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86172
•
Characterization of rpoB Mutations in Rifampin-Resistant Clinical Isolates of Mycobacterium tuberculosis from Turkey by DNA Sequencing and Line Probe Assay. by Cavusoglu C, Hilmioglu S, Guneri S, Bilgic A. 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=154651
•
Characterization of T cells that confer a high degree of protective immunity against tuberculosis in mice after vaccination with tumor cells expressing mycobacterial hsp65. by Silva CL, Silva MF, Pietro RC, Lowrie DB. 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=174089
•
Characterization of the Secreted MPT53 Antigen of Mycobacterium tuberculosis. by Johnson S, Brusasca P, Lyashchenko K, Spencer JS, Wiker HG, Bifani P, Shashkina E, Kreiswirth B, Harboe M, Schluger N, Gomez M, Gennaro ML. 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98717
•
Clarithromycin is inactive against Mycobacterium tuberculosis. by Truffot-Pernot C, Lounis N, Grosset JH, Ji B. 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163042
•
Clearance and Organ Distribution of Mycobacterium tuberculosis Lipoarabinomannan (LAM) in the Presence and Absence of LAM-Binding Immunoglobulin M. by Glatman-Freedman A, Mednick AJ, Lendvai N, Casadevall A. 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97139
•
Clinical Evaluation of Anti-Tuberculous Glycolipid Immunoglobulin G Antibody Assay for Rapid Serodiagnosis of Pulmonary Tuberculosis. by Maekura R, Okuda Y,
Studies 139
Nakagawa M, Hiraga T, Yokota S, Ito M, Yano I, Kohno H, Wada M, Abe C, Toyoda T, Kishimoto T, Ogura T. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88396 •
Clinical Evaluation of the BDProbeTec ET System for Rapid Detection of Mycobacterium tuberculosis. by Bergmann JS, Keating WE, Woods GL. 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86226
•
Clinical Evaluation of the Enhanced Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for Rapid Diagnosis of Tuberculosis in Prison Inmates. by Bergmann JS, Yuoh G, Fish G, Woods GL. 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84791
•
Clinical Evaluation of the Gen-Probe Amplified Direct Test for Detection of Mycobacterium tuberculosis Complex Organisms in Cerebrospinal Fluid. by Lang AM, Feris-Iglesias J, Pena C, Sanchez JF, Stockman L, Rys P, Roberts GD, Henry NK, Persing DH, Cockerill FR III. 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105005
•
Clinical Evaluation of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for Rapid Detection of Mycobacterium tuberculosis in Select Nonrespiratory Specimens. by Woods GL, Bergmann JS, Williams-Bouyer N. 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87811
•
Colonic tuberculosis mimicking Crohn's disease: case report. by Chatzicostas C, Koutroubakis IE, Tzardi M, Roussomoustakaki M, Prassopoulos P, Kouroumalis EA. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115203
•
Combinatorial Use of Antibodies to Secreted Mycobacterial Proteins in a Host Immune System-Independent Test for Tuberculosis. by Landowski CP, Godfrey HP, Bentley-Hibbert SI, Liu X, Huang Z, Sepulveda R, Huygen K, Gennaro ML, Moy FH, Lesley SA, Haak-Frendscho M. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88164
•
Comparative and Prospective Study of Different Immune Parameters in Healthy Subjects at Risk for Tuberculosis and in Tuberculosis Patients. by Portales-Perez DP, Baranda L, Layseca E, Fierro NA, de la Fuente H, Rosenstein Y, Gonzalez-Amaro R. 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=119924
•
Comparative Evaluation of Initial and New Versions of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for Direct Detection of Mycobacterium tuberculosis in Respiratory and Nonrespiratory Specimens. by Gamboa F, Fernandez G, Padilla E, Manterola JM, Lonca J, Cardona PJ, Matas L, Ausina V. 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104609
•
Comparative Evaluation of Low-Molecular-Mass Proteins from Mycobacterium tuberculosis Identifies Members of the ESAT-6 Family as Immunodominant T-Cell
140 Tuberculosis
Antigens. by Skjot RL, Oettinger T, Rosenkrands I, Ravn P, Brock I, Jacobsen S, Andersen P. 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97123 •
Comparative Immune Response to PE and PE_PGRS Antigens of Mycobacterium tuberculosis. by Delogu G, Brennan MJ. 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98675
•
Comparison of C18-Carboxypropylbetaine and Standard N-Acetyl-l-Cysteine-NaOH Processing of Respiratory Specimens for Increasing Tuberculosis Smear Sensitivity in Brazil. by Scott CP, dos Anjos Filho L, de Queiroz Mello FC, Thornton CG, Bishai WR, Fonseca LS, Kritski AL, Chaisson RE, Manabe YC. 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130741
•
Comparison of Enhanced Mycobacterium tuberculosis Amplified Direct Test with COBAS AMPLICOR Mycobacterium tuberculosis Assay for Direct Detection of Mycobacterium tuberculosis Complex in Respiratory and Extrapulmonary Specimens. by Scarparo C, Piccoli P, Rigon A, Ruggiero G, Scagnelli M, Piersimoni C. 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86489
•
Comparison of in vitro models for the study of Mycobacterium tuberculosis invasion and intracellular replication. by Mehta PK, King CH, White EH, Murtagh JJ Jr, Quinn FD. 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=174125
•
Comparison of Methods Based on Different Molecular Epidemiological Markers for Typing of Mycobacterium tuberculosis Complex Strains: Interlaboratory Study of Discriminatory Power and Reproducibility. by Kremer K, van Soolingen D, Frothingham R, Haas WH, Hermans PW, Martin C, Palittapongarnpim P, Plikaytis BB, Riley LW, Yakrus MA, Musser JM, van Embden JD. 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85295
•
Comparison of Nucleic Acid Amplification Tests for Tuberculosis. by Dawson DJ. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88689
•
Comparison of Roche Cobas Amplicor Mycobacterium tuberculosis Assay with InHouse PCR and Culture for Detection of M. tuberculosis. by Eing BR, Becker A, Sohns A, Ringelmann R. 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104971
•
Comparison of the ABI 7700 System (TaqMan) and Competitive PCR for Quantification of IS6110 DNA in Sputum during Treatment of Tuberculosis. by Desjardin LE, Chen Y, Perkins MD, Teixeira L, Cave MD, Eisenach KD. 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104961
Studies 141
•
Comparison of Three Molecular Assays for Rapid Detection of Rifampin Resistance in Mycobacterium tuberculosis. by Watterson SA, Wilson SM, Yates MD, Drobniewski FA. 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104962
•
Consequence of Nramp1 Deletion to Mycobacterium tuberculosis Infection in Mice. by North RJ, LaCourse R, Ryan L, Gros P. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96959
•
Construction and Characterization of a Mycobacterium tuberculosis Mutant Lacking the Alternate Sigma Factor Gene, sigF. by Chen P, Ruiz RE, Li Q, Silver RF, Bishai WR. 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=101508
•
Contribution of CD8 + T Cells to Gamma Interferon Production in Human Tuberculosis. by Shams H, Wizel B, Weis SE, Samten B, Barnes PF. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98319
•
Cord Formation in BACTEC Medium Is a Reliable, Rapid Method for Presumptive Identification of Mycobacterium tuberculosis Complex. by McCarter YS, Ratkiewicz IN, Robinson A. 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105205
•
Correlation of ESAT-6-Specific Gamma Interferon Production with Pathology in Cattle following Mycobacterium bovis BCG Vaccination against Experimental Bovine Tuberculosis. by Vordermeier HM, Chambers MA, Cockle PJ, Whelan AO, Simmons J, Hewinson RG. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=128013
•
CpG Oligodeoxynucleotides and Interleukin-12 Improve the Efficacy of Mycobacterium bovis BCG Vaccination in Mice Challenged with M. tuberculosis. by Freidag BL, Melton GB, Collins F, Klinman DM, Cheever A, Stobie L, Suen W, Seder RA. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97508
•
CpG Oligodeoxynucleotides Enhance Host Defense during Murine Tuberculosis. by Juffermans NP, Leemans JC, Florquin S, Verbon A, Kolk AH, Speelman P, van Deventer SJ, van der Poll T. 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127605
•
Criteria for the control of drug-resistant tuberculosis. by Dye C, Williams BG. 2000 Jul 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16690
142 Tuberculosis
•
Cytokine Profiles for Peripheral Blood Lymphocytes from Patients with Active Pulmonary Tuberculosis and Healthy Household Contacts in Response to the 30Kilodalton Antigen of Mycobacterium tuberculosis. by Torres M, Herrera T, Villareal H, Rich EA, Sada E. 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=107874
•
Decreased Infectivity despite Unaltered C3 Binding by a [Delta]hbhA Mutant of Mycobacterium tuberculosis. by Mueller-Ortiz SL, Sepulveda E, Olsen MR, Jagannath C, Wanger AR, Norris SJ. 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=133004
•
Depressed CD40 Ligand Expression Contributes to Reduced Gamma Interferon Production in Human Tuberculosis. by Samten B, Thomas EK, Gong J, Barnes PF. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97518
•
Depressed Interleukin-12 (IL-12), but not IL-18, Production in Response to a 30- or 32Kilodalton Mycobacterial Antigen in Patients with Active Pulmonary Tuberculosis. by Song CH, Kim HJ, Park JK, Lim JH, Kim UO, Kim JS, Paik TH, Kim KJ, Suhr JW, Jo EK. 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98352
•
Depressed Phagocytosis and Oxidative Burst in Polymorphonuclear Leukocytes from Individuals with Pulmonary Tuberculosis with or without Human Immunodeficiency Virus Type 1 Infection. by Shalekoff S, Tiemessen CT, Gray CM, Martin DJ. 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=121389
•
Detection of a Previously Unamplified Spacer within the DR Locus of Mycobacterium tuberculosis: Epidemiological Implications. by Filliol I, Sola C, Rastogi N. 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86384
•
Detection of mRNA Transcripts and Active Transcription in Persistent Mycobacterium tuberculosis Induced by Exposure to Rifampin or Pyrazinamide. by Hu Y, Mangan JA, Dhillon J, Sole KM, Mitchison DA, Butcher PD, Coates AR. 2000 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=94781
•
Detection of pulmonary and extrapulmonary tuberculosis patients with the 38kilodalton antigen from Mycobacterium tuberculosis in a rapid membrane-based assay. by Zhou AT, Ma WL, Zhang PY, Cole RA. 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=170343
Studies 143
•
Detection of Rifampin-Resistant Mycobacterium tuberculosis in Sputa by Nested PCR-Linked Single-Strand Conformation Polymorphism and DNA Sequencing. by Kim BJ, Lee KH, Park BN, Kim SJ, Park EM, Park YG, Bai GH, Kim SJ, Kook YH. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88194
•
Detection of Viable Mycobacterium tuberculosis by Reverse Transcriptase-Strand Displacement Amplification of mRNA. by Hellyer TJ, DesJardin LE, Teixeira L, Perkins MD, Cave MD, Eisenach KD. 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84447
•
Determinants of cluster distribution in the molecular epidemiology of tuberculosis. by Murray M. 2002 Feb 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122226
•
Development of a Human Gamma Interferon Enzyme Immunoassay and Comparison with Tuberculin Skin Testing for Detection of Mycobacterium tuberculosis Infection. by Desem N, Jones SL. 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95613
•
Development of Antigen Detection Assay for Diagnosis of Tuberculosis Using Sputum Samples. by Pereira Arias-Bouda LM, Nguyen LN, Ho LM, Kuijper S, Jansen HM, Kolk AH. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86781
•
Diagnosis of Tuberculosis Based on the Two Specific Antigens ESAT-6 and CFP10. by van Pinxteren LA, Ravn P, Agger EM, Pollock J, Andersen P. 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95842
•
Dichotomy of Cytokine Profiles in Patients and High-Risk Healthy Subjects Exposed to Tuberculosis. by Bhattacharyya S, Singla R, Dey AB, Prasad HK. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96931
•
Different Innate Ability of I/St and A/Sn Mice To Combat Virulent Mycobacterium tuberculosis: Phenotypes Expressed in Lung and Extrapulmonary Macrophages. by Majorov KB, Lyadova IV, Kondratieva TK, Eruslanov EB, Rubakova EI, Orlova MO, Mischenko VV, Apt AS. 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=145363
•
Differential Gene Expression in Response to Adjunctive Recombinant Human Interleukin-2 Immunotherapy in Multidrug-Resistant Tuberculosis Patients. by Johnson BJ, Estrada I, Shen Z, Ress S, Willcox P, Colston MJ, Kaplan G. 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108220
•
Differential Protective Efficacy of DNA Vaccines Expressing Secreted Proteins of Mycobacterium tuberculosis. by Kamath AT, Feng CG, Macdonald M, Briscoe H, Britton WJ. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96517
144 Tuberculosis
•
Differential Responses of Bovine Macrophages to Mycobacterium avium subsp. paratuberculosis and Mycobacterium avium subsp. avium. by Weiss DJ, Evanson OA, Moritz A, Deng MQ, Abrahamsen MS. 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=128321
•
Differentiation of Clinical Mycobacterium tuberculosis Complex Isolates by gyrB DNA Sequence Polymorphism Analysis. by Niemann S, Harmsen D, Rusch-Gerdes S, Richter E. 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87363
•
Diminished Adherence and/or Ingestion of Virulent Mycobacterium tuberculosis by Monocyte-Derived Macrophages from Patients with Tuberculosis. by Zabaleta J, Arias M, Maya JR, Garcia LF. 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95641
•
Distinct Response Kinetics of Gamma Interferon and Interleukin-4 in Bovine Tuberculosis. by Rhodes SG, Palmer N, Graham SP, Bianco AE, Hewinson RG, Vordermeier HM. 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=101803
•
Distinctiveness of Mycobacterium tuberculosis Genotypes from Human Immunodeficiency Virus Type 1-Seropositive and -Seronegative Patients in Lima, Peru. by Ahmed N, Caviedes L, Alam M, Rao KR, Sangal V, Sheen P, Gilman RH, Hasnain SE. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153905
•
Divergent effect of bacillus Calmette --Guerin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: Implications for primate models in tuberculosis vaccine research. by Langermans JA, Andersen P, van Soolingen D, Vervenne RA, Frost PA, van der Laan T, van Pinxteren LA, van den Hombergh J, Kroon S, Peekel I, Florquin S, Thomas AW. 2001 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58758
•
Diversity of Antigen Recognition by Serum Antibodies in Experimental Bovine Tuberculosis. by Lyashchenko KP, Pollock JM, Colangeli R, Gennaro ML. 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108668
•
DNA Fingerprinting of Mycobacterium tuberculosis Complex Culture Isolates Collected in Brazil and Spotted onto Filter Paper. by Burger M, Raskin S, Brockelt SR, Amthor B, Geiss HK, Haas WH. 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104581
•
DNA Immunization in a Mouse Model of Latent Tuberculosis: Effect of DNA Vaccination on Reactivation of Disease and on Reinfection with a Secondary Challenge. by Repique CJ, Li A, Collins FM, Morris SL. 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=128037
Studies 145
•
DNA Vaccination against Tuberculosis: Expression of a Ubiquitin-Conjugated Tuberculosis Protein Enhances Antimycobacterial Immunity. by Delogu G, Howard A, Collins FM, Morris SL. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97537
•
DNA Vaccine Combinations Expressing Either Tissue Plasminogen Activator Signal Sequence Fusion Proteins or Ubiquitin-Conjugated Antigens Induce Sustained Protective Immunity in a Mouse Model of Pulmonary Tuberculosis. by Delogu G, Li A, Repique C, Collins F, Morris SL. 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127618
•
Drug resistant tuberculosis in prisons in Azerbaijan: case study. by Coninx R, Pfyffer GE, Mathieu C, Savina D, Debacker M, Jafarov F, Jabrailov I, Ismailov A, Mirzoev F, de Haller R, Portaels F. 1998 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28539
•
Drug Tolerance in Mycobacterium tuberculosis. by Wallis RS, Patil S, Cheon SH, Edmonds K, Phillips M, Perkins MD, Joloba M, Namale A, Johnson JL, Teixeira L, Dietze R, Siddiqi S, Mugerwa RD, Eisenach K, Ellner JJ. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89531
•
Drug-resistant tuberculosis. by Long R. 2000 Aug 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=80378
•
Duplex PCR for Differential Identification of Mycobacterium bovis, M. avium, and M. avium subsp. paratuberculosis in Formalin- Fixed Paraffin-Embedded Tissues from Cattle. by Coetsier C, Vannuffel P, Blondeel N, Denef JF, Cocito C, Gala JL. 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87183
•
Early Bactericidal Activity of Paromomycin (Aminosidine) in Patients with SmearPositive Pulmonary Tuberculosis. by Donald PR, Sirgel FA, Kanyok TP, Danziger LH, Venter A, Botha FJ, Parkin DP, Seifart HI, Van de Wal BW, Maritz JS, Mitchison DA. 2000 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90193
•
Early Emergence of CD8 + T Cells Primed for Production of Type 1 Cytokines in the Lungs of Mycobacterium tuberculosis-Infected Mice. by Serbina NV, Flynn JL. 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96683
•
Ecological analysis of ethnic differences in relation between tuberculosis and poverty. by Hawker JI, Bakhshi SS, Ali S, Farrington CP. 1999 Oct 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28253
•
Effect of katG Mutations on the Virulence of Mycobacterium tuberculosis and the Implication for Transmission in Humans. by Pym AS, Saint-Joanis B, Cole ST. 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=128294
146 Tuberculosis
•
Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials. by Wilkinson D, Squire SB, Garner P. 1998 Sep 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28654
•
Effective Treatment of Acute and Chronic Murine Tuberculosis with LiposomeEncapsulated Clofazimine. by Adams LB, Sinha I, Franzblau SG, Krahenbuhl JL, Mehta RT. 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89336
•
Effectiveness of Once-Weekly Rifapentine and Moxifloxacin Regimens against Mycobacterium tuberculosis in Mice. by Lounis N, Bentoucha A, Truffot-Pernot C, Ji B, O'Brien RJ, Vernon A, Roscigno G, Grosset J. 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90857
•
Effects of gamma interferon and nitric oxide on the interaction of Mycobacterium avium subsp. paratuberculosis with bovine monocytes. by Zhao B, Collins MT, Czuprynski CJ. 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=175213
•
Effects of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis. by Chan J, Tanaka K, Carroll D, Flynn J, Bloom BR. 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=173063
•
Effects of protein calorie malnutrition on tuberculosis in mice. by Chan J, Tian Y, Tanaka KE, Tsang MS, Yu K, Salgame P, Carroll D, Kress Y, Teitelbaum R, Bloom BR. 1996 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26226
•
Effects of Tumor Necrosis Factor Alpha on Host Immune Response in Chronic Persistent Tuberculosis: Possible Role for Limiting Pathology. by Mohan VP, Scanga CA, Yu K, Scott HM, Tanaka KE, Tsang E, Tsai MC, Flynn JL, Chan J. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98092
•
Efficacy of Microencapsulated Rifampin in Mycobacterium tuberculosis-Infected Mice. by Quenelle DC, Staas JK, Winchester GA, Barrow EL, Barrow WW. 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89124
•
Enhanced Amplified Mycobacterium Tuberculosis Direct Test for Detection of Mycobacterium tuberculosis Complex in Positive BACTEC 12B Broth Cultures of Respiratory Specimens. by Bergmann JS, Woods GL. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85048
•
Enhanced Immunogenicity of CD4 + T-Cell Responses and Protective Efficacy of a DNA-Modified Vaccinia Virus Ankara Prime-Boost Vaccination Regimen for Murine Tuberculosis. by McShane H, Brookes R, Gilbert SC, Hill AV. 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97939
Studies 147
•
Epidemiologic Usefulness of Spoligotyping for Secondary Typing of Mycobacterium tuberculosis Isolates with Low Copy Numbers of IS6110. by Cronin WA, Golub JE, Magder LS, Baruch NG, Lathan MJ, Mukasa LN, Hooper N, Razeq JH, Mulcahy D, Benjamin WH, Bishai WR. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88414
•
Epidemiology of Tuberculosis in Hamburg, Germany: Long-Term Population-Based Analysis Applying Classical and Molecular Epidemiological Techniques. by Diel R, Schneider S, Meywald-Walter K, Ruf CM, Rusch-Gerdes S, Niemann S. 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153391
•
Estimation of the Rate of Unrecognized Cross-Contamination with Mycobacterium tuberculosis in London Microbiology Laboratories. by Ruddy M, McHugh TD, Dale JW, Banerjee D, Maguire H, Wilson P, Drobniewski F, Butcher P, Gillespie SH. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=139701
•
Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. by DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE 3rd. 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16924
•
Evaluation of a Bacteriophage-Based Assay (Phage Amplified Biologically Assay) as a Rapid Screen for Resistance to Isoniazid, Ethambutol, Streptomycin, Pyrazinamide, and Ciprofloxacin among Clinical Isolates of Mycobacterium tuberculosis. by Eltringham IJ, Wilson SM, Drobniewski FA. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85685
•
Evaluation of a Rapid PCR-Based Epidemiological Typing Method for Routine Studies of Mycobacterium tuberculosis. by Yates MD, Drobniewski FA, Wilson SM. 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153374
•
Evaluation of an In-House-Developed Radioassay Kit for Antibody Detection in Cases of Pulmonary Tuberculosis and Tuberculous Meningitis. by Kameswaran M, Shetty K, Ray MK, Jaleel MA, Kadival GV. 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120075
•
Evaluation of BACTEC MGIT 960 and BACTEC 460TB Systems for Recovery of Mycobacteria from Clinical Specimens of a University Hospital with Low Incidence of Tuberculosis. by Leitritz L, Schubert S, Bucherl B, Masch A, Heesemann J, Roggenkamp A. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88429
•
Evaluation of BACTEC Mycobacteria Growth Indicator Tube (MGIT 960) Automated System for Drug Susceptibility Testing of Mycobacterium tuberculosis. by Ardito F, Posteraro B, Sanguinetti M, Zanetti S, Fadda G. 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88562
148 Tuberculosis
•
Evaluation of Four DNA Typing Techniques in Epidemiological Investigations of Bovine Tuberculosis. by Cousins D, Williams S, Liebana E, Aranaz A, Bunschoten A, Van Embden J, Ellis T. 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=124829
•
Evaluation of New Vaccines in the Mouse and Guinea Pig Model of Tuberculosis. by Baldwin SL, D'Souza C, Roberts AD, Kelly BP, Frank AA, Lui MA, Ulmer JB, Huygen K, McMurray DM, Orme IM. 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108294
•
Evaluation of Once-Weekly Therapy for Tuberculosis Using Isoniazid plus Rifamycins in the Mouse Aerosol Infection Model. by Brooks JV, Orme IM. 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105994
•
Evaluation of PCR in Detection of Mycobacterium tuberculosis from Formalin-Fixed, Paraffin-Embedded Tissues: Comparison of Four Amplification Assays. by Marchetti G, Gori A, Catozzi L, Vago L, Nebuloni M, Rossi MC, Esposti AD, Bandera A, Franzetti F. 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104869
•
Evaluation of Reverse Transcription-PCR and a Bacteriophage-Based Assay for Rapid Phenotypic Detection of Rifampin Resistance in Clinical Isolates of Mycobacterium tuberculosis. by Eltringham IJ, Drobniewski FA, Mangan JA, Butcher PD, Wilson SM. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85684
•
Evaluation of Rifalazil in Long-Term Treatment Regimens for Tuberculosis in Mice. by Shoen CM, Chase SE, DeStefano MS, Harpster TS, Chmielewski AJ, Cynamon MH. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89897
•
Evaluation of Rifapentine in Long-Term Treatment Regimens for Tuberculosis in Mice. by Lenaerts AM, Chase SE, Chmielewski AJ, Cynamon MH. 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89482
•
Evaluation of the Abbott LCx Mycobacterium tuberculosis Assay for Direct Detection of Mycobacterium tuberculosis Complex in Human Samples. by Garrino MG, Glupczynski Y, Degraux J, Nizet H, Delmee M. 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84218
•
Evaluation of the BACTEC MGIT 960 and MB BAC/T Systems for Routine Detection of Mycobacterium tuberculosis. by Whyte T, Hanahoe B, Collins T. 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87212
Studies 149
•
Evaluation of the BDProbeTec ET System for Direct Detection of Mycobacterium tuberculosis in Pulmonary and Extrapulmonary Samples: a Multicenter Study. by Mazzarelli G, Rindi L, Piccoli P, Scarparo C, Garzelli C, Tortoli E. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153925
•
Evaluation of the INNO-LiPA Rif. TB assay, a reverse hybridization assay for the simultaneous detection of Mycobacterium tuberculosis complex and its resistance to rifampin. by Rossau R, Traore H, De Beenhouwer H, Mijs W, Jannes G, De Rijk P, Portaels F. 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=164076
•
Evaluation of the Mycobacterium bovis Restriction Fragment Length Polymorphism Probe pUCD, in Combination with the Direct Repeat Probe, for Molecular Typing of Mycobacterium tuberculosis Strains in Ireland. by Cameron H, O'Brien R, Murray A, Cryan B, Hone R, Rogers M. 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88556
•
Evaluation of Three Nucleic Acid Amplification Methods for Direct Detection of Mycobacterium tuberculosis Complex in Respiratory Specimens. by Wang SX, Tay L. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84988
•
Evidence from Molecular Fingerprinting of Limited Spread of Drug-Resistant Tuberculosis in Texas. by Wilson RW, Yang Z, Kelley M, Cave MD, Pogoda JM, Wallace RJ Jr, Cegielski JP, Dunbar DF, Bergmire-Sweat D, Elliott LB, Barnes PF. 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85543
•
Evidence Inconsistent with a Negative Influence of T Helper 2 Cells on Protection Afforded by a Dominant T Helper 1 Response against Mycobacterium tuberculosis Lung Infection in Mice. by Jung YJ, LaCourse R, Ryan L, North RJ. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130368
•
Evolution and Clonal Traits of Mycobacterium tuberculosis Complex in GuineaBissau. by Kallenius G, Koivula T, Ghebremichael S, Hoffner SE, Norberg R, Svensson E, Dias F, Marklund BI, Svenson SB. 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85833
•
Evolution of Drug-Resistant Tuberculosis: A Tale of Two Species. by Iseman MD. 1994 Mar 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43383
•
Evolution of the IS6110-Based Restriction Fragment Length Polymorphism Pattern during the Transmission of Mycobacterium tuberculosis. by Warren RM, van der Spuy GD, Richardson M, Beyers N, Booysen C, Behr MA, van Helden PD. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=140391
150 Tuberculosis
•
Experimental versus In Silico Fluorescent Amplified Fragment Length Polymorphism Analysis of Mycobacterium tuberculosis: Improved Typing with an Extended Fragment Range. by Sims EJ, Goyal M, Arnold C. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=139697
•
Exposure to Antibiotics Induces Expression of the Mycobacterium tuberculosis sigF Gene: Implications for Chemotherapy against Mycobacterial Persistors. by Michele TM, Ko C, Bishai WR. 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89054
•
Expression and Characterization of the Mycobacterium tuberculosis Serine/Threonine Protein Kinase PknB. by Av-Gay Y, Jamil S, Drews SJ. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96941
•
Expression of a Mycobacterium tuberculosis Arabinomannan Antigen In Vitro and In Vivo. by Schwebach JR, Casadevall A, Schneerson R, Dai Z, Wang X, Robbins JB, Glatman-Freedman A. 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98683
•
Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung. by Cooper AM, Pearl JE, Brooks JV, Ehlers S, Orme IM. 2000 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97793
•
Extensive Cross-Contamination of Specimens with Mycobacterium tuberculosis in a Reference Laboratory. by de C. Ramos M, Soini H, Roscanni GC, Jaques M, Villares MC, Musser JM. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88624
•
Extrapulmonary and Pulmonary Tuberculosis in Antananarivo (Madagascar): High Clustering Rate in Female Patients. by Rasolofo Razanamparany V, Menard D, Auregan G, Gicquel B, Chanteau S. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=139634
•
Failure of Commercial Ligase Chain Reaction To Detect Mycobacterium tuberculosis DNA in Sputum Samples from a Patient with Smear-Positive Pulmonary Tuberculosis Due to a Deletion of the Target Region. by Gilpin CM, Dawson DJ, O'Kane G, Armstrong JG, Coulter C. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130798
•
Failure of the Mycobacterium bovis BCG Vaccine: Some Species of Environmental Mycobacteria Block Multiplication of BCG and Induction of Protective Immunity to Tuberculosis. by Brandt L, Feino Cunha J, Weinreich Olsen A, Chilima B, Hirsch P, Appelberg R, Andersen P. 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127715
Studies 151
•
False Molecular Clusters due to Nonrandom Association of IS6110 with Mycobacterium tuberculosis. by Gillespie SH, Dickens A, McHugh TD. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86733
•
False-Positive Gen-Probe Direct Mycobacterium tuberculosis Amplification Test Results for Patients with Pulmonary M. kansasii and M. avium Infections. by Jorgensen JH, Salinas JR, Paxson R, Magnon K, Patterson JE, Patterson TF. 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84200
•
False-Positive Results for Mycobacterium celatum with the AccuProbe Mycobacterium tuberculosis Complex Assay. by Somoskovi A, Hotaling JE, Fitzgerald M, Jonas V, Stasik D, Parsons LM, Salfinger M. 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87016
•
Field Evaluation of a Rapid Immunochromatographic Test for Tuberculosis. by Gounder C, de Queiroz Mello FC, Conde MB, Bishai WR, Kritski AL, Chaisson RE, Dorman SE. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130763
•
Frequency of rpoB Mutations Inside and Outside the Cluster I Region in RifampinResistant Clinical Mycobacterium tuberculosis Isolates. by Heep M, Brandstatter B, Rieger U, Lehn N, Richter E, Rusch-Gerdes S, Niemann S. 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87688
•
Gamma Interferon-Producing CD4 + T Lymphocytes in the Lung Correlate with Resistance to Infection with Mycobacterium tuberculosis. by Chackerian AA, Perera TV, Behar SM. 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98205
•
Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. by Kramnik I, Dietrich WF, Demant P, Bloom BR. 2000 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26987
•
Genetic Diversity of Mycobacterium tuberculosis in Sicily Based on Spoligotyping and Variable Number of Tandem DNA Repeats and Comparison with a Spoligotyping Database for Population-Based Analysis. by Sola C, Ferdinand S, Mammina C, Nastasi A, Rastogi N. 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87970
•
Genetic Regulation of Acquired Immune Responses to Antigens of Mycobacterium tuberculosis: a Study of Twins in West Africa. by Jepson A, Fowler A, Banya W, Singh M, Bennett S, Whittle H, Hill AV. 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98461
•
Genome Scale Comparison of Mycobacterium avium subsp. paratuberculosis with Mycobacterium avium subsp. avium Reveals Potential Diagnostic Sequences. by Bannantine JP, Baechler E, Zhang Q, Li L, Kapur V. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=140397
152 Tuberculosis
•
Genome-Sequence-Based Fluorescent Amplified-Fragment Length Polymorphism Analysis of Mycobacterium tuberculosis. by Goulding JN, Stanley J, Saunders N, Arnold C. 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86353
•
Guidelines for the investigation and follow-up of individuals under medical surveillance for tuberculosis after arriving in Canada: a summary. by Heywood N, Kawa B, Long R, Njoo H, Panaro L, Wobeser W, Committee OB. 2003 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=156689
•
Heterogeneous Antibody Responses in Tuberculosis. by Lyashchenko K, Colangeli R, Houde M, Al Jahdali H, Menzies D, Gennaro ML. 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108457
•
High Prevalence of KatG Ser315Thr Substitution among Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates from Northwestern Russia, 1996 to 2001. by Mokrousov I, Narvskaya O, Otten T, Limeschenko E, Steklova L, Vyshnevskiy B. 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127151
•
High-Dose Isoniazid Therapy for Isoniazid-Resistant Murine Mycobacterium tuberculosis Infection. by Cynamon MH, Zhang Y, Harpster T, Cheng S, DeStefano MS. 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89588
•
High-resolution minisatellite-based typing as a portable approach to global analysis of Mycobacterium tuberculosis molecular epidemiology. by Mazars E, Lesjean S, Banuls AL, Gilbert M, Vincent V, Gicquel B, Tibayrenc M, Locht C, Supply P. 2001 Feb 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29354
•
Homogeneity of Antibody Responses in Tuberculosis Patients. by Samanich K, Belisle JT, Laal S. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98537
•
Human CD8 + T Cells Specific for Mycobacterium tuberculosis Secreted Antigens in Tuberculosis Patients and Healthy BCG-Vaccinated Controls in The Gambia. by Smith SM, Klein MR, Malin AS, Sillah J, Huygen K, Andersen P, McAdam KP, Dockrell HM. 2000 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97828
•
Human cytolytic and interferon [gamma]-secreting CD8 + T lymphocytes specific for Mycobacterium tuberculosis. by Lalvani A, Brookes R, Wilkinson RJ, Malin AS, Pathan AA, Andersen P, Dockrell H, Pasvol G, Hill AV. 1998 Jan 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18198
Studies 153
•
Human Immunodeficiency Virus Type 1 (HIV-1) Quasispecies at the Sites of Mycobacterium tuberculosis Infection Contribute to Systemic HIV-1 Heterogeneity. by Collins KR, Quinones-Mateu ME, Wu M, Luzze H, Johnson JL, Hirsch C, Toossi Z, Arts EJ. 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=135892
•
Identification and Characterization of Protective T Cells in hsp65 DNA-Vaccinated and Mycobacterium tuberculosis-Infected Mice. by Bonato VL, Lima VM, Tascon RE, Lowrie DB, Silva CL. 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=107873
•
Identification and HLA Restriction of Naturally Derived Th1-Cell Epitopes from the Secreted Mycobacterium tuberculosis Antigen 85B Recognized by Antigen-Specific Human CD4 + T-Cell Lines. by Mustafa AS, Shaban FA, Abal AT, Al-Attiyah R, Wiker HG, Lundin KE, Oftung F, Huygen K. 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=101670
•
Identification of a Contaminating Mycobacterium tuberculosis Strain with a Transposition of an IS6110 Insertion Element Resulting in an Altered Spoligotype. by Benjamin WH Jr, Lok KH, Harris R, Brook N, Bond L, Mulcahy D, Robinson N, Pruitt V, Kirkpatrick DP, Kimerling ME, Dunlap NE. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87878
•
Identification of a Mycobacterium bovis BCG Auxotrophic Mutant That Protects Guinea Pigs against M. bovis and Hematogenous Spread of Mycobacterium tuberculosis without Sensitization to Tuberculin. by Chambers MA, Williams A, Gavier-Widen D, Whelan A, Hall G, Marsh PD, Bloom BR, Jacobs WR, Hewinson RG. 2000 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97820
•
Identification of a Promiscuous T-Cell Epitope in Mycobacterium tuberculosis Mce Proteins. by Panigada M, Sturniolo T, Besozzi G, Boccieri MG, Sinigaglia F, Grassi GG, Grassi F. 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127636
•
Identification of Amino Acid Residues of the T-Cell Epitope of Mycobacterium tuberculosis [alpha] Antigen Critical for V[beta]11 + Th1 Cells. by Kariyone A, Higuchi K, Yamamoto S, Nagasaka-Kametaka A, Harada M, Takahashi A, Harada N, Ogasawara K, Takatsu K. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96746
•
Identification of Mycobacterium tuberculosis DNA in a Pre-Columbian Peruvian Mummy. by Salo WL, Aufderheide AC, Buikstra J, Holcomb TA. 1994 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43315
•
Identification of nitric oxide synthase as a protective locus against tuberculosis. by MacMicking JD, North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan CF. 1997 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24663
154 Tuberculosis
•
Identification of Novel Mycobacterium tuberculosis Antigens with Potential as Diagnostic Reagents or Subunit Vaccine Candidates by Comparative Genomics. by Cockle PJ, Gordon SV, Lalvani A, Buddle BM, Hewinson RG, Vordermeier HM. 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=132958
•
Identification of Rifampin-Resistant Mycobacterium tuberculosis Strains by Hybridization, PCR, and Ligase Detection Reaction on Oligonucleotide Microchips. by Mikhailovich V, Lapa S, Gryadunov D, Sobolev A, Strizhkov B, Chernyh N, Skotnikova O, Irtuganova O, Moroz A, Litvinov V, Vladimirskii M, Perelman M, Chernousova L, Erokhin V, Zasedatelev A, Mirzabekov A. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88181
•
Immune Responses to the Mycobacterium tuberculosis-Specific Antigen ESAT-6 Signal Subclinical Infection among Contacts of Tuberculosis Patients. by Doherty TM, Demissie A, Olobo J, Wolday D, Britton S, Eguale T, Ravn P, Andersen P. 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153355
•
Immunoblot analysis for serodiagnosis of tuberculosis using a 45/47-kilodalton antigen complex of Mycobacterium tuberculosis. by Diagbouga S, Fumoux F, Zoubga A, Sanou PT, Marchal G. 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=170528
•
Immunogenicity of DNA Vaccines Expressing Tuberculosis Proteins Fused to Tissue Plasminogen Activator Signal Sequences. by Li Z, Howard A, Kelley C, Delogu G, Collins F, Morris S. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96809
•
Immunological Basis for Reactivation of Tuberculosis in Mice. by Turner J, GonzalezJuarrero M, Saunders BM, Brooks JV, Marietta P, Ellis DL, Frank AA, Cooper AM, Orme IM. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98285
•
Immunopathogenesis of Pulmonary Granulomas in the Guinea Pig after Infection with Mycobacterium tuberculosis. by Turner OC, Basaraba RJ, Orme IM. 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=145351
•
Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis. by Sterling TR, Lehmann HP, Frieden TR. 2003 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151519
•
Implications of Low Frequency of IS6110 in Fingerprinting Field Isolates of Mycobacterium tuberculosis from Kerala, India. by Radhakrishnan I, K. MY, Kumar RA, Mundayoor S. 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88004
Studies 155
•
Improved Tuberculosis DNA Vaccines by Formulation in Cationic Lipids. by D'Souza S, Rosseels V, Denis O, Tanghe A, De Smet N, Jurion F, Palfliet K, Castiglioni N, Vanonckelen A, Wheeler C, Huygen K. 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=128113
•
Improvement of Differentiation and Interpretability of Spoligotyping for Mycobacterium tuberculosis Complex Isolates by Introduction of New Spacer Oligonucleotides. by van der Zanden AG, Kremer K, Schouls LM, Caimi K, Cataldi A, Hulleman A, Nagelkerke NJ, van Soolingen D. 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=154657
•
In Situ Detection of Mycobacterium tuberculosis Transcripts in Human Lung Granulomas Reveals Differential Gene Expression in Necrotic Lesions. by Fenhalls G, Stevens L, Moses L, Bezuidenhout J, Betts JC, Helden PV, Lukey PT, Duncan K. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130373
•
In Vitro and In Vivo Activities of Gatifloxacin against Mycobacterium tuberculosis. by Alvirez-Freites EJ, Carter JL, Cynamon MH. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127120
•
In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis. by JI B, Lounis N, Truffot-Pernot C, Grosset J. 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=162738
•
In Vitro and In Vivo Activities of Moxifloxacin and Clinafloxacin against Mycobacterium tuberculosis. by Ji B, Lounis N, Maslo C, Truffot-Pernot C, Bonnafous P, Grosset J. 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105862
•
In vitro and in vivo activities of the benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis. by Hirata T, Saito H, Tomioka H, Sato K, Jidoi J, Hosoe K, Hidaka T. 1995 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=162932
•
In vitro bactericidal and in vivo therapeutic activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis. by Yamamoto T, Amitani R, Suzuki K, Tanaka E, Murayama T, Kuze F. 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163127
•
In Vivo Efficacy of ABT-255 against Drug-Sensitive and -Resistant Mycobacterium tuberculosis Strains. by Oleksijew A, Meulbroek J, Ewing P, Jarvis K, Mitten M, Paige L, Tovcimak A, Nukkula M, Chu D, Alder JD. 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105917
156 Tuberculosis
•
Increase in Gamma Interferon-Secreting CD8 +, as Well as CD4 +, T Cells in Lungs following Aerosol Infection with Mycobacterium tuberculosis. by Feng CG, Bean AG, Hooi H, Briscoe H, Britton WJ. 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=116502
•
Increased Numbers of ESAT-6- and Purified Protein Derivative-Specific Gamma Interferon-Producing Cells in Subclinical and Active Tuberculosis Infection. by Ulrichs T, Anding P, Porcelli S, Kaufmann SH, Munk ME. 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=101578
•
Increased risk of tuberculosis in health care workers: a retrospective survey at a teaching hospital in Istanbul, Turkey. by Cuhadaroglu C, Erelel M, Tabak L, Kilicaslan Z. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122064
•
Increased Sensitivity of the BACTEC 460 Mycobacterial Radiometric Broth Culture System Does Not Decrease the Number of Respiratory Specimens Required for a Definitive Diagnosis of Pulmonary Tuberculosis. by Harvell JD, Hadley WK, Ng VL. 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87444
•
Induction of a type 1 immune response to a recombinant antigen from Mycobacterium tuberculosis expressed in Mycobacterium vaccae. by Abou-Zeid C, Gares MP, Inwald J, Janssen R, Zhang Y, Young DB, Hetzel C, Lamb JR, Baldwin SL, Orme IM, Yeremeev V, Nikonenko BV, Apt AS. 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=175231
•
Induction of an AIDS Virus-Related Tuberculosis-Like Disease in Macaques: a Model of Simian Immunodeficiency Virus- Mycobacterium Coinfection. by Shen Y, Zhou D, Chalifoux L, Shen L, Simon M, Zeng X, Lai X, Li Y, Sehgal P, Letvin NL, Chen ZW. 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127670
•
Inhibition of Isoniazid-Induced Expression of Mycobacterium tuberculosis Antigen 85 in Sputum: Potential Surrogate Marker in Tuberculosis Chemotherapy Trials. by Wallis RS, Phillips M, Johnson JL, Teixeira L, Rocha LM, Maciel E, Rose L, Wells C, Palaci M, Dietze R, Eisenach K, Ellner JJ. 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90462
•
Inhibition of Mycobacterium tuberculosis Glutamine Synthetase as a Novel Antibiotic Strategy against Tuberculosis: Demonstration of Efficacy In Vivo. by Harth G, Horwitz MA. 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=143262
•
Inhibitory Effect of Alpha-Tec XPR-Plus Phosphate Buffer on the Enhanced GenProbe Amplified Mycobacterium Tuberculosis Direct Test. by Della-Latta P. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88688
Studies 157
•
Innate Immunity to Mycobacterium tuberculosis. by van Crevel R, Ottenhoff TH, van der Meer JW. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=118070
•
Interleukin-6 Induces Early Gamma Interferon Production in the Infected Lung but Is Not Required for Generation of Specific Immunity to Mycobacterium tuberculosis Infection. by Saunders BM, Frank AA, Orme IM, Cooper AM. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97591
•
Interleukin-7 or Interleukin-15 Enhances Survival of Mycobacterium tuberculosisInfected Mice. by Maeurer MJ, Trinder P, Hommel G, Walter W, Freitag K, Atkins D, Storkel S. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97510
•
Involvement of Antilipoarabinomannan Antibodies in Classical Complement Activation in Tuberculosis. by Hetland G, Wiker HG, Hogasen K, Hamasur B, Svenson SB, Harboe M. 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=121360
•
Lack of Protection in Mice and Necrotizing Bronchointerstitial Pneumonia with Bronchiolitis in Guinea Pigs Immunized with Vaccines Directed against the hsp60 Molecule of Mycobacterium tuberculosis. by Turner OC, Roberts AD, Frank AA, Phalen SW, McMurray DM, Content J, Denis O, D'Souza S, Tanghe A, Huygen K, Orme IM. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97658
•
Latent tuberculosis infection: old problem, new priorities. by Schwartzman K. 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=99454
•
Local Role for Tumor Necrosis Factor Alpha in the Pulmonary Inflammatory Response to Mycobacterium tuberculosis Infection. by Smith S, Liggitt D, Jeromsky E, Tan X, Skerrett SJ, Wilson CB. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127827
•
Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis. by Kelly BP, Furney SK, Jessen MT, Orme IM. 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163627
•
Lymphocyte populations during tuberculosis infection: V beta repertoires. by Gambon-Deza F, Pacheco Carracedo M, Cerda Mota T, Montes Santiago J. 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=173140
•
Major Histocompatibility Complex Class I-Restricted T Cells are Required for Resistance to Mycobacterium tuberculosis Infection. by Flynn JL, Goldstein MM, Triebold KJ, Koller B, Bloom BR. 1992 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50688
158 Tuberculosis
•
Mapping of IS6110 Insertion Sites in Two Epidemic Strains of Mycobacterium tuberculosis. by Beggs ML, Eisenach KD, Cave MD. 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87149
•
Mapping of Murine Th1 Helper T-Cell Epitopes of Mycolyl Transferases Ag85A, Ag85B, and Ag85C from Mycobacterium tuberculosis. by D'Souza S, Rosseels V, Romano M, Tanghe A, Denis O, Jurion F, Castiglione N, Vanonckelen A, Palfliet K, Huygen K. 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=143283
•
Mass Spectrometric Identification of Mtb81, a Novel Serological Marker for Tuberculosis. by Hendrickson RC, Douglass JF, Reynolds LD, McNeill PD, Carter D, Reed SG, Houghton RL. 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86802
•
Method for Inactivating and Fixing Unstained Smear Preparations of Mycobacterium tuberculosis for Improved Laboratory Safety. by Chedore P, Th'ng C, Nolan DH, Churchwell GM, Sieffert DE, Hale YM, Jamieson F. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=139704
•
Metronidazole Therapy in Mice Infected with Tuberculosis. by Brooks JV, Furney SK, Orme IM. 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89261
•
Misidentification and Diagnostic Delay Caused by a False-Positive Amplified Mycobacterium tuberculosis Direct Test in an Immunocompetent Patient with a Mycobacterium celatum Infection. by Tjhie JH, van Belle AF, Dessens-Kroon M, van Soolingen D. 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88133
•
Modeling the impact of global tuberculosis control strategies. by Murray CJ, Salomon JA. 1998 Nov 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24946
•
Modification of Results of Drug Susceptibility Tests by Coexistence of Mycobacterium avium Complex with Mycobacterium tuberculosis in a Sputum Sample: Case Report and Experimental Considerations. by Suzuki K, Kimoto T, Tsuyuguchi K, Matsumoto H, Niimi A, Tanaka E, Murayama T, Amitani R. 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105198
•
Molecular and Conventional Epidemiology of Mycobacterium tuberculosis in Botswana: a Population-Based Prospective Study of 301 Pulmonary Tuberculosis Patients. by Lockman S, Sheppard JD, Braden CR, Mwasekaga MJ, Woodley CL, Kenyon TA, Binkin NJ, Steinman M, Montsho F, Kesupile-Reed M, Hirschfeldt C, Notha M, Moeti T, Tappero JW. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87871
•
Molecular and Immunological Characterization of Mycobacterium tuberculosis CFP10, an Immunodiagnostic Antigen Missing in Mycobacterium bovis BCG. by Dillon
Studies 159
DC, Alderson MR, Day CH, Bement T, Campos-Neto A, Skeiky YA, Vedvick T, Badaro R, Reed SG, Houghton R. 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87375 •
Molecular Characterization and Human T-Cell Responses to a Member of a Novel Mycobacterium tuberculosis mtb39 Gene Family. by Dillon DC, Alderson MR, Day CH, Lewinsohn DM, Coler R, Bement T, Campos-Neto A, Skeiky YA, Orme IM, Roberts A, Steen S, Dalemans W, Badaro R, Reed SG. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96604
•
Molecular Characterization of Mycobacterium tuberculosis H37Rv/Ra Variants: Distinguishing the Mycobacterial Laboratory Strain. by Bifani P, Moghazeh S, Shopsin B, Driscoll J, Ravikovitch A, Kreiswirth BN. 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87354
•
Molecular Characterization of Rifampin-Resistant Isolates of Mycobacterium tuberculosis from Hungary by DNA Sequencing and the Line Probe Assay. by Bartfai Z, Somoskovi A, Kodmon C, Szabo N, Puskas E, Kosztolanyi L, Farago E, Mester J, Parsons LM, Salfinger M. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88421
•
Molecular Epidemiologic Evaluation of Transmissibility and Virulence of Mycobacterium tuberculosis. by Rhee JT, Piatek AS, Small PM, Harris LM, Chaparro SV, Kramer FR, Alland D. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84945
•
Molecular Epidemiology and Drug Resistance of Mycobacterium tuberculosis Isolates from Ethiopian Pulmonary Tuberculosis Patients with and without Human Immunodeficiency Virus Infection. by Bruchfeld J, Aderaye G, Palme IB, Bjorvatn B, Ghebremichael S, Hoffner S, Lindquist L. 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130945
•
Molecular epidemiology and the dynamics of tuberculosis transmission among foreign-born people. by Murray MB. 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=117849
•
Molecular Epidemiology of Mycobacterium tuberculosis in Norway. by Dahle UR, Sandven P, Heldal E, Caugant DA. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88029
•
Molecular Epidemiology of Mycobacterium tuberculosis Infection in Israel. by Ravins M, Bercovier H, Chemtob D, Fishman Y, Rahav G. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87899
160 Tuberculosis
•
Molecular Epidemiology of Tuberculosis in a Rural Area of High Prevalence in South India: Implications for Disease Control and Prevention. by Narayanan S, Das S, Garg R, Hari L, Rao VB, Frieden TR, Narayanan PR. 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=154620
•
Molecular Epidemiology of Tuberculosis in Malaysia. by Dale JW, Nor RM, Ramayah S, Tang TH, Zainuddin ZF. 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84747
•
Molecular epidemiology of tuberculosis in Montreal. by Kulaga S, Behr M, Musana K, Brinkman J, Menzies D, Brassard P, Kunimoto D, Tannenbaum TN, Thibert L, Joseph L, Boivin JF, Schwartzman K. 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117848
•
Molecular Epidemiology Study of Exogenous Reinfection in an Area with a Low Incidence of Tuberculosis. by Bandera A, Gori A, Catozzi L, Esposti AD, Marchetti G, Molteni C, Ferrario G, Codecasa L, Penati V, Matteelli A, Franzetti F. 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88113
•
Molecular Evidence for Heterogeneity of the Multiple-Drug-Resistant Mycobacterium tuberculosis Population in Scotland (1990 to 1997). by Fang Z, Doig C, Rayner A, Kenna DT, Watt B, Forbes KJ. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88639
•
Molecular Evidence for Independent Occurrence of IS6110 Insertions at the Same Sites of the Genome of Mycobacterium tuberculosis in Different Clinical Isolates. by Fang Z, Kenna DT, Doig C, Smittipat DN, Palittapongarnpim P, Watt B, Forbes KJ. 2001 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95409
•
Molecular Fingerprinting of Mycobacterium tuberculosis and Risk Factors for Tuberculosis Transmission in Paris, France, and Surrounding Area. by Gutierrez MC, Vincent V, Aubert D, Bizet J, Gaillot O, Lebrun L, Le Pendeven C, Le Pennec MP, Mathieu D, Offredo C, Pangon B, Pierre-Audigier C. 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104565
•
Molecular Fingerprinting of Mycobacterium tuberculosis Isolates Obtained in Havana, Cuba, by IS6110 Restriction Fragment Length Polymorphism Analysis and by the Double-Repetitive-Element PCR Method. by Montoro E, Valdivia J, Leao SC. 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105126
•
Molecular Markers Demonstrate that the First Described Multidrug-Resistant Mycobacterium bovis Outbreak Was Due to Mycobacterium tuberculosis. by Gutierrez MC, Galan JC, Blazquez J, Bouvet E, Vincent V. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88634
Studies 161
•
Molecular Typing of Mycobacterium tuberculosis Based on Variable Number of Tandem DNA Repeats Used Alone and in Association with Spoligotyping. by Filliol I, Ferdinand S, Negroni L, Sola C, Rastogi N. 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86957
•
Monitoring of Transmission of Tuberculosis between Wild Boars and Cattle: Genotypical Analysis of Strains by Molecular Epidemiology Techniques. by Serraino A, Marchetti G, Sanguinetti V, Rossi MC, Zanoni RG, Catozzi L, Bandera A, Dini W, Mignone W, Franzetti F, Gori A. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85373
•
Monitoring Treatment of Patients with Pulmonary Tuberculosis: Can PCR Be Applied? by Thomsen VO, Kok-Jensen A, Buser M, Philippi-Schulz S, Burkardt HJ. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85703
•
Moxifloxacin (BAY12-8039), a New 8-Methoxyquinolone, Is Active in a Mouse Model of Tuberculosis. by Miyazaki E, Miyazaki M, Chen JM, Chaisson RE, Bishai WR. 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89025
•
Multidrug resistant tuberculosis in France 1992-4: two case-control studies. by Schwoebel V, Decludt B, de Benoist AC, Haeghebaert S, Torrea G, Vincent V, Grosset J. 1998 Sep 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28656
•
Multigenic Control of Disease Severity after Virulent Mycobacterium tuberculosis Infection in Mice. by Sanchez F, Radaeva TV, Nikonenko BV, Persson AS, Sengul S, Schalling M, Schurr E, Apt AS, Lavebratt C. 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=143141
•
Multiple Mycobacterium tuberculosis Strains in Early Cultures from Patients in a High-Incidence Community Setting. by Richardson M, Carroll NM, Engelke E, van der Spuy GD, Salker F, Munch Z, Gie RP, Warren RM, Beyers N, van Helden PD. 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120639
•
Mutations in the rpoB and katG Genes Leading to Drug Resistance in Mycobacterium tuberculosis in Latvia. by Tracevska T, Jansone I, Broka L, Marga O, Baumanis V. 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130873
•
Mutations in the rpoB Gene of Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates from India. by Mani C, Selvakumar N, Narayanan S, Narayanan PR. 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88277
162 Tuberculosis
•
Mutations in the rpoB Gene of Multidrug-Resistant Mycobacterium tuberculosis Isolates from Brazil. by Valim AR, Rossetti ML, Ribeiro MO, Zaha A. 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87207
•
Mutations in the rpoB Gene of Rifampin-Resistant Mycobacterium tuberculosis Isolates in Spain and Their Rapid Detection by PCR --Enzyme-Linked Immunosorbent Assay. by Garcia L, Alonso-Sanz M, Rebollo MJ, Tercero JC, Chaves F. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88031
•
Mutations in the rpoB Gene of Rifampin-Resistant Mycobacterium tuberculosis Strains Isolated Mostly in Asian Countries and Their Rapid Detection by Line Probe Assay. by Hirano K, Abe C, Takahashi M. 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85308
•
Mycobacterial Antigens Exacerbate Disease Manifestations in Mycobacterium tuberculosis-Infected Mice. by Moreira AL, Tsenova L, Haile Aman M, Bekker LG, Freeman S, Mangaliso B, Schroder U, Jagirdar J, Rom WN, Tovey MG, Freedman VH, Kaplan G. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127838
•
Mycobacterium africanum Subtype II Is Associated with Two Distinct Genotypes and Is a Major Cause of Human Tuberculosis in Kampala, Uganda. by Niemann S, Rusch-Gerdes S, Joloba ML, Whalen CC, Guwatudde D, Ellner JJ, Eisenach K, Fumokong N, Johnson JL, Aisu T, Mugerwa RD, Okwera A, Schwander SK. 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130701
•
Mycobacterium bovis BCG Vaccination Augments Interleukin-8 mRNA Expression and Protein Production in Guinea Pig Alveolar Macrophages Infected with Mycobacterium tuberculosis. by Lyons MJ, Yoshimura T, McMurray DN. 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=128323
•
Mycobacterium microti Infection (Vole Tuberculosis) in Wild Rodent Populations. by Cavanagh R, Begon M, Bennett M, Ergon T, Graham IM, de Haas PE, Hart CA, Koedam M, Kremer K, Lambin X, Roholl P, Soolingen DV. 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130808
•
Mycobacterium tuberculosis CDC1551 Is Resistant to Reactive Nitrogen and Oxygen Intermediates In Vitro. by Firmani MA, Riley LW. 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=128088
•
Mycobacterium tuberculosis Des protein: an immunodominant target for the humoral response of tuberculous patients. by Jackson M, Portnoi D, Catheline D, Dumail L, Rauzier J, Legrand P, Gicquel B. 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=175405
Studies 163
•
Mycobacterium tuberculosis in Chemokine Receptor 2-Deficient Mice: Influence of Dose on Disease Progression. by Scott HM, Flynn JL. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130313
•
Mycobacterium tuberculosis in the Extracellular Compartment: an Underestimated Adversary. by Grosset J. 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=149338
•
Mycobacterium tuberculosis induces apoptosis in gamma/delta T lymphocytes from patients with advanced clinical forms of active tuberculosis. by Duarte R, Kindlelan JM, Carracedo J, Sanchez-Guijo P, Ramirez R. 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=170469
•
Mycobacterium tuberculosis Infection in a Green-Winged Macaw (Ara chloroptera): Report with Public Health Implications. by Washko RM, Hoefer H, Kiehn TE, Armstrong D, Dorsinville G, Frieden TR. 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104697
•
Mycobacterium tuberculosis Uptake by Recipient Host Macrophages Is Influenced by Environmental Conditions in the Granuloma of the Infectious Individual and Is Associated with Impaired Production of Interleukin-12 and Tumor Necrosis Factor Alpha. by Li YJ, Petrofsky M, Bermudez LE. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130307
•
Mycobacterium tuberculosis WhiB3 interacts with RpoV to affect host survival but is dispensable for in vivo growth. by Steyn AJ, Collins DM, Hondalus MK, Jacobs WR Jr, Kawakami RP, Bloom BR. 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122487
•
Necrosis of Lung Epithelial Cells during Infection with Mycobacterium tuberculosis Is Preceded by Cell Permeation. by Dobos KM, Spotts EA, Quinn FD, King CH. 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97713
•
Neutrophils Play a Protective Nonphagocytic Role in Systemic Mycobacterium tuberculosis Infection of Mice. by Pedrosa J, Saunders BM, Appelberg R, Orme IM, Silva MT, Cooper AM. 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97179
•
Novel IS6110 Insertion Sites in the Direct Repeat Locus of Mycobacterium tuberculosis Clinical Strains from the St. Petersburg Area of Russia and Evolutionary and Epidemiological Considerations. by Mokrousov I, Narvskaya O, Limeschenko E, Otten T, Vyshnevskiy B. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=140396
164 Tuberculosis
•
Oral Delivery of Mycobacterium bovis BCG in a Lipid Formulation Induces Resistance to Pulmonary Tuberculosis in Mice. by Aldwell FE, Tucker IG, de Lisle GW, Buddle BM. 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=143408
•
Osteoarticular tuberculosis: a case report and discussion. by Payne K, Yang J. 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=99407
•
Pathogenesis of tuberculosis in mice exposed to low and high doses of an environmental mycobacterial saprophyte before infection. by Hernandez-Pando R, Pavon L, Arriaga K, Orozco H, Madrid-Marina V, Rook G. 1997 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=175470
•
Pathophysiology of Antigen 85 in Patients with Active Tuberculosis: Antigen 85 Circulates as Complexes with Fibronectin and Immunoglobulin G. by Bentley-Hibbert SI, Quan X, Newman T, Huygen K, Godfrey HP. 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96358
•
Patient and health service delay in the diagnosis of pulmonary tuberculosis in Ethiopia. by Demissie M, Lindtjorn B, Berhane Y. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130033
•
PCR-Based Method To Differentiate the Subspecies of the Mycobacterium tuberculosis Complex on the Basis of Genomic Deletions. by Huard RC, de Oliveira Lazzarini LC, Butler WR, van Soolingen D, Ho JL. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153936
•
PCR-Based Rapid Detection of Mycobacterium tuberculosis in Blood from Immunocompetent Patients with Pulmonary Tuberculosis. by Ahmed N, Mohanty AK, Mukhopadhyay U, Batish VK, Grover S. 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105124
•
Performance Assessment of Two Commercial Amplification Assays for Direct Detection of Mycobacterium tuberculosis Complex from Respiratory and Extrapulmonary Specimens. by Piersimoni C, Scarparo C, Piccoli P, Rigon A, Ruggiero G, Nista D, Bornigia S. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=139632
•
Persistence and Protective Efficacy of a Mycobacterium tuberculosis Auxotroph Vaccine. by Jackson M, Phalen SW, Lagranderie M, Ensergueix D, Chavarot P, Marchal G, McMurray DN, Gicquel B, Guilhot C. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96594
•
Plasma-Soluble CD30 in Childhood Tuberculosis: Effects of Disease Severity, Nutritional Status, and Vitamin A Therapy. by Hanekom WA, Hussey GD, Hughes EJ, Potgieter S, Yogev R, Check IJ. 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95688
Studies 165
•
pncA Mutations as a Major Mechanism of Pyrazinamide Resistance in Mycobacterium tuberculosis: Spread of a Monoresistant Strain in Quebec, Canada. by Cheng SJ, Thibert L, Sanchez T, Heifets L, Zhang Y. 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89721
•
Predictors of clustering of tuberculosis in Greater Vancouver: a molecular epidemiologic study. by Hernandez-Garduno E, Kunimoto D, Wang L, Rodrigues M, Elwood RK, Black W, Mak S, FitzGerald JM. 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117847
•
Preventive chemotherapy of tuberculosis in Cornell model mice with combinations of rifampin, isoniazid, and pyrazinamide. by Dhillon J, Dickinson JM, Sole K, Mitchison DA. 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163156
•
Priming by DNA Immunization Augments Protective Efficacy of Mycobacterium bovis Bacille Calmette-Guerin against Tuberculosis. by Feng CG, Palendira U, Demangel C, Spratt JM, Malin AS, Britton WJ. 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98488
•
Production of Monocyte Chemoattractant Protein 1 in Tuberculosis Patients. by Lin Y, Gong J, Zhang M, Xue W, Barnes PF. 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108197
•
Protection against Mycobacterium tuberculosis Infection by CD8 + T Cells Requires the Production of Gamma Interferon. by Tascon RE, Stavropoulos E, Lukacs KV, Colston MJ. 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=107978
•
Protection of Mice with a Tuberculosis Subunit Vaccine Based on a Fusion Protein of Antigen 85B and ESAT-6. by Olsen AW, van Pinxteren LA, Okkels LM, Rasmussen PB, Andersen P. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98224
•
Protective Immunity Against Tuberculosis Induced by Vaccination with Major Extracellular Proteins of Mycobacterium tuberculosis. by Horwitz MA, Lee BE, Dillon BJ, Harth G. 1995 Feb 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42553
•
Protein Deficiency Induces Alterations in the Distribution of T-Cell Subsets in Experimental Pulmonary Tuberculosis. by Mainali ES, McMurray DN. 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=107997
•
Pulmonary Bovine-Type Tuberculosis in Rabbits: Bacillary Virulence, Inhaled Dose Effects, Tuberculin Sensitivity, and Mycobacterium vaccae Immunotherapy. by Converse PJ, Dannenberg AM Jr, Shigenaga T, McMurray DN, Phalen SW, Stanford JL, Rook GA, Koru-Sengul T, Abbey H, Estep JE, Pitt ML. 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96217
166 Tuberculosis
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Pulmonary Necrosis Resulting from DNA Vaccination against Tuberculosis. by Taylor JL, Turner OC, Basaraba RJ, Belisle JT, Huygen K, Orme IM. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=152079
•
Pyrazinamide-Monoresistant Mycobacterium tuberculosis in the United States. by Hannan MM, Desmond EP, Morlock GP, Mazurek GH, Crawford JT. 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87792
•
Rapid and Simple Approach for Identification of Mycobacterium tuberculosis Complex Isolates by PCR-Based Genomic Deletion Analysis. by Parsons LM, Brosch R, Cole ST, Somoskovi A, Loder A, Bretzel G, van Soolingen D, Hale YM, Salfinger M. 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120548
•
Rapid Detection of Mycobacterium tuberculosis in Contaminated BACTEC 12B Broth Cultures by Testing with Amplified Mycobacterium Tuberculosis Direct Test. by Zheng X, Pang M, Engler HD, Tanaka S, Reppun T. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88416
•
Rapid Detection of Pyrazinamide-Resistant Mycobacterium tuberculosis by a PCRBased In Vitro System. by Suzuki Y, Suzuki A, Tamaru A, Katsukawa C, Oda H. 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153375
•
Rapid Detection of Smear-Negative Mycobacterium tuberculosis by PCR and Sequencing for Rifampin Resistance with DNA Extracted Directly from Slides. by Patnaik M, Liegmann K, Peter JB. 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87678
•
Rapid Diagnosis of Extrapulmonary Tuberculosis by Ligase Chain Reaction Amplification. by Gamboa F, Dominguez J, Padilla E, Manterola JM, Gazapo E, Lonca J, Matas L, Hernandez A, Cardona PJ, Ausina V. 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104821
•
Rapid Diagnosis of Pulmonary Tuberculosis with the LCx Mycobacterium tuberculosis Assay and Comparison with Conventional Diagnostic Techniques. by Rohner P, Jahn EI, Ninet B, Ionati C, Weber R, Auckenthaler R, Pfyffer GE. 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105109
•
Rapid Film-Based Determination of Antibiotic Susceptibilities of Mycobacterium tuberculosis Strains by Using a Luciferase Reporter Phage and the Bronx Box. by Riska PF, Su Y, Bardarov S, Freundlich L, Sarkis G, Hatfull G, Carriere C, Kumar V, Chan J, Jacobs WR Jr. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88662
Studies 167
•
Rapid Identification of Laboratory Contamination with Mycobacterium tuberculosis Using Variable Number Tandem Repeat Analysis. by Gascoyne-Binzi DM, Barlow RE, Frothingham R, Robinson G, Collyns TA, Gelletlie R, Hawkey PM. 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87682
•
Rapid Immunochromatographic Assay for Diagnosis of Tuberculosis. by Grobusch MP, Schurmann D, Schwenke S, Teichmann D, Klein E. 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105356
•
Rapid Immunochromatographic Assay for Diagnosis of Tuberculosis: Antibodies Detected May Not Be Specific. by Freeman R, Magee J, Barratt A. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85054
•
Rapid, Efficient Detection and Drug Susceptibility Testing of Mycobacterium tuberculosis in Sputum by Microscopic Observation of Broth Cultures. by Caviedes L, Lee TS, Gilman RH, Sheen P, Spellman E, Lee EH, Berg DE, Montenegro-James S. 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86377
•
Rapid, Low-Technology MIC Determination with Clinical Mycobacterium tuberculosis Isolates by Using the Microplate Alamar Blue Assay. by Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G, Hernandez A, Degnan MT, Cook MB, Quenzer VK, Ferguson RM, Gilman RH. 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104543
•
Reactivation of Latent Tuberculosis: Variations on the Cornell Murine Model. by Scanga CA, Mohan VP, Joseph H, Yu K, Chan J, Flynn JL. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96774
•
Recombinant Gamma Interferon Stimulates Signal Transduction and Gene Expression in Alveolar Macrophages In Vitro and in Tuberculosis Patients. by Condos R, Raju B, Canova A, Zhao BY, Weiden M, Rom WN, Pine R. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=152019
•
Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative [final sigma] factor, SigH. by Kaushal D, Schroeder BG, Tyagi S, Yoshimatsu T, Scott C, Ko C, Carpenter L, Mehrotra J, Manabe YC, Fleischmann RD, Bishai WR. 2002 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123067
•
Regulation of Macrophage Gene Expression by Mycobacterium tuberculosis: DownRegulation of Mitochondrial Cytochrome c Oxidase. by Ragno S, Estrada-Garcia I, Butler R, Colston MJ. 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108461
•
Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice. by Sousa AO, Mazzaccaro RJ, Russell RG, Lee FK, Turner OC, Hong S, Van Kaer L, Bloom BR. 2000 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18197
168 Tuberculosis
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Removal of PCR Inhibitors by Silica Membranes: Evaluating the Amplicor Mycobacterium tuberculosis Kit. by Boddinghaus B, Wichelhaus TA, Brade V, Bittner T. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88425
•
Restriction Fragment Length Polymorphism Analysis of Mycobacterium tuberculosis Isolated from Countries in the Western Pacific Region. by Park YK, Bai GH, Kim SJ. 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88694
•
Results from 5 Years of Nationwide DNA Fingerprinting of Mycobacterium tuberculosis Complex Isolates in a Country with a Low Incidence of M. tuberculosis Infection. by Bauer J, Yang Z, Poulsen S, Andersen AB. 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=124862
•
Retrospective Analysis of the Beijing Family of Mycobacterium tuberculosis in Preserved Lung Tissues. by Qian L, Van Embden JD, Van Der Zanden AG, Weltevreden EF, Duanmu H, Douglas JT. 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84346
•
Reverse Dot Blot Assay (Insertion Site Typing) for Precise Detection of Sites of IS6110 Insertion in the Mycobacterium tuberculosis Genome. by Steinlein LM, Crawford JT. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87843
•
Risk of Mycobacterium tuberculosis Transmission in a Low-Incidence Country Due to Immigration from High-Incidence Areas. by Lillebaek T, Andersen AB, Bauer J, Dirksen A, Glismann S, de Haas P, Kok-Jensen A. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87841
•
Role of Trehalose Dimycolate in Recruitment of Cells and Modulation of Production of Cytokines and NO in Tuberculosis. by Lima VM, Bonato VL, Lima KM, Dos Santos SA, Dos Santos RR, Goncalves ED, Faccioli LH, Brandao IT, Rodrigues-Junior JM, Silva CL. 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98639
•
rpoB Mutations in Multidrug-Resistant Strains of Mycobacterium tuberculosis Isolated in Italy. by Pozzi G, Meloni M, Iona E, Orru G, Thoresen OF, Ricci ML, Oggioni MR, Fattorini L, Orefici G. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88675
•
Safety and Bactericidal Activity of Rifalazil in Patients with Pulmonary Tuberculosis. by Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, Rose L, Eisenach K, Ellner JJ. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90587
Studies 169
•
Secondary Typing of Mycobacterium tuberculosis Isolates with Matching IS6110 Fingerprints from Different Geographic Regions of the United States. by Yang ZH, Bates JH, Eisenach KD, Cave MD. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88010
•
Selective increases in antibody isotypes and immunoglobulin G subclass responses to secreted antigens in tuberculosis patients and healthy household contacts of the patients. by Hussain R, Dawood G, Abrar N, Toossi Z, Minai A, Dojki M, Ellner JJ. 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=170229
•
Selective T-Cell Recognition of the N-Terminal Peptide of GroES in Tuberculosis. by Chua-Intra B, Wilkinson RJ, Ivanyi J. 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127756
•
Sequestration of Mycobacterium tuberculosis in tight vacuoles in vivo in lung macrophages of mice infected by the respiratory route. by Moreira AL, Wang J, Tsenova-Berkova L, Hellmann W, Freedman VH, Kaplan G. 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=174592
•
Serodiagnosis of Tuberculosis: Comparison of Immunoglobulin A (IgA) Response to Sulfolipid I with IgG and IgM Responses to 2,3-Diacyltrehalose, 2,3,6Triacyltrehalose, and Cord Factor Antigens. by Julian E, Matas L, Perez A, Alcaide J, Laneelle MA, Luquin M. 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130848
•
Serodiagnostic Potential of Culture Filtrate Antigens of Mycobacterium tuberculosis. by Samanich KM, Keen MA, Vissa VD, Harder JD, Spencer JS, Belisle JT, Zolla-Pazner S, Laal S. 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95931
•
Serological Expression Cloning and Immunological Evaluation of MTB48, a Novel Mycobacterium tuberculosis Antigen. by Lodes MJ, Dillon DC, Mohamath R, Day CH, Benson DR, Reynolds LD, McNeill P, Sampaio DP, Skeiky YA, Badaro R, Persing DH, Reed SG, Houghton RL. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88174
•
Serum Therapy for Tuberculosis Revisited: Reappraisal of the Role of AntibodyMediated Immunity against Mycobacterium tuberculosis. by Glatman-Freedman A, Casadevall A. 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88894
•
Simple and Rapid Identification of the Mycobacterium tuberculosis Complex by Immunochromatographic Assay Using Anti-MPB64 Monoclonal Antibodies. by Abe C, Hirano K, Tomiyama T. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85727
170 Tuberculosis
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Simultaneous Infection with Two Drug-Susceptible Mycobacterium tuberculosis Strains in an Immunocompetent Host. by Pavlic M, Allerberger F, Dierich MP, Prodinger WM. 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85908
•
Single-Tube Balanced Heminested PCR for Detecting Mycobacterium tuberculosis in Smear-Negative Samples. by Garcia-Quintanilla A, Garcia L, Tudo G, Navarro M, Gonzalez J, Jimenez de Anta MT. 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86365
•
Specificity and Diversity of Antibodies to Mycobacterium tuberculosis Arabinomannan. by Navoa JA, Laal S, Pirofski LA, McLean GR, Dai Z, Robbins JB, Schneerson R, Casadevall A, Glatman-Freedman A. 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=145285
•
Specificity of IS6110-Based DNA Fingerprinting and Diagnostic Techniques for Mycobacterium tuberculosis Complex. by Githui WA, Wilson SM, Drobniewski FA. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88683
•
Spoligotyping and Polymorphic GC-Rich Repetitive Sequence Fingerprinting of Mycobacterium tuberculosis Strains Having Few Copies of IS6110. by Yang ZH, Ijaz K, Bates JH, Eisenach KD, Cave MD. 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87438
•
Spread of Drug-Resistant Mycobacterium tuberculosis Strains of the Beijing Genotype in the Archangel Oblast, Russia. by Toungoussova OS, Sandven P, Mariandyshev AO, Nizovtseva NI, Bjune G, Caugant DA. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130821
•
Spread of Drug-Resistant Pulmonary Tuberculosis in Estonia. by Kruuner A, Hoffner SE, Sillastu H, Danilovits M, Levina K, Svenson SB, Ghebremichael S, Koivula T, Kallenius G. 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88341
•
Sputum Cytokine Levels in Patients with Pulmonary Tuberculosis as Early Markers of Mycobacterial Clearance. by Ribeiro-Rodrigues R, Resende Co T, Johnson JL, Ribeiro F, Palaci M, Sa RT, Maciel EL, Pereira Lima FE, Dettoni V, Toossi Z, Boom WH, Dietze R, Ellner JJ, Hirsch CS. 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120011
•
Stability of IS6110 Restriction Fragment Length Polymorphism Patterns of Mycobacterium tuberculosis Strains in Actual Chains of Transmission. by Niemann S, Rusch-Gerdes S, Richter E, Thielen H, Heykes-Uden H, Diel R. 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86969
•
Stability of Mycobacterium tuberculosis IS6110 Restriction Fragment Length Polymorphism Patterns and Spoligotypes Determined by Analyzing Serial Isolates
Studies 171
from Patients with Drug-Resistant Tuberculosis. by Niemann S, Richter E, RuschGerdes S. 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84323 •
Subcellular Localization of the Intracellular Survival-Enhancing Eis Protein of Mycobacterium tuberculosis. by Dahl JL, Wei J, Moulder JW, Laal S, Friedman RL. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98499
•
Synergistic activities of clarithromycin and pyrazinamide against Mycobacterium tuberculosis in human macrophages. by Mor N, Esfandiari A. 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=164062
•
T-Cell Hyporesponsiveness Induced by Activated Macrophages through Nitric Oxide Production in Mice Infected with Mycobacterium tuberculosis. by Nabeshima S, Nomoto M, Matsuzaki G, Kishihara K, Taniguchi H, Yoshida SI, Nomoto K. 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=116499
•
T-Cell Recognition of Mycobacterium tuberculosis Culture Filtrate Fractions in Tuberculosis Patients and Their Household Contacts. by Demissie A, Ravn P, Olobo J, Doherty TM, Eguale T, Geletu M, Hailu W, Andersen P, Britton S. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96981
•
T-Cell Responses to the Mycobacterium tuberculosis-Specific Antigen ESAT-6 in Brazilian Tuberculosis Patients. by Cardoso FL, Antas PR, Milagres AS, Geluk A, Franken KL, Oliveira EB, Teixeira HC, Nogueira SA, Sarno EN, Klatser P, Ottenhoff TH, Sampaio EP. 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=132944
•
Temporal and Spatial Arrangement of Lymphocytes within Lung Granulomas Induced by Aerosol Infection with Mycobacterium tuberculosis. by Gonzalez-Juarrero M, Turner OC, Turner J, Marietta P, Brooks JV, Orme IM. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98078
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The Apa Protein of Mycobacterium tuberculosis Stimulates Gamma InterferonSecreting CD4 + and CD8 + T Cells from Purified Protein Derivative-Positive Individuals and Affords Protection in a Guinea Pig Model. by Kumar P, Amara RR, Challu VK, Chadda VK, Satchidanandam V. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=152084
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The Inducible Nitric Oxide Synthase Locus Confers Protection against Aerogenic Challenge of Both Clinical and Laboratory Strains of Mycobacterium tuberculosis in Mice. by Scanga CA, Mohan VP, Tanaka K, Alland D, Flynn JL, Chan J. 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98866
•
The IS6110 Restriction Fragment Length Polymorphism in Particular MultidrugResistant Mycobacterium tuberculosis Strains May Evolve Too Fast for Reliable Use
172 Tuberculosis
in Outbreak Investigation. by Alito A, Morcillo N, Scipioni S, Dolmann A, Romano MI, Cataldi A, van Soolingen D. 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84556 •
The MB/BacT Is a Sensitive Method of Isolating Mycobacterium tuberculosis from Clinical Specimens in a Laboratory with a Low Rate of Isolation. by Benjamin WH Jr, Waites KB, Moser SA. 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87213
•
The Susceptibility of Mycobacterium tuberculosis to Isoniazid and the Arg[right arrow]Leu Mutation at Codon 463 of katG Are Not Associated. by van Doorn HR, Kuijper EJ, van der Ende A, Welten AG, van Soolingen D, de Haas PE, Dankert J. 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87976
•
Therapeutic Potential of Human Neutrophil Peptide 1 against Experimental Tuberculosis. by Sharma S, Verma I, Khuller GK. 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90345
•
Transmission Dynamics and Molecular Characterization of Mycobacterium tuberculosis Isolates with Low Copy Numbers of IS6110. by Soini H, Pan X, Teeter L, Musser JM, Graviss EA. 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87705
•
Transmission Dynamics of Tuberculosis in a High-Incidence Country: Prospective Analysis by PCR DNA Fingerprinting. by Haas WH, Engelmann G, Amthor B, Shyamba S, Mugala F, Felten M, Rabbow M, Leichsenring M, Oosthuizen OJ, Bremer HJ. 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85859
•
Transmission of Drug-Resistant Tuberculosis in Texas and Mexico. by Quitugua TN, Seaworth BJ, Weis SE, Taylor JP, Gillette JS, Rosas II, Jost, Jr. KC, Magee DM, Cox RA. 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120686
•
Tuberculin Skin Testing Compared with T-Cell Responses to Mycobacterium tuberculosis-Specific and Nonspecific Antigens for Detection of Latent Infection in Persons with Recent Tuberculosis Contact. by Arend SM, Engelhard AC, Groot G, de Boer K, Andersen P, Ottenhoff TH, van Dissel JT. 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96231
•
Tuberculin-Purified Protein Derivative-, MPT-64-, and ESAT-6-Stimulated Gamma Interferon Responses in Medical Students before and after Mycobacterium bovis BCG Vaccination and in Patients with Tuberculosis. by Johnson PD, Stuart RL, Grayson ML, Olden D, Clancy A, Ravn P, Andersen P, Britton WJ, Rothel JS. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95801
Studies 173
•
Tuberculosis Contacts but Not Patients Have Higher Gamma Interferon Responses to ESAT-6 than Do Community Controls in The Gambia. by Vekemans J, Lienhardt C, Sillah JS, Wheeler JG, Lahai GP, Doherty MT, Corrah T, Andersen P, McAdam KP, Marchant A. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98797
•
Tuberculosis DNA Vaccine Encoding Ag85A Is Immunogenic and Protective When Administered by Intramuscular Needle Injection but Not by Epidermal Gene Gun Bombardment. by Tanghe A, Denis O, Lambrecht B, Motte V, van den Berg T, Huygen K. 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=101658
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Tuberculosis in the AIDS era. by Sepkowitz KA, Raffalli J, Riley L, Kiehn TE, Armstrong D. 1995 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=172855
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Tuberculosis Transmission in Botswana. by Bonora S, Boffito M, Audagnotto S, Di Perri G. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88447
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Tuberculosis: Latency and Reactivation. by Flynn JL, Chan J. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98451
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Tuberculosis: Old problems and new approaches. by Anderson RM. 1998 Nov 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33914
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Tumour necrosis factor-[alpha] inhibitors and the reactivation of latent tuberculosis infection. by Long R, Gardam M. 2003 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153687
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Two Liquid Medium Systems, Mycobacteria Growth Indicator Tube and MB Redox Tube, for Mycobacterium tuberculosis Isolation from Sputum Specimens. by Heifets L, Linder T, Sanchez T, Spencer D, Brennan J. 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86383
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Use of 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl Tetrazolium Bromide for Rapid Detection of Rifampin-Resistant Mycobacterium tuberculosis. by Mshana RN, Tadesse G, Abate G, Miorner H. 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104802
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Use of Equivocal Zone in Interpretation of Results of the Amplified Mycobacterium Tuberculosis Direct Test for Diagnosis of Tuberculosis. by Kerleguer A, Koeck JL, Fabre M, Gerome P, Teyssou R, Herve V. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=153920
174 Tuberculosis
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Use of Multiepitope Polyproteins in Serodiagnosis of Active Tuberculosis. by Houghton RL, Lodes MJ, Dillon DC, Reynolds LD, Day CH, McNeill PD, Hendrickson RC, Skeiky YA, Sampaio DP, Badaro R, Lyashchenko KP, Reed SG. 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120014
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Use of Mycobacterium tuberculosis Complex-Specific Antigen Cocktails for a Skin Test Specific for Tuberculosis. by Lyashchenko K, Manca C, Colangeli R, Heijbel A, Williams A, Gennaro ML. 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108392
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Use of Pulsed-Field Gel Electrophoresis for Molecular Epidemiologic and Population Genetic Studies of Mycobacterium tuberculosis. by Singh SP, Salamon H, Lahti CJ, Farid-Moyer M, Small PM. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84986
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Use of Real-Time PCR and Fluorimetry for Rapid Detection of Rifampin and Isoniazid Resistance-Associated Mutations in Mycobacterium tuberculosis. by Torres MJ, Criado A, Palomares JC, Aznar J. 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87353
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Use of Recommended Laboratory Testing Methods among Patients with Tuberculosis in California. by Kellam S, Pascopella L, Desmond E, Reingold A, Chin DP. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88060
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Use of Roche AMPLICOR Mycobacterium tuberculosis PCR in Early Diagnosis of Tuberculous Meningitis. by Bonington A, Strang JI, Klapper PE, Hood SV, Rubombora W, Penny M, Willers R, Wilkins EG. 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104809
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Use of Spoligotyping for Accurate Classification of Recurrent Tuberculosis. by Warren RM, Streicher EM, Charalambous S, Churchyard G, van der Spuy GD, Grant AD, van Helden PD, Victor TC. 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130897
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Use of Synthetic Peptides Derived from the Antigens ESAT-6 and CFP-10 for Differential Diagnosis of Bovine Tuberculosis in Cattle. by Vordermeier HM, Whelan A, Cockle PJ, Farrant L, Palmer N, Hewinson RG. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96103
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Use of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for Early Detection of Mycobacterium tuberculosis in BACTEC 12B Medium. by Desmond EP, Loretz K. 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88067
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Usefulness of Spoligotyping To Discriminate IS6110 Low-Copy-Number Mycobacterium tuberculosis Complex Strains Cultured in Denmark. by Bauer J, Andersen AB, Kremer K, Miorner H. 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85294
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Vaccinated Mice Remain More Susceptible to Mycobacterium tuberculosis Infection Initiated via the Respiratory Route than via the Intravenous Route. by North RJ, LaCourse R, Ryan L. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96560
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Vaccination of Cattle with Mycobacterium bovis Culture Filtrate Proteins and Interleukin-2 for Protection against Bovine Tuberculosis. by Wedlock DN, Vesosky B, Skinner MA, de Lisle GW, Orme IM, Buddle BM. 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=101541
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Vaccination of Guinea Pigs with Nutritionally Impaired Avirulent Mutants of Mycobacterium bovis Protects against Tuberculosis. by de Lisle GW, Wilson T, Collins DM, Buddle BM. 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=116014
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Value of Examining Three Acid-Fast Bacillus Sputum Smears for Removal of Patients Suspected of Having Tuberculosis from the "Airborne Precautions" Category. by Craft DW, Jones MC, Blanchet CN, Hopfer RL. 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87587
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Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-[alpha] /[beta]. by Manca C, Tsenova L, Bergtold A, Freeman S, Tovey M, Musser JM, Barry CE III, Freedman VH, Kaplan G. 2001 May 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33285
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Virulence of Mycobacterium tuberculosis CDC1551 and H37Rv in Rabbits Evaluated by Lurie's Pulmonary Tubercle Count Method. by Bishai WR, Dannenberg AM Jr, Parrish N, Ruiz R, Chen P, Zook BC, Johnson W, Boles JW, Pitt ML. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96831
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Virulence, Immunogenicity, and Protective Efficacy of Two Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Strains Expressing the Antigen ESAT-6 from Mycobacterium tuberculosis. by Bao L, Chen W, Zhang H, Wang X. 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=152063
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Which aminoglycoside or fluoroquinolone is more active against Mycobacterium tuberculosis in mice? by Lounis N, Ji B, Truffot-Pernot C, Grosset J. 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163759
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Whole-Genome Comparison of Mycobacterium tuberculosis Clinical and Laboratory Strains. by Fleischmann RD, Alland D, Eisen JA, Carpenter L, White O, Peterson J, DeBoy R, Dodson R, Gwinn M, Haft D, Hickey E, Kolonay JF, Nelson WC, Umayam LA,
176 Tuberculosis
Ermolaeva M, Salzberg SL, Delcher A, Utterback T, Weidman J, Khouri H, Gill J, Mikula A, Bishai W, Jacobs, Jr. WR, Venter JC, Fraser CM. 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=135346
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with tuberculosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “tuberculosis” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for tuberculosis (hyperlinks lead to article summaries): •
A case of multidrug-resistant (MDR) tuberculosis with collapse of the left lung after hemoptysis. Author(s): Abe Y, Kurita S, Ohkubo Y, Hashizume T, Fujino T. Source: Kekkaku. 2002 April; 77(4): 373-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12030044&dopt=Abstract
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A case of primary esophageal tuberculosis diagnosed by identification of Mycobacteria in paraffin-embedded esophageal biopsy specimens by polymerase chain reaction. Author(s): Fujiwara T, Yoshida Y, Yamada S, Kawamata H, Fujimori T, Imawari M. Source: Journal of Gastroenterology. 2003; 38(1): 74-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560925&dopt=Abstract
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A case of sarcoidosis following exposure to Mycobacterium tuberculosis (MTb). Author(s): Rutherford RM, Gilmartin JJ. Source: Ir Med J. 2003 February; 96(2): 58-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674162&dopt=Abstract
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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
Studies 177
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A case report of difficult diagnosis in the patient with advanced laryngeal tuberculosis. Author(s): Kenmochi M, Ohashi T, Nishino H, Sato S, Tanaka Y, Koizuka I, Shinagawa T. Source: Auris, Nasus, Larynx. 2003 February; 30 Suppl: S131-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543178&dopt=Abstract
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A clinical dilemma: abdominal tuberculosis. Author(s): Uygur-Bayramicli O, Dabak G, Dabak R. Source: World Journal of Gastroenterology : Wjg. 2003 May; 9(5): 1098-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717865&dopt=Abstract
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A clinical evaluation of children under the age of five years who are household contacts of adults with sputum positive tuberculosis in Harare, Zimbabwe. Author(s): Mtombeni S, Mahomva A, Siziya S, Sanyika C, Doolabh R, Nathoo KJ. Source: Cent Afr J Med. 2002 March-April; 48(3-4): 28-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12971154&dopt=Abstract
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A clonal expansion of methicillin-resistant Staphylococcus aureus (MRSA) in a tuberculosis ward. Author(s): Hosoda M, Toyama J, Hasada K, Fujino T, Ohtsuki R, Kirikae T. Source: Japanese Journal of Infectious Diseases. 2002 December; 55(6): 219-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606837&dopt=Abstract
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A comparison of dual skin test with mycobacterial antigens and tuberculin skin test alone in estimating prevalence of Mycobacterium tuberculosis infection from population surveys. Author(s): Bierrenbach AL, Floyd S, Cunha SC, Dourado I, Barreto ML, Pereira SM, Hijjar MA, Rodrigues LC. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 3129. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729335&dopt=Abstract
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A comprehensive study of the efficiency of the routine pulmonary tuberculosis diagnostic process in Nairobi. Author(s): van Cleeff MR, Kivihya-Ndugga L, Githui W, Nganga L, Odhiambo J, Klatser PR. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 February; 7(2): 186-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588021&dopt=Abstract
178 Tuberculosis
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A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis. Author(s): Hesseling AC, Schaaf HS, Gie RP, Starke JR, Beyers N. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1038-45. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546110&dopt=Abstract
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A dangerous liaison between two major killers: Mycobacterium tuberculosis and HIV target dendritic cells through DC-SIGN. Author(s): Kaufmann SH, Schaible UE. Source: The Journal of Experimental Medicine. 2003 January 6; 197(1): 1-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515808&dopt=Abstract
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A decade of change: tuberculosis in England and Wales 1988-98. Author(s): Balasegaram S, Watson JM, Rose AM, Charlett A, Nunn AJ, Rushdy A, Leese J, Ormerod LP; Public Health Laboratory Service/British Thoracic Society/Department of Health Collaborative Group. Source: Archives of Disease in Childhood. 2003 September; 88(9): 772-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937094&dopt=Abstract
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A DNA prime-Mycobacterium bovis BCG boost vaccination strategy for cattle induces protection against bovine tuberculosis. Author(s): Skinner MA, Buddle BM, Wedlock DN, Keen D, de Lisle GW, Tascon RE, Ferraz JC, Lowrie DB, Cockle PJ, Vordermeier HM, Hewinson RG. Source: Infection and Immunity. 2003 September; 71(9): 4901-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933831&dopt=Abstract
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A family of acr-coregulated Mycobacterium tuberculosis genes shares a common DNA motif and requires Rv3133c (dosR or devR) for expression. Author(s): Florczyk MA, McCue LA, Purkayastha A, Currenti E, Wolin MJ, McDonough KA. Source: Infection and Immunity. 2003 September; 71(9): 5332-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933881&dopt=Abstract
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A high prevalence of culture-positive extrapulmonary tuberculosis in a large Dutch teaching hospital. Author(s): Hesselink DA, Yoo SM, Verhoeven GT, Brouwers JW, Smit FJ, van Saase JL. Source: The Netherlands Journal of Medicine. 2003 March; 61(3): 65-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765226&dopt=Abstract
Studies 179
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A high tuberculosis case-fatality rate in a setting of effective tuberculosis control: implications for acceptable treatment success rates. Author(s): Fielder JF, Chaulk CP, Dalvi M, Gachuhi R, Comstock GW, Sterling TR. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1114-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546121&dopt=Abstract
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A literature review of the problems of delayed presentation for treatment and noncompletion of treatment for tuberculosis in less developed countries and ways of addressing these problems using particular implementations of the DOTS strategy. Author(s): Thomas C. Source: Journal of Management in Medicine. 2002; 16(4-5): 371-400. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12463651&dopt=Abstract
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A low cost, home-made, reverse-line blot hybridisation assay for rapid detection of rifampicin resistance in Mycobacterium tuberculosis. Author(s): Morcillo N, Zumarraga M, Alito A, Dolmann A, Schouls L, Cataldi A, Kremer K, van Soolingen D. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 959-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475141&dopt=Abstract
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A milestone in tuberculosis control. Author(s): Drazen JM. Source: The New England Journal of Medicine. 2002 October 31; 347(18): 1444. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409549&dopt=Abstract
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A prospective, multicenter study of laboratory cross-contamination of Mycobacterium tuberculosis cultures. Author(s): Jasmer RM, Roemer M, Hamilton J, Bunter J, Braden CR, Shinnick TM, Desmond EP. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1260-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453353&dopt=Abstract
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A rare site for tuberculosis. Author(s): Monga A, Arora A, Makkar RP, Gupta AK. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2002 November 12; 167(10): 1149-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427710&dopt=Abstract
180 Tuberculosis
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A retrospective evaluation of a score system adopted by the Ministry of Health, Brazil in the diagnosis of pulmonary tuberculosis in childhood: a case control study. Author(s): Sant'Anna CC, Orfaliais CT, March Mde F. Source: Revista Do Instituto De Medicina Tropical De Sao Paulo. 2003 March-April; 45(2): 103-5. Epub 2003 May 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12754577&dopt=Abstract
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A short history of Robert Koch's fight against tuberculosis: those who do not remember the past are condemned to repeat it. Author(s): Kaufmann SH. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 86-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758195&dopt=Abstract
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A starting point to a better detection of active and latent tuberculosis infection in HIV-positive individuals. Author(s): Jalba MS. Source: Aids (London, England). 2003 August 15; 17(12): 1859; Author Reply 1860-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891078&dopt=Abstract
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A suspected case of tuberculosis of the temporomandibular joint. Author(s): Soman D, Davies SJ. Source: British Dental Journal. 2003 January 11; 194(1): 23-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540933&dopt=Abstract
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A triad of radiologic signs. Tuberculosis of the 1st metatarsophalangeal joint. Author(s): Asrani A, Chavan G, Jain J. Source: Journal of Postgraduate Medicine. 2002 October-December; 48(4): 279, 289. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12613475&dopt=Abstract
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Abdominal computed tomographic findings of Mycobacterium tuberculosis and Mycobacterium avium intracellulare infection in HIV seropositive patients. Author(s): Koh DM, Burn PR, Mathews G, Nelson M, Healy JC. Source: Canadian Association of Radiologists Journal = Journal L'association Canadienne Des Radiologistes. 2003 February; 54(1): 45-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625084&dopt=Abstract
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Abdominal tuberculosis in children. Author(s): Ozbey H, Tireli GA, Salman T. Source: European Journal of Pediatric Surgery : Official Journal of Austrian Association of Pediatric Surgery. [et Al] = Zeitschrift Fur Kinderchirurgie. 2003 April; 13(2): 116-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12776244&dopt=Abstract
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Abdominal tuberculosis mimicking Crohn's disease: a difficult diagnosis. Report of a case. Author(s): Petroianni A, Mugnaini L, Laurendi G, Giousue S, Schinina V, Bibbolino C, Bisetti A. Source: Panminerva Medica. 2002 June; 44(2): 155-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032437&dopt=Abstract
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Abdominal tuberculosis with pancreatic involvement: a case report. Author(s): Panzuto F, D'Amato A, Laghi A, Cadau G, D'Ambra G, Aguzzi D, Iannaccone R, Montesani C, Caprilli R, Delle Fave G. Source: Dig Liver Dis. 2003 April; 35(4): 283-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801041&dopt=Abstract
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Abdominal tuberculosis: diagnosis by laparoscopy and colonoscopy. Author(s): Ibrarullah M, Mohan A, Sarkari A, Srinivas M, Mishra A, Sundar TS. Source: Trop Gastroenterol. 2002 July-September; 23(3): 150-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693163&dopt=Abstract
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Acquired systemic-to-pulmonary arteriovenous malformation secondary to Mycobacterium tuberculosis empyema. Author(s): Denlinger CE, Egan TM, Jones DR. Source: The Annals of Thoracic Surgery. 2002 October; 74(4): 1229-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12400775&dopt=Abstract
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Adherence to tuberculosis treatment: lessons from the urban setting of Delhi, India. Author(s): Jaiswal A, Singh V, Ogden JA, Porter JD, Sharma PP, Sarin R, Arora VK, Jain RC. Source: Tropical Medicine & International Health : Tm & Ih. 2003 July; 8(7): 625-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828545&dopt=Abstract
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Adulthood mortality of infants isolated at birth due to tuberculosis in the family. Author(s): Veijola JM, Maki PH, Joukamaa MI, Laara E, Hakko H, Nieminen MM, Isohanni MK. Source: Scandinavian Journal of Public Health. 2003; 31(1): 69-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623528&dopt=Abstract
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Adult-to-child transmission of tuberculosis: household or community contact? Author(s): Schaaf HS, Michaelis IA, Richardson M, Booysen CN, Gie RP, Warren R, van Helden PD, Beyers N. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 42631. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757042&dopt=Abstract
182 Tuberculosis
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Africa has a right to support from international community in its fight against HIV/AIDS, malaria, and tuberculosis. Author(s): McConnell H. Source: Bmj (Clinical Research Ed.). 2003 July 19; 327(7407): 124. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869447&dopt=Abstract
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Africa seeks new tuberculosis control methods. Author(s): Siringi S. Source: Lancet. 2003 June 21; 361(9375): 2135. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826444&dopt=Abstract
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AIDS and tuberculosis in medical inpatients in Malawi. Author(s): Weismuller MM, Meijnen S, Claessens NJ, Salaniponi FM, Harries AD. Source: Trop Doct. 2003 July; 33(3): 167-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870607&dopt=Abstract
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Allele frequencies for glutathione S-transferase and N-acetyltransferase 2 differ in African population groups and may be associated with oesophageal cancer or tuberculosis incidence. Author(s): Adams CH, Werely CJ, Victor TC, Hoal EG, Rossouw G, van Helden PD. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2003 April; 41(4): 600-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747608&dopt=Abstract
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Allele-specific rpoB PCR assays for detection of rifampin-resistant Mycobacterium tuberculosis in sputum smears. Author(s): Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O. Source: Antimicrobial Agents and Chemotherapy. 2003 July; 47(7): 2231-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821473&dopt=Abstract
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American cutaneous leishmaniasis, lepromatous leprosy, and pulmonary tuberculosis coinfection with downregulation of the T-helper 1 cell response. Author(s): Delobel P, Launois P, Djossou F, Sainte-Marie D, Pradinaud R. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 September 1; 37(5): 628-33. Epub 2003 August 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942392&dopt=Abstract
Studies 183
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American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Author(s): Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, Jasmer RM, Koppaka V, Menzies RI, O'Brien RJ, Reves RR, Reichman LB, Simone PM, Starke JR, Vernon AA; American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society. Source: American Journal of Respiratory and Critical Care Medicine. 2003 February 15; 167(4): 603-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588714&dopt=Abstract
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Americans' knowledge and perceived risk of tuberculosis. Author(s): Ailinger RL, Lasus H, Dear M. Source: Public Health Nursing (Boston, Mass.). 2003 May-June; 20(3): 211-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716401&dopt=Abstract
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An evaluation of the BD ProbeTec ET system for the direct detection of Mycobacterium tuberculosis in respiratory samples. Author(s): Barrett A, Magee JG, Freeman R. Source: Journal of Medical Microbiology. 2002 October; 51(10): 895-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435071&dopt=Abstract
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An unusual case of primary nasal tuberculosis with epistaxis and epilepsy. Author(s): Batra K, Chaudhary N, Motwani G, Rai AK. Source: Ear, Nose, & Throat Journal. 2002 December; 81(12): 842-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516380&dopt=Abstract
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Analysis of tuberculosis surveillance in Hungary in 2000. Author(s): Mester J, Vadasz I, Pataki G, Parsons L, Fodor T, Salfinger M, Somoskovi A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 966-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475142&dopt=Abstract
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Annual Mycobacterium tuberculosis infection risk and interpretation of clustering statistics. Author(s): Vynnycky E, Borgdorff MW, van Soolingen D, Fine PE. Source: Emerging Infectious Diseases. 2003 February; 9(2): 176-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603987&dopt=Abstract
184 Tuberculosis
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Anterior plating for lower cervical spine tuberculosis. Author(s): Hassan MG. Source: International Orthopaedics. 2003; 27(2): 73-7. Epub 2002 December 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700928&dopt=Abstract
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Anterior radical debridement and anterior instrumentation in tuberculosis spondylitis. Author(s): Benli IT, Acaroglu E, Akalin S, Kis M, Duman E, Un A. Source: European Spine Journal : Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2003 April; 12(2): 224-34. Epub 2002 September 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12709862&dopt=Abstract
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Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Author(s): Delgado JC, Tsai EY, Thim S, Baena A, Boussiotis VA, Reynes JM, Sath S, Grosjean P, Yunis EJ, Goldfeld AE. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 May 28; 99(11): 7576-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032325&dopt=Abstract
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Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS. Author(s): Williams BG, Dye C. Source: Science. 2003 September 12; 301(5639): 1535-7. Epub 2003 August 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920302&dopt=Abstract
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Antitubercular isoniazid and drug resistance of Mycobacterium tuberculosis--a review. Author(s): Scior T, Meneses Morales I, Garces Eisele SJ, Domeyer D, Laufer S. Source: Archiv Der Pharmazie. 2002; 335(11-12): 511-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12596216&dopt=Abstract
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Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Author(s): Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, Vinh DC. Source: The Lancet Infectious Diseases. 2003 March; 3(3): 148-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614731&dopt=Abstract
Studies 185
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Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Author(s): Schaible UE, Winau F, Sieling PA, Fischer K, Collins HL, Hagens K, Modlin RL, Brinkmann V, Kaufmann SH. Source: Nature Medicine. 2003 August; 9(8): 1039-46. Epub 2003 July 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12872166&dopt=Abstract
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Arthritis associated with tuberculosis. Author(s): Malaviya AN, Kotwal PP. Source: Best Practice & Research. Clinical Rheumatology. 2003 April; 17(2): 319-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12787528&dopt=Abstract
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Aseptic cerebral venous thrombosis associated with abdominal tuberculosis. Author(s): Kakkar N, Banerjee AK, Vasishta RK, Marwaha N, Deodhar SD. Source: Neurology India. 2003 March; 51(1): 128-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865551&dopt=Abstract
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Aspiration cytology for diagnosis of tuberculosis--perspectives in India. Author(s): Verma K, Kapila K. Source: Indian J Pediatr. 2002 November; 69 Suppl 1: S39-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501924&dopt=Abstract
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Assessment by meta-analysis of PCR for diagnosis of smear-negative pulmonary tuberculosis. Author(s): Sarmiento OL, Weigle KA, Alexander J, Weber DJ, Miller WC. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 3233-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843069&dopt=Abstract
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Assessment of the impact of BCG vaccination on tuberculosis incidence in south Asian adult immigrants. Author(s): Chaloner JH, Ormerod LP. Source: Commun Dis Public Health. 2002 December; 5(4): 338-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12564256&dopt=Abstract
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Assessment of tuberculosis treatment completion in an ethnically diverse population using two data sources. Implications for treatment interventions. Author(s): Morisky DE, Ebin VJ, Malotte CK, Coly A, Kominski G. Source: Evaluation & the Health Professions. 2003 March; 26(1): 43-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629921&dopt=Abstract
186 Tuberculosis
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Association between interleukin-8 gene alleles and human susceptibility to tuberculosis disease. Author(s): Ma X, Reich RA, Wright JA, Tooker HR, Teeter LD, Musser JM, Graviss EA. Source: The Journal of Infectious Diseases. 2003 August 1; 188(3): 349-55. Epub 2003 July 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870115&dopt=Abstract
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Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Author(s): Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG. Source: Lancet. 2003 May 31; 361(9372): 1871-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788577&dopt=Abstract
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Association of a polymorphism in the P2X7 gene with tuberculosis in a Gambian population. Author(s): Li CM, Campbell SJ, Kumararatne DS, Bellamy R, Ruwende C, McAdam KP, Hill AV, Lammas DA. Source: The Journal of Infectious Diseases. 2002 November 15; 186(10): 1458-62. Epub 2002 October 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12404161&dopt=Abstract
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Association of high HIV-1 RNA levels and homozygosity at HLA class II DRB1 in adults coinfected with Mycobacterium tuberculosis in Harare, Zimbabwe. Author(s): Zijenah LS, Hartogensis WE, Katzenstein DA, Tobaiwa O, Mutswangwa J, Mason PR, Louie LG. Source: Human Immunology. 2002 November; 63(11): 1026-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12392855&dopt=Abstract
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Associations between toll-like receptors and interleukin-4 in the lungs of patients with tuberculosis. Author(s): Fenhalls G, Squires GR, Stevens-Muller L, Bezuidenhout J, Amphlett G, Duncan K, Lukey PT. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 July; 29(1): 28-38. Epub 2002 December 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12600829&dopt=Abstract
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Atypical intradural spinal tuberculosis: report of three cases. Author(s): Tanriverdi T, Kizilkilic O, Hanci M, Kaynar MY, Unalan H, Oz B. Source: Spinal Cord : the Official Journal of the International Medical Society of Paraplegia. 2003 July; 41(7): 403-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12815372&dopt=Abstract
Studies 187
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Atypical mycobacterial tuberculosis--a diagnostic and therapeutic dilemma? Case reports and review of the literature. Author(s): Dunne AA, Kim-Berger HS, Zimmermann S, Moll R, Lippert BM, Werner JA. Source: Otolaryngol Pol. 2003; 57(1): 17-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12741139&dopt=Abstract
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Atypical tuberculosis skin test reaction. Author(s): Blossom AP, Cleary JD. Source: The Annals of Pharmacotherapy. 2003 March; 37(3): 451. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639180&dopt=Abstract
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Audit of transthoracic fine needle aspiration of the lung: cytological subclassification of bronchogenic carcinomas and diagnosis of tuberculosis. Author(s): Tan KB, Thamboo TP, Wang SC, Nilsson B, Rajwanshi A, Salto-Tellez M. Source: Singapore Med J. 2002 November; 43(11): 570-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680526&dopt=Abstract
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Bacillarity at autopsy in pulmonary tuberculosis. Mycobacterium tuberculosis is often disseminated. Author(s): Lillebaek T, Kok-Jensen A, Viskum K. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2002 September; 110(9): 625-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529015&dopt=Abstract
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Bacterial endocarditis: a role for Mycobacterium tuberculosis? Author(s): Fumagalli J, Bonifacio C, Gulotta H, Shinzato R, Troncoso A. Source: Aids (London, England). 2002 September 6; 16(13): 1845-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12218405&dopt=Abstract
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Bactericidal activities of commonly used antiseptics against multidrug-resistant mycobacterium tuberculosis. Author(s): Rikimaru T, Kondo M, Kajimura K, Hashimoto K, Oyamada K, Sagawa K, Tanoue S, Oizumi K. Source: Dermatology (Basel, Switzerland). 2002; 204 Suppl 1: 15-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12011515&dopt=Abstract
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Bactericidal activity in whole blood as a potential surrogate marker of immunity after vaccination against tuberculosis. Author(s): Cheon SH, Kampmann B, Hise AG, Phillips M, Song HY, Landen K, Li Q, Larkin R, Ellner JJ, Silver RF, Hoft DF, Wallis RS. Source: Clinical and Diagnostic Laboratory Immunology. 2002 July; 9(4): 901-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12093693&dopt=Abstract
188 Tuberculosis
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Bacteriological conversion in twenty urinary tuberculosis patients treated with ofloxacin, rifampin and isoniazid: a 10-year follow-up study. Author(s): Castineiras AA, Perez-Pascual P, Zarranz JE, Della-Latta P, Herreras A. Source: International Microbiology : the Official Journal of the Spanish Society for Microbiology. 2002 September; 5(3): 139-44. Epub 2002 June 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12207216&dopt=Abstract
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Bacteriological follow-up of tuberculosis treatment: a comparative study of smear microscopy and culture results at the second month of treatment. Author(s): Ramarokoto H, Randriamiharisoa H, Rakotoarisaonina A, Rasolovavalona T, Rasolofo V, Chanteau S, Ralamboson M, Cauchoix B, Rakotondramarina D. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 October; 6(10): 909-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12365578&dopt=Abstract
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Bartonella quintana and Mycobacterium tuberculosis coinfection in an HIV-infected patient with lymphadenitis. Author(s): Bernit E, Veit V, La Scola B, Tissot-Dupont H, Gachon J, Raoult D, Harle JR. Source: The Journal of Infection. 2003 May; 46(4): 244-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799150&dopt=Abstract
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Basic concepts in the treatment of tuberculosis. Author(s): Swaminathan S. Source: Indian J Pediatr. 2002 November; 69 Suppl 1: S44-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501925&dopt=Abstract
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BCG installations for bladder cancer and latent tuberculosis infection. Author(s): Hanson K. Source: Urologic Nursing : Official Journal of the American Urological Association Allied. 2002 April; 22(2): 132-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11993243&dopt=Abstract
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BCG vaccination and tuberculosis in Japan. Author(s): Rahman M, Takahashi O, Goto M, Fukui T. Source: J Epidemiol. 2003 May; 13(3): 127-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749599&dopt=Abstract
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Behavioral interventions for the control of tuberculosis among adolescents. Author(s): Morisky DE, Malotte CK, Ebin V, Davidson P, Cabrera D, Trout PT, Coly A. Source: Public Health Reports (Washington, D.C. : 1974). 2001 November-December; 116(6): 568-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196616&dopt=Abstract
Studies 189
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beta-1,3-Glucan reduces growth of Mycobacterium tuberculosis in macrophage cultures. Author(s): Hetland G, Sandven P. Source: Fems Immunology and Medical Microbiology. 2002 March 25; 33(1): 41-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11985967&dopt=Abstract
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Bilateral chalazia of the lower eyelids associated with pulmonary tuberculosis. Author(s): Aoki M, Kawana S. Source: Acta Dermato-Venereologica. 2002; 82(5): 386-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12430745&dopt=Abstract
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Bilateral pneumothorax complicating miliary tuberculosis in children: case report and review of the literature. Author(s): Wammanda RD, Ameh EA, Ali FU. Source: Annals of Tropical Paediatrics. 2003 June; 23(2): 149-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803746&dopt=Abstract
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Biochemical and histochemical changes pertaining to active and healed cutaneous tuberculosis. Author(s): Jayasankar K, Shakila H, Umapathy KC, Ramanathan VD. Source: The British Journal of Dermatology. 2002 June; 146(6): 977-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12072065&dopt=Abstract
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Blood agar and Mycobacterium tuberculosis: the end of a dogma. Author(s): Drancourt M, Carrieri P, Gevaudan MJ, Raoult D. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1710-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682165&dopt=Abstract
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Breast mass caused by rib tuberculosis abscess. Author(s): Eroglu A, Kurkcuoglu C, Karaoglanoglu N, Kaynar H. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2002 August; 22(2): 324-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12142213&dopt=Abstract
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Bronchoesophageal fistulae secondary to tuberculosis. Author(s): Lado Lado FL, Golpe Gomez A, Cabarcos Ortiz de Barron A, Antunez Lopez JR. Source: Respiration; International Review of Thoracic Diseases. 2002; 69(4): 362-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12169754&dopt=Abstract
190 Tuberculosis
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Building a better tuberculosis vaccine. Author(s): Young DB. Source: Nature Medicine. 2003 May; 9(5): 503-4. Epub 2003 April 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692547&dopt=Abstract
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Caecal amoeboma simulating malignant neoplasia, ileocaecal tuberculosis and Crohn's disease. Author(s): Majeed SK, Ghazanfar A, Ashraf J. Source: J Coll Physicians Surg Pak. 2003 February; 13(2): 116-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12685960&dopt=Abstract
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Can tuberculosis be controlled? Author(s): Frieden TR. Source: International Journal of Epidemiology. 2002 October; 31(5): 894-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435756&dopt=Abstract
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Capsule endoscopy appearances of small-bowel tuberculosis. Author(s): Reddy DN, Sriram PV, Rao GV, Reddy DB. Source: Endoscopy. 2003 January; 35(1): 99. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12510241&dopt=Abstract
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Care-seeking behavioural patterns, awareness and diagnostic processes in patients with smear- and culture-positive pulmonary tuberculosis in Lagos, Nigeria. Author(s): Enwuru CA, Idigbe EO, Ezeobi NV, Otegbeye AF. Source: Trans R Soc Trop Med Hyg. 2002 November-December; 96(6): 614-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625134&dopt=Abstract
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Cavitary pulmonary lesions noted after blunt thoracic trauma: causative relation or pre-existing tuberculosis? Author(s): Protopapas AD, Riga AT. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2003 June; 23(6): 1076; Author Reply 1076-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829098&dopt=Abstract
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CD40 ligand trimer enhances the response of CD8+ T cells to Mycobacterium tuberculosis. Author(s): Samten B, Wizel B, Shams H, Weis SE, Klucar P, Wu S, Vankayalapati R, Thomas EK, Okada S, Krensky AM, Barnes PF. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 March 15; 170(6): 3180-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12626576&dopt=Abstract
Studies 191
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Cerebral hemorrhage associated with vitamin K deficiency in congenital tuberculosis treated with isoniazid and rifampin. Author(s): Kobayashi K, Haruta T, Maeda H, Kubota M, Nishio T. Source: The Pediatric Infectious Disease Journal. 2002 November; 21(11): 1088-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458578&dopt=Abstract
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Cervical tuberculosis in early childhood. Author(s): Dogulu F, Baykaner MK, Onk A, Celik B, Ceviker N. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. 2003 March; 19(3): 192-4. Epub 2003 February 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644873&dopt=Abstract
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Changes in the transmission of tuberculosis in New York. Author(s): John TJ. Source: The New England Journal of Medicine. 2002 October 31; 347(18): 1453-5; Author Reply 1453-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12418042&dopt=Abstract
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Characteristics of pulmonary Mycobacterium avium-intracellulare complex (MAC) infection in comparison with those of tuberculosis. Author(s): Watanabe K, Fujimura M, Kasahara K, Yasui M, Myou S, Watanabe A, Nakao S. Source: Respiratory Medicine. 2003 June; 97(6): 654-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814150&dopt=Abstract
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Characterization of Finnish Mycobacterium tuberculosis isolates by spoligotyping. Author(s): Puustinen K, Marjamaki M, Rastogi N, Sola C, Filliol I, Ruutu P, Holmstrom P, Viljanen MK, Soini H. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1525-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682140&dopt=Abstract
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Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping. Author(s): Zink AR, Sola C, Reischl U, Grabner W, Rastogi N, Wolf H, Nerlich AG. Source: Journal of Clinical Microbiology. 2003 January; 41(1): 359-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517873&dopt=Abstract
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Characterization of rifampicin-resistant Mycobacterium tuberculosis in Taiwan. Author(s): Hwang HY, Chang CY, Chang LL, Chang SF, Chang YH, Chen YJ. Source: Journal of Medical Microbiology. 2003 March; 52(Pt 3): 239-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621089&dopt=Abstract
192 Tuberculosis
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Characterization of rpoB mutations in rifampin-resistant clinical isolates of Mycobacterium tuberculosis from Turkey by DNA sequencing and line probe assay. Author(s): Cavusoglu C, Hilmioglu S, Guneri S, Bilgic A. Source: Journal of Clinical Microbiology. 2002 December; 40(12): 4435-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454132&dopt=Abstract
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Characterization of the Manila family of Mycobacterium tuberculosis. Author(s): Douglas JT, Qian L, Montoya JC, Musser JM, Van Embden JD, Van Soolingen D, Kremer K. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2723-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791915&dopt=Abstract
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Children and multidrug-resistant tuberculosis in Mumbai (Bombay), India. Author(s): Karande S, Bavdekar SB. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1360-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453371&dopt=Abstract
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Choroidal tubercles in disseminated tuberculosis diagnosed by the polymerase chain reaction of aqueous humor. A case report and review of the literature. Author(s): Biswas J, Shome D. Source: Ocular Immunology and Inflammation. 2002 December; 10(4): 293-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854038&dopt=Abstract
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Choroidal tuberculoma in miliary tuberculosis. Author(s): Sharma PM, Singh RP, Kumar A, Prakash G, Mathur MB, Malik P. Source: Retina (Philadelphia, Pa.). 2003 February; 23(1): 101-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12652241&dopt=Abstract
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Circulating antioxidants and lipid peroxidation products in untreated tuberculosis patients in Ethiopia. Author(s): Madebo T, Lindtjorn B, Aukrust P, Berge RK. Source: The American Journal of Clinical Nutrition. 2003 July; 78(1): 117-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816780&dopt=Abstract
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Clinical analysis of pulmonary tuberculosis in association with corticosteroid therapy. Author(s): Kobashi Y, Matsushima T. Source: Intern Med. 2002 December; 41(12): 1103-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12521197&dopt=Abstract
Studies 193
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Clinical and radiographic features of pulmonary tuberculosis in non-AIDS immunocompromised patients. Author(s): Kiyan E, Kilicaslan Z, Gurgan M, Tunaci A, Yildiz A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 764-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921153&dopt=Abstract
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Clinical and radiological features in relation to urinary excretion of lipoarabinomannan in Ethiopian tuberculosis patients. Author(s): Tessema TA, Bjune G, Assefa G, Svenson S, Hamasur B, Bjorvatn B. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(3): 167-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12030387&dopt=Abstract
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Clinical characteristics and treatment response among patients with multidrugresistant tuberculosis: a retrospective study. Author(s): Subhash HS, Ashwin I, Jesudason MV, Abharam OC, John G, Cherian AM, Thomas K. Source: Indian J Chest Dis Allied Sci. 2003 April-June; 45(2): 97-103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12715931&dopt=Abstract
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Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Author(s): Ordway D, Viveiros M, Leandro C, Bettencourt R, Almeida J, Martins M, Kristiansen JE, Molnar J, Amaral L. Source: Antimicrobial Agents and Chemotherapy. 2003 March; 47(3): 917-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604522&dopt=Abstract
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Clinical diagnosis of smear-negative pulmonary tuberculosis in low-income countries: the current evidence. Author(s): Siddiqi K, Lambert ML, Walley J. Source: The Lancet Infectious Diseases. 2003 May; 3(5): 288-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12726978&dopt=Abstract
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Clinical practice. Latent tuberculosis infection. Author(s): Jasmer RM, Nahid P, Hopewell PC. Source: The New England Journal of Medicine. 2002 December 5; 347(23): 1860-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466511&dopt=Abstract
194 Tuberculosis
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Clinical presentation and survival of smear-positive pulmonary tuberculosis patients of a university general hospital in a developing country. Author(s): Carvalho AC, Nunes ZB, Martins M, Araujo RO, Comelli M, Marinoni A, Kritski AL. Source: Memorias Do Instituto Oswaldo Cruz. 2002 December; 97(8): 1225-30. Epub 2003 January 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12563494&dopt=Abstract
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Clinical spectrum of hepatic tuberculosis: comparison between immunocompetent and immunocompromised hosts. Author(s): Vilaichone RK, Vilaichone W, Tumwasorn S, Suwanagool P, Wilde H, Mahachai V. Source: J Med Assoc Thai. 2003 June; 86 Suppl 2: S432-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930021&dopt=Abstract
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Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor beta1 deficiency. Author(s): Caragol I, Raspall M, Fieschi C, Feinberg J, Larrosa MN, Hernandez M, Figueras C, Bertran JM, Casanova JL, Espanol T. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 July 15; 37(2): 302-6. Epub 2003 Jul 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856223&dopt=Abstract
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Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. Author(s): Oliva J, Moreno S, Sanz J, Ribera E, Molina JA, Rubio R, Casas E, Marino A. Source: Aids (London, England). 2003 March 7; 17(4): 637-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598789&dopt=Abstract
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Combined use of serum and urinary antibody for diagnosis of tuberculosis. Author(s): Singh KK, Dong Y, Hinds L, Keen MA, Belisle JT, Zolla-Pazner S, Achkar JM, Nadas AJ, Arora VK, Laal S. Source: The Journal of Infectious Diseases. 2003 August 1; 188(3): 371-7. Epub 2003 July 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870118&dopt=Abstract
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Community participation in primary health care (PHC) programmes: lessons from tuberculosis treatment delivery in South Africa. Author(s): Kironde S, Kahirimbanyi M. Source: Afr Health Sci. 2002 April; 2(1): 16-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789110&dopt=Abstract
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Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. Author(s): Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcantara F, Sanchez E, Sarria M, Becerra M, Fawzi MC, Kapiga S, Neuberg D, Maguire JH, Kim JY, Farmer P. Source: The New England Journal of Medicine. 2003 January 9; 348(2): 119-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519922&dopt=Abstract
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Comparative analysis of HLA class I antigens in pulmonary sarcoidosis and tuberculosis in the same ethnic group. Author(s): Dubaniewicz A, Szczerkowska Z, Hoppe A. Source: Mayo Clinic Proceedings. 2003 April; 78(4): 436-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12683696&dopt=Abstract
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Comparative antimicrobial activities of gatifloxacin, sitafloxacin and levofloxacin against Mycobacterium tuberculosis replicating within Mono Mac 6 human macrophage and A-549 type II alveolar cell lines. Author(s): Sato K, Tomioka H, Sano C, Shimizu T, Sano K, Ogasawara K, Cai S, Kamei T. Source: The Journal of Antimicrobial Chemotherapy. 2003 August; 52(2): 199-203. Epub 2003 July 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865388&dopt=Abstract
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Comparative studies of the cell structures of Mycobacterium leprae and M. tuberculosis using the electron microscopy freeze-substitution technique. Author(s): Takade A, Umeda A, Matsuoka M, Yoshida S, Nakamura M, Amako K. Source: Microbiol Immunol. 2003; 47(4): 265-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801063&dopt=Abstract
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Comparison of polymerase chain reaction with histopathologic features for diagnosis of tuberculosis in formalin-fixed, paraffin-embedded histologic specimens. Author(s): Park do Y, Kim JY, Choi KU, Lee JS, Lee CH, Sol MY, Suh KS. Source: Archives of Pathology & Laboratory Medicine. 2003 March; 127(3): 326-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653577&dopt=Abstract
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Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Author(s): Ewer K, Deeks J, Alvarez L, Bryant G, Waller S, Andersen P, Monk P, Lalvani A. Source: Lancet. 2003 April 5; 361(9364): 1168-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686038&dopt=Abstract
196 Tuberculosis
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Comparison of tuberculosis tests: finding truth or confirming prejudice? Author(s): Rothel JS, Radford AJ. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 May 1; 36(9): 1206-7; Author Reply 1209-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12715322&dopt=Abstract
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Congenital spine tuberculosis: early diagnosis by imaging studies. Author(s): Grover SB, Pati NK, Mehta R, Mahajan H. Source: American Journal of Perinatology. 2003 April; 20(3): 147-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802714&dopt=Abstract
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Congenital tuberculosis proven by percutaneous liver biopsy: report of a case. Author(s): Chou YH. Source: Journal of Perinatal Medicine. 2002; 30(5): 423-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12442608&dopt=Abstract
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Congenital tuberculosis with facial nerve palsy. Author(s): Pejham S, Altman R, Li KI, Munoz JL. Source: The Pediatric Infectious Disease Journal. 2002 November; 21(11): 1085-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458576&dopt=Abstract
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Congenital tuberculosis. Author(s): Ray M, Dixit A, Vaipei K, Singhi PD. Source: Indian Pediatrics. 2002 December; 39(12): 1167-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522285&dopt=Abstract
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Contact investigation of a case of pulmonary and laryngeal tuberculosis. Author(s): Muecke C, Brassard P, Isler M, Tannenbaum TN, Menzies D, Carsley J. Source: Can Commun Dis Rep. 2003 May 15; 29(10): 91-2. English, French. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762133&dopt=Abstract
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Contact tracing and population screening for tuberculosis--who should be assessed? Author(s): Underwood BR, White VL, Baker T, Law M, Moore-Gillon JC. Source: Journal of Public Health Medicine. 2003 March; 25(1): 59-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669920&dopt=Abstract
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Contact tracing using DNA fingerprinting in an asylum seeker with pulmonary tuberculosis. Author(s): van Loenhout-Rooyacke JH, Sebek MM, Verbeek AL. Source: The Netherlands Journal of Medicine. 2002 August; 60(7): 281-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12430574&dopt=Abstract
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Continued low rates of transmission of Mycobacterium tuberculosis in Norway. Author(s): Dahle UR, Sandven P, Heldal E, Caugant DA. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 2968-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843028&dopt=Abstract
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Control of anti-tuberculosis drug resistance in Botswana. Author(s): Talbot EA, Kenyon TA, Mwasekaga MJ, Moeti TL, Mallon V, Binkin NJ. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 72-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701838&dopt=Abstract
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Control of bovine tuberculosis. Author(s): Minor R. Source: The Veterinary Record. 2003 May 10; 152(19): 603-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762494&dopt=Abstract
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Controlling tuberculosis in India. Author(s): Schaller JG, Starke J. Source: The New England Journal of Medicine. 2003 February 20; 348(8): 758-9; Author Reply 758-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12596749&dopt=Abstract
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Controlling tuberculosis in India. Author(s): Udwadia ZF. Source: The New England Journal of Medicine. 2003 February 20; 348(8): 758-9; Author Reply 758-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12594325&dopt=Abstract
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Correlation of the rate of protein synthesis and the third power of the RNA : protein ratio in Escherichia coli and Mycobacterium tuberculosis. Author(s): Cox RA. Source: Microbiology (Reading, England). 2003 March; 149(Pt 3): 729-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634341&dopt=Abstract
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Cost-effectiveness analysis of the gen-probe amplified mycobacterium tuberculosis direct test as used routinely on smear-positive respiratory specimens. Author(s): Dowdy DW, Maters A, Parrish N, Beyrer C, Dorman SE. Source: Journal of Clinical Microbiology. 2003 March; 41(3): 948-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624014&dopt=Abstract
198 Tuberculosis
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Cost-effectiveness of different treatment strategies for tuberculosis in Egypt and Syria. Author(s): Vassall A, Bagdadi S, Bashour H, Zaher H, Maaren PV. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1083-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546116&dopt=Abstract
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Cotrimoxazole prophylaxis in HIV-infected individuals after completing antituberculosis treatment in Thyolo, Malawi. Author(s): Zachariah R, Spielmann MP, Harries AD, Gomani P, Bakali E. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1046-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546111&dopt=Abstract
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Cross-jurisdictional transmission of Mycobacterium tuberculosis in Maryland and Washington, D C, 1996-2000, linked to the homeless. Author(s): Lathan M, Mukasa LN, Hooper N, Golub J, Baruch N, Mulcahy D, Benjamin W, Cronin WA. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1249-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453350&dopt=Abstract
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Crystallization and preliminary X-ray diffraction studies of an alpha-methylacyl-CoA racemase from Mycobacterium tuberculosis. Author(s): Bhaumik P, Kursula P, Ratas V, Conzelmann E, Hiltunen JK, Schmitz W, Wierenga RK. Source: Acta Crystallographica. Section D, Biological Crystallography. 2003 February; 59(Pt 2): 353-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554951&dopt=Abstract
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CT and MRI in the diagnosis of tuberculosis. Author(s): Buxi TB, Sud S, Vohra R. Source: Indian J Pediatr. 2002 November; 69(11): 965-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503662&dopt=Abstract
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Current medical treatment for tuberculosis. Author(s): Chan ED, Iseman MD. Source: Bmj (Clinical Research Ed.). 2002 November 30; 325(7375): 1282-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458250&dopt=Abstract
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Current medical treatment for tuberculosis. Resources used for screening could be spent more usefully elsewhere. Author(s): Whitfield RJ, Khan R, Smith A, Rayner CF. Source: Bmj (Clinical Research Ed.). 2003 March 8; 326(7388): 550. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627580&dopt=Abstract
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Current medical treatment for tuberculosis. Aspects of chemotherapy and management need clarifying. Author(s): Ormerod LP, Campbell IA, Davies PD. Source: Bmj (Clinical Research Ed.). 2003 March 8; 326(7388): 550; Author Reply 550. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623923&dopt=Abstract
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Current medical treatment for tuberculosis. More weight was given to observational studies than randomised controlled trials. Author(s): Fretheim A. Source: Bmj (Clinical Research Ed.). 2003 March 8; 326(7388): 550; Author Reply 550. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627579&dopt=Abstract
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Current thinking on the management of tuberculosis. Author(s): Bastian I, Stapledon R, Colebunders R. Source: Current Opinion in Pulmonary Medicine. 2003 May; 9(3): 186-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682563&dopt=Abstract
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Curvilinear membranous formations in lymph node cells of an African AIDS patient with tuberculosis. Author(s): Marquart KH. Source: Ultrastructural Pathology. 2003 January-February; 27(1): 49-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554536&dopt=Abstract
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Cutting edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase. Author(s): Malik ZA, Thompson CR, Hashimi S, Porter B, Iyer SS, Kusner DJ. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 March 15; 170(6): 2811-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12626530&dopt=Abstract
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Cytokine polarization in miliary and pleural tuberculosis. Author(s): Sharma SK, Mitra DK, Balamurugan A, Pandey RM, Mehra NK. Source: Journal of Clinical Immunology. 2002 November; 22(6): 345-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12462334&dopt=Abstract
200 Tuberculosis
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Cytokine production and expression of leucocyte-differentiation antigens by human mononuclear cells in response to mycobacterium tuberculosis antigens. Author(s): Cubillas-Tejeda AC, Ruiz-Arguelles A, Bernal-Fernandez G, QuirozCompean L, Lopez-Davila A, Reynaga-Hernandez E, Gonzalez-Amaro R. Source: Scandinavian Journal of Immunology. 2003 February; 57(2): 115-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588657&dopt=Abstract
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Cytokine profile, HLA restriction and TCR sequence analysis of human CD4+ T clones specific for an immunodominant epitope of Mycobacterium tuberculosis 16kDa protein. Author(s): Caccamo N, Barera A, Di Sano C, Meraviglia S, Ivanyi J, Hudecz F, Bosze S, Dieli F, Salerno A. Source: Clinical and Experimental Immunology. 2003 August; 133(2): 260-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869033&dopt=Abstract
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DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. Author(s): Tailleux L, Schwartz O, Herrmann JL, Pivert E, Jackson M, Amara A, Legres L, Dreher D, Nicod LP, Gluckman JC, Lagrange PH, Gicquel B, Neyrolles O. Source: The Journal of Experimental Medicine. 2003 January 6; 197(1): 121-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515819&dopt=Abstract
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Death due to pulmonary tuberculosis in progressive systemic sclerosis. Author(s): Manz B, Noack-Wiemers F, Mittag M, Haustein UF, Nenoff P. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2002 November; 16(6): 647-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12482061&dopt=Abstract
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Deaths in patients with pulmonary tuberculosis: an analysis of a chest diseases hospital in Istanbul, Turkey. Author(s): Kartaloglu Z, Ilvan A, Kilic E, Okutan O, Cerrahoglu K, Ciftci F. Source: Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre. 2003 January-March; 12(1): 30-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566965&dopt=Abstract
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Decentralizing tuberculosis treatment: follow-up of patients during the transitional period. Author(s): Arnadottir T, Phongosa B, Chittamany P, Soukaseum H. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 July; 6(7): 60914. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12102300&dopt=Abstract
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Deciphering an outbreak of drug-resistant Mycobacterium tuberculosis. Author(s): Dahle UR, Sandven P, Heldal E, Mannsaaker T, Caugant DA. Source: Journal of Clinical Microbiology. 2003 January; 41(1): 67-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517827&dopt=Abstract
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Decreased infectivity despite unaltered C3 binding by a DeltahbhA mutant of Mycobacterium tuberculosis. Author(s): Mueller-Ortiz SL, Sepulveda E, Olsen MR, Jagannath C, Wanger AR, Norris SJ. Source: Infection and Immunity. 2002 December; 70(12): 6751-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438350&dopt=Abstract
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Deep venous thrombosis associated with pulmonary tuberculosis and transient protein S deficiency. Author(s): Casanova-Roman M, Rios J, Sanchez-Porto A, Casanova-Bellido M. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(5): 393-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069029&dopt=Abstract
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Deficiency in mycolipenate- and mycosanoate-derived acyltrehaloses enhances early interactions of Mycobacterium tuberculosis with host cells. Author(s): Rousseau C, Neyrolles O, Bordat Y, Giroux S, Sirakova TD, Prevost MC, Kolattukudy PE, Gicquel B, Jackson M. Source: Cellular Microbiology. 2003 June; 5(6): 405-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780778&dopt=Abstract
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Delay in diagnosis among hospitalized patients with active tuberculosis--predictors and outcomes. Author(s): Byrd RP Jr, Mehta JB, Roy TM. Source: American Journal of Respiratory and Critical Care Medicine. 2003 January 15; 167(2): 278; Author Reply 278. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524258&dopt=Abstract
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Delay in starting treatment for tuberculosis in east London. Author(s): Lewis KE, Stephens C, Shahidi MM, Packe G. Source: Commun Dis Public Health. 2003 June; 6(2): 133-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12889293&dopt=Abstract
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Delay in the diagnosis of pulmonary tuberculosis, London, 1998-2000: analysis of surveillance data. Author(s): Rodger A, Jaffar S, Paynter S, Hayward A, Carless J, Maguire H. Source: Bmj (Clinical Research Ed.). 2003 April 26; 326(7395): 909-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12714470&dopt=Abstract
202 Tuberculosis
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Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette-Guerin attenuation. Author(s): Lewis KN, Liao R, Guinn KM, Hickey MJ, Smith S, Behr MA, Sherman DR. Source: The Journal of Infectious Diseases. 2003 January 1; 187(1): 117-23. Epub 2002 December 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508154&dopt=Abstract
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Demonstration of spread by Mycobacterium tuberculosis bacilli in A549 epithelial cell monolayers. Author(s): Castro-Garza J, King CH, Swords WE, Quinn FD. Source: Fems Microbiology Letters. 2002 July 2; 212(2): 145-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12113926&dopt=Abstract
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Dendritic cells are decreased in blood and accumulated in granuloma in tuberculosis. Author(s): Uehira K, Amakawa R, Ito T, Tajima K, Naitoh S, Ozaki Y, Shimizu T, Yamaguchi K, Uemura Y, Kitajima H, Yonezu S, Fukuhara S. Source: Clinical Immunology (Orlando, Fla.). 2002 December; 105(3): 296-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12498811&dopt=Abstract
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Depressed interleukin-12 production by peripheral blood mononuclear cells after in vitro stimulation with the 30-kDa antigen in recurrent pulmonary tuberculosis patients. Author(s): Lee JS, Song CH, Kim CH, Kong SJ, Shon MH, Suhr JW, Jung SS, Lim JH, Kim HJ, Park JK, Paik TH, Jo EK. Source: Medical Microbiology and Immunology. 2003 May; 192(2): 61-9. Epub 2002 October 31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736818&dopt=Abstract
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Design of the Brazilian BCG-REVAC trial against tuberculosis: a large, simple randomized community trial to evaluate the impact on tuberculosis of BCG revaccination at school age. Author(s): Barreto ML, Rodrigues LC, Cunha SS, Pereira S, Hijjar MA, Ichihara MY, de Brito SC, Dourado I. Source: Controlled Clinical Trials. 2002 October; 23(5): 540-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12392870&dopt=Abstract
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Detection and drug-susceptibility testing of M. tuberculosis from sputum samples using luciferase reporter phage: comparison with the Mycobacteria Growth Indicator Tube (MGIT) system. Author(s): Bardarov S Jr, Dou H, Eisenach K, Banaiee N, Ya S, Chan J, Jacobs WR Jr, Riska PF. Source: Diagnostic Microbiology and Infectious Disease. 2003 January; 45(1): 53-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573551&dopt=Abstract
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Detection of antibody to Mycobacterium tuberculosis protein antigens in the cerebrospinal fluid of patients with tuberculous meningitis. Author(s): Chandramuki A, Lyashchenko K, Kumari HB, Khanna N, Brusasca P, Gourie-Devi M, Satishchandra P, Shankar SK, Ravi V, Alcabes P, Kanaujia GV, Gennaro ML. Source: The Journal of Infectious Diseases. 2002 September 1; 186(5): 678-83. Epub 2002 August 05. Erratum In: J Infect Dis. 2003 January 1; 187(1): 163. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195355&dopt=Abstract
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Detection of embB306 mutations in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis from Northwestern Russia: implications for genotypic resistance testing. Author(s): Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O. Source: Journal of Clinical Microbiology. 2002 October; 40(10): 3810-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12354887&dopt=Abstract
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Detection of latent tuberculosis among HIV-infected patients after initiation of highly active antiretroviral therapy. Author(s): Fisk TL, Hon HM, Lennox JL, Fordham von Reyn C, Horsburgh CR Jr. Source: Aids (London, England). 2003 May 2; 17(7): 1102-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700468&dopt=Abstract
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Detection of Mycobacterium tuberculosis DNA from peripheral blood in patients with HIV-seronegative and new cases of smear-positive pulmonary tuberculosis by polymerase chain reaction. Author(s): Taci N, Yurdakul AS, Ceyhan I, Berktas MB, Ogretensoy M. Source: Respiratory Medicine. 2003 June; 97(6): 676-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814154&dopt=Abstract
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Detection of Mycobacterium tuberculosis infection by whole-blood interferongamma release assay. Author(s): Mazurek GH, LoBue PA, Daley CL, Bernardo J, Lardizabal AA, Iademarco MF. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 May 1; 36(9): 1207-8; Author Reply 1209-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12715323&dopt=Abstract
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Determination of the acetylator phenotype in Moroccan tuberculosis patients using isoniazid as metabolic probe. Author(s): Ait Moussa L, Khassouani CE, Hue B, Jana M, Begaud B, Soulaymani R. Source: Int J Clin Pharmacol Ther. 2002 December; 40(12): 548-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503812&dopt=Abstract
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Developing operational research capacity in hospital tuberculosis control officers in Malawi. Author(s): Harries AD, Kemp JR, Salaniponi FM. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 March; 7(3): 26670. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12661842&dopt=Abstract
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Development and clinical trial of fluorescence PCR diagnostic kit to detect Mycobacterium tuberculosis. Author(s): Cheng G, He YS, Zhou XY, Deng WG, Li H. Source: Di Yi June Yi Da Xue Xue Bao. 2002 June; 22(6): 533-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297478&dopt=Abstract
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Development of a culturally sensitive educational intervention program to reduce the high incidence of tuberculosis among foreign-born Vietnamese. Author(s): Houston HR, Harada N, Makinodan T. Source: Ethnicity & Health. 2002 November; 7(4): 255-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12772545&dopt=Abstract
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Development of new vaccines and diagnostic reagents against tuberculosis. Author(s): Mustafa AS. Source: Molecular Immunology. 2002 September; 39(1-2): 113-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12213334&dopt=Abstract
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Diabetes modifies the male:female ratio in pulmonary tuberculosis. Author(s): Perez-Guzman C, Vargas MH, Torres-Cruz A, Perez-Padilla JR, Furuya ME, Villarreal-Velarde H. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 3548. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729341&dopt=Abstract
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Diagnosis and treatment of latent tuberculosis infection in liver transplant recipients in an endemic area. Author(s): Benito N, Sued O, Moreno A, Horcajada JP, Gonzalez J, Navasa M, Rimola A. Source: Transplantation. 2002 November 27; 74(10): 1381-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12451235&dopt=Abstract
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Diagnosis of Mycobacterium tuberculosis in cases of pulmonary infections from Jordanian hospitals. Author(s): Saadoun I, Nimri L, Amer J. Source: Journal of Basic Microbiology. 2003; 43(2): 131-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746855&dopt=Abstract
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Diagnosis of tuberculosis. Author(s): Radford AJ, Rothel JS. Source: Lancet. 2003 June 14; 361(9374): 2083. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814739&dopt=Abstract
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Diagnosis of tuberculosis. Author(s): Bothamley GH. Source: Lancet. 2003 June 14; 361(9374): 2082; Author Reply 2082-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814737&dopt=Abstract
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Diagnosis of tuberculosis. Author(s): Agadi S. Source: Lancet. 2003 June 14; 361(9374): 2082; Author Reply 2082-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814736&dopt=Abstract
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Diagnosis of tuberculosis. Author(s): Wood PR, Jones SL. Source: Lancet. 2003 June 14; 361(9374): 2081-2; Author Reply 2082-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814735&dopt=Abstract
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Diagnostic contribution of gastric and bronchial lavage examinations in cases suggestive of pulmonary tuberculosis. Author(s): Okutan O, Kartaloglu Z, Kilic E, Bozkanat E, Ilvan A. Source: Yonsei Medical Journal. 2003 April 30; 44(2): 242-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728464&dopt=Abstract
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Diagnostic evaluation of pulmonary tuberculosis: what do doctors of modern medicine do in India? Author(s): Prasad R, Nautiyal RG, Mukherji PK, Jain A, Singh K, Ahuja RC. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 52-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701835&dopt=Abstract
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Diagnostic testing in the control of tuberculosis. Author(s): Perkins MD, Kritski AL. Source: Bulletin of the World Health Organization. 2002; 80(6): 512-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12132012&dopt=Abstract
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Differences in rate and variability of intracellular growth of a panel of Mycobacterium tuberculosis clinical isolates within a human monocyte model. Author(s): Li Q, Whalen CC, Albert JM, Larkin R, Zukowski L, Cave MD, Silver RF. Source: Infection and Immunity. 2002 November; 70(11): 6489-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379735&dopt=Abstract
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Differential decline in tuberculosis incidence among US- and non-US-born persons in New York City. Author(s): Li JH, Driver CR, Munsiff SS, Yip R, Fujiwara PI. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 451-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757046&dopt=Abstract
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Differential induction of P-glycoprotein and MRP by rifamycins in T lymphocytes from HIV-1/tuberculosis co-infected patients. Author(s): Lucia MB, Rutella S, Golotta C, Leone G, Cauda R. Source: Aids (London, England). 2002 July 26; 16(11): 1563-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12131199&dopt=Abstract
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Differentiation between intestinal tuberculosis and Crohn's disease in endoscopic biopsy specimens by polymerase chain reaction. Author(s): Gan HT, Chen YQ, Ouyang Q, Bu H, Yang XY. Source: The American Journal of Gastroenterology. 2002 June; 97(6): 1446-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12094863&dopt=Abstract
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Diffuse glomerulonephritis associated with rifampicin treatment for tuberculosis. Author(s): Yong JL, Killingsworth MC. Source: Pathology. 2002 June; 34(3): 295-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12109797&dopt=Abstract
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Directly observed therapy for treating tuberculosis. Author(s): Volmink J, Garner P. Source: Cochrane Database Syst Rev. 2003; (1): Cd003343. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535470&dopt=Abstract
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Dissection of the heat-shock response in Mycobacterium tuberculosis using mutants and microarrays. Author(s): Stewart GR, Wernisch L, Stabler R, Mangan JA, Hinds J, Laing KG, Young DB, Butcher PD. Source: Microbiology (Reading, England). 2002 October; 148(Pt 10): 3129-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368446&dopt=Abstract
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Disseminated erythematous papules in a renal transplant recipient: a case of disseminated tuberculosis. Author(s): Park KW, Kim US, Shin JW, Yoo CG, Oh MD, Choe K. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(10): 775-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477335&dopt=Abstract
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Disseminated tuberculosis presenting as hemobilia, successfully treated by arterial embolization. Author(s): Das D, Mandal SK, Majumder D, De BK. Source: J Assoc Physicians India. 2003 February; 51: 229-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725278&dopt=Abstract
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Distinctiveness of Mycobacterium tuberculosis genotypes from human immunodeficiency virus type 1-seropositive and -seronegative patients in Lima, Peru. Author(s): Ahmed N, Caviedes L, Alam M, Rao KR, Sangal V, Sheen P, Gilman RH, Hasnain SE. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1712-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682166&dopt=Abstract
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District-randomized phased implementation: strengthening the evidence base for cotrimoxazole for HIV-positive tuberculosis patients. Author(s): Godfrey-Faussett P. Source: Aids (London, England). 2003 May 2; 17(7): 1079-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700460&dopt=Abstract
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DNA fingerprinting of Mycobacterium tuberculosis isolates from epidemiologically linked case pairs. Author(s): Bennett DE, Onorato IM, Ellis BA, Crawford JT, Schable B, Byers R, Kammerer JS, Braden CR. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1224-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453346&dopt=Abstract
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DNA fngerprinting of Mycobacterium tuberculosis: lessons learned and implications for the future. Author(s): McNabb SJ, Braden CR, Navin TR. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1314-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453363&dopt=Abstract
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DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis. Author(s): Boshoff HI, Reed MB, Barry CE 3rd, Mizrahi V. Source: Cell. 2003 April 18; 113(2): 183-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12705867&dopt=Abstract
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Does diabetes predispose to the development of multidrug-resistant tuberculosis? Author(s): Singla R, Khan N. Source: Chest. 2003 January; 123(1): 308-9; Author Reply 309. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527642&dopt=Abstract
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Does the use of fluoroquinolones for the empiric treatment of pneumonia delay initiation of treatment of tuberculosis? Author(s): Abiad H. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 December 15; 35(12): 1572; Author Reply 1572-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471582&dopt=Abstract
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DOTS strategy for control of tuberculosis epidemic. Author(s): Murali MS, Sajjan BS. Source: Indian Journal of Medical Sciences. 2002 January; 56(1): 16-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508626&dopt=Abstract
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DOTS versus self administered therapy (SAT) for patients of pulmonary tuberculosis: a randomised trial at a tertiary care hospital. Author(s): Tandon M, Gupta M, Tandon S, Gupta KB. Source: Indian Journal of Medical Sciences. 2002 January; 56(1): 19-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12508627&dopt=Abstract
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DOTS-based tuberculosis treatment and control during civil conflict and an HIV epidemic, Churachandpur District, India. Author(s): Rodger AJ, Toole M, Lalnuntluangi B, Muana V, Deutschmann P. Source: Bulletin of the World Health Organization. 2002; 80(6): 451-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12132001&dopt=Abstract
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DOTS-Plus for multidrug-resistant tuberculosis in the Philippines: global assistance urgently needed. Author(s): Tupasi TE, Quelapio MI, Orillaza RB, Alcantara C, Mira NR, Abeleda MR, Belen VT, Arnisto NM, Rivera AB, Grimaldo ER, Derilo JO, Dimarucut W, Arabit M, Urboda D. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 52-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758189&dopt=Abstract
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Down-regulation of T helper 1 responses to mycobacterial antigens due to maturation of dendritic cells by 10-kDa mycobacterium tuberculosis secretory antigen. Author(s): Natarajan K, Latchumanan VK, Singh B, Singh S, Sharma P. Source: The Journal of Infectious Diseases. 2003 March 15; 187(6): 914-28. Epub 2003 Mar 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660938&dopt=Abstract
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Drug resistance and genotypes of strains of Mycobacterium tuberculosis isolated from human immunodeficiency virus-infected and non-infected tuberculosis patients in Bauru, Sao Paulo, Brazil. Author(s): Baptista IM, Oelemann MC, Opromolla DV, Suffys PN. Source: Memorias Do Instituto Oswaldo Cruz. 2002 December; 97(8): 1147-52. Epub 2003 January 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12563482&dopt=Abstract
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Drug resistance in pulmonary tuberculosis in Istanbul. Author(s): Kilicaslan Z, Albal H, Kiyan E, Aydemir N, Seber E. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2002 October; 21(10): 7634. Epub 2002 October 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12415480&dopt=Abstract
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Drug resistant tuberculosis in diabetes mellitus: a retrospective study from south India. Author(s): Subhash HS, Ashwin I, Mukundan U, Danda D, John G, Cherian AM, Thomas K. Source: Trop Doct. 2003 July; 33(3): 154-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870601&dopt=Abstract
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Drug resistant tuberculosis. Author(s): Kamholz SL. Source: J Assoc Acad Minor Phys. 2002 April; 13(2): 53-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362568&dopt=Abstract
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Drug-drug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak. Author(s): Spradling P, Drociuk D, McLaughlin S, Lee LM, Peloquin CA, Gallicano K, Pozsik C, Onorato I, Castro KG, Ridzon R. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 November 1; 35(9): 1106-12. Epub 2002 October 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384845&dopt=Abstract
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Drug-resistant Mycobacterium tuberculosis among new tuberculosis patients, Yangon, Myanmar. Author(s): Phyu S, Ti T, Jureen R, Hmun T, Myint H, Htun A, Grewal HM, Bjorvatn B. Source: Emerging Infectious Diseases. 2003 February; 9(2): 274-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604008&dopt=Abstract
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Drug-resistant tuberculosis in Ethiopia: problem scenarios and recommendation. Author(s): Abate G. Source: Ethiop Med J. 2002 January; 40(1): 79-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12240570&dopt=Abstract
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Drug-resistant tuberculosis in India. Author(s): Almeida D, Udwadia ZF, Rodrigues C, Mehta A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 1033. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475152&dopt=Abstract
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Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. Author(s): Schroeder EK, de Souza N, Santos DS, Blanchard JS, Basso LA. Source: Current Pharmaceutical Biotechnology. 2002 September; 3(3): 197-225. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12164478&dopt=Abstract
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Drug-susceptible Mycobacterium tuberculosis Beijing genotype does not develop mutation-conferred resistance to rifampin at an elevated rate. Author(s): Werngren J, Hoffner SE. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1520-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682139&dopt=Abstract
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Dual skin testing for latent tuberculosis infection: a decision analysis. Author(s): Hersh AL, Tosteson AN, von Reyn CF. Source: American Journal of Preventive Medicine. 2003 April; 24(3): 254-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657344&dopt=Abstract
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Dynamics of cytokine generation in patients with active pulmonary tuberculosis. Author(s): Jo EK, Park JK, Dockrell HM. Source: Current Opinion in Infectious Diseases. 2003 June; 16(3): 205-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821809&dopt=Abstract
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Early detection of central nervous system tuberculosis with the gen-probe nucleic Acid amplification assay: utility in an inner city hospital. Author(s): Baker CA, Cartwright CP, Williams DN, Nelson SM, Peterson PK. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 August 1; 35(3): 339-42. Epub 2002 July 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12115103&dopt=Abstract
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Early identification of Mycobacterium tuberculosis complex in BACTEC cultures by ligase chain reaction. Author(s): Wang SX, Tay L. Source: Journal of Medical Microbiology. 2002 August; 51(8): 710-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12171305&dopt=Abstract
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Effect of an immunomodulator containing Mycobacterium w on sputum conversion in pulmonary tuberculosis. Author(s): Patel N, Deshpande MM, Shah M. Source: J Indian Med Assoc. 2002 March; 100(3): 191-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12408283&dopt=Abstract
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Effect of directly observed preventive therapy for latent tuberculosis infection in San Francisco. Author(s): White MC, Gournis E, Kawamura M, Menendez E, Tulsky JP. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 30-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701832&dopt=Abstract
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Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Author(s): Pym AS, Saint-Joanis B, Cole ST. Source: Infection and Immunity. 2002 September; 70(9): 4955-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183541&dopt=Abstract
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Effect of Mycobacterium tuberculosis-specific 10-kilodalton antigen on macrophage release of tumor necrosis factor alpha and nitric oxide. Author(s): Trajkovic V, Singh G, Singh B, Singh S, Sharma P. Source: Infection and Immunity. 2002 December; 70(12): 6558-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438325&dopt=Abstract
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Effect of zinc on the tuberculin response of children exposed to adults with smearpositive tuberculosis. Author(s): Cuevas LE, Almeida LM, Mazunder P, Paixao AC, Silva AM, Maciel L, Hart CA, Coulter JB. Source: Annals of Tropical Paediatrics. 2002 December; 22(4): 313-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12530280&dopt=Abstract
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Effectiveness of tuberculosis control programmes in prisons, Barcelona 1987-2000. Author(s): Rodrigo T, Cayla JA, Garcia de Olalla P, Brugal MT, Jansa JM, Guerrero R, Marco A, Martin V. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1091-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546117&dopt=Abstract
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Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Author(s): Korenromp EL, Scano F, Williams BG, Dye C, Nunn P. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 July 1; 37(1): 101-12. Epub 2003 June 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830415&dopt=Abstract
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Elevated levels of serum macrophage migration inhibitory factor in patients with pulmonary tuberculosis. Author(s): Yamada G, Shijubo N, Takagi-Takahashi Y, Nishihira J, Mizue Y, Kikuchi K, Abe S. Source: Clinical Immunology (Orlando, Fla.). 2002 August; 104(2): 123-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12165273&dopt=Abstract
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Eleven years of experience with dialysis associated tuberculosis. Author(s): Malik GH, Al-Harbi AS, Al-Mohaya S, Al-Khawajah H, Kechrid M, Al Hassan AO, Balbaid K, Shetia MS. Source: Clinical Nephrology. 2002 November; 58(5): 356-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12425486&dopt=Abstract
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Empiric treatment of community-acquired pneumonia with fluoroquinolones, and delays in the treatment of tuberculosis. Author(s): Dooley KE, Golub J, Goes FS, Merz WG, Sterling TR. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 June 15; 34(12): 1607-12. Epub 2002 May 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032896&dopt=Abstract
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Employers encouraged to help control TB. WHO and the International Labour Organisation strengthen public/private partnership for tuberculosis control. Author(s): Ashraf H. Source: Lancet. 2003 June 21; 361(9375): 2135. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826445&dopt=Abstract
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Encephalopathy caused by isoniazid in a patient with end stage renal disease with extrapulmonary tuberculosis. Author(s): Wang HY, Chien CC, Chen YM, Huang CC. Source: Renal Failure. 2003 January; 25(1): 135-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617341&dopt=Abstract
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Endobronchial tuberculosis and the surgeon. Author(s): Gupta A, Narasimhan KL. Source: Indian Pediatrics. 2002 October; 39(10): 977. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12428049&dopt=Abstract
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Endobronchial tuberculosis. Author(s): Kashyap S, Mohapatra PR, Saini V. Source: Indian J Chest Dis Allied Sci. 2003 October-December; 45(4): 247-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962459&dopt=Abstract
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Endoscopic appearance of colonic tuberculosis. Author(s): Barriga JA, Fry LC, Monkemuller KE. Source: Endoscopy. 2003 March; 35(3): 256. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584654&dopt=Abstract
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Endoscopic features of esophageal tuberculosis. Author(s): Abid S, Jafri W, Hamid S, Khan H, Hussainy A. Source: Gastrointestinal Endoscopy. 2003 May; 57(6): 759-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12739552&dopt=Abstract
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Enrico Pieragnoli and the prevention of tuberculosis: Florence 1906. Author(s): Conti AA, Lippi D, Gensini GF. Source: Vesalius. 2002 December; 8(2): 26-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713011&dopt=Abstract
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Enterococcus gallinarum bacteriascites in a patient with active tuberculosis and HCV cirrhosis. Author(s): Alvarez MA, Domenech E, Rosinach M, Lorenzo-Zuniga V, Montoliu S, Planas R. Source: The American Journal of Gastroenterology. 2002 October; 97(10): 2681-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12385466&dopt=Abstract
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Epidemiological, clinical, and prognostic differences between the diseases caused by Mycobacterium kansasii and Mycobacterium tuberculosis in patients infected with human immunodeficiency virus: a multicenter study. Author(s): Canueto-Quintero J, Caballero-Granado FJ, Herrero-Romero M, DominguezCastellano A, Martin-Rico P, Verdu EV, Santamaria DS, Cerquera RC, Torres-Tortosa M; Grupo Andaluz para el Estudio de las Esfermedades Infecciosas. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 August 15; 37(4): 584-90. Epub 2003 Aug 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905144&dopt=Abstract
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Epidemiology and control of tuberculosis in Taipei. Author(s): Wang PD. Source: The Journal of Infection. 2002 August; 45(2): 82-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217708&dopt=Abstract
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Epidemiology and control of tuberculosis in Western European cities. Author(s): Hayward AC, Darton T, Van-Tam JN, Watson JM, Coker R, Schwoebel V. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 751-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921151&dopt=Abstract
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Epidemiology of HIV/AIDS, hepatitis B, hepatitis C, and tuberculosis among minority injection drug users. Author(s): Estrada AL. Source: Public Health Reports (Washington, D.C. : 1974). 2002; 117 Suppl 1: S126-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435836&dopt=Abstract
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Epidemiology of tuberculosis in Kuwait from 1965 to 1999. Author(s): Behbehani N, Abal A, Al-Shami A, Enarson DA. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 June; 6(6): 465-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12068976&dopt=Abstract
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Epidemiology of tuberculosis on Gran Canaria: a 4 year population study using traditional and molecular approaches. Author(s): Pena MJ, Caminero JA, Campos-Herrero MI, Rodriguez-Gallego JC, GarciaLaorden MI, Cabrera P, Torres MJ, Lafarga B, Rodriguez de Castro F, Samper S, Canas F, Enarson DA, Martin C. Source: Thorax. 2003 July; 58(7): 618-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832681&dopt=Abstract
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Epidemiology, diagnostic possibilities, and treatment of tuberculosis. Author(s): Kurth R, Haas WH. Source: Annals of the Rheumatic Diseases. 2002 November; 61 Suppl 2: Ii59-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379624&dopt=Abstract
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Erythroderma: an unusual presentation of pulmonary tuberculosis. Author(s): Chan YC, Yosipovitch G. Source: The British Journal of Dermatology. 2003 February; 148(2): 346-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588391&dopt=Abstract
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Esophageal tuberculosis associated with esophagotracheal or esophagomediastinal fistula: report of 10 cases. Author(s): Devarbhavi HC, Alvares JF, Radhikadevi M. Source: Gastrointestinal Endoscopy. 2003 April; 57(4): 588-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665778&dopt=Abstract
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Esophageal tuberculosis manifesting as submucosal abscess. Author(s): Lee KH, Kim HJ, Kim KH, Kim HG. Source: Ajr. American Journal of Roentgenology. 2003 May; 180(5): 1482-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12704077&dopt=Abstract
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Esophageal tuberculosis presenting with an appearance similar to that of carcinoma of the esophagus. Author(s): Fujiwara Y, Osugi H, Takada N, Takemura M, Lee S, Ueno M, Fukuhara K, Tanaka Y, Nishizawa S, Kinoshita H. Source: Journal of Gastroenterology. 2003; 38(5): 477-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12768391&dopt=Abstract
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Esophageal tuberculosis: is it so rare? Report of 12 cases and review of the literature. Author(s): Shah S. Source: Indian J Gastroenterol. 2002 July-August; 21(4): 170. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12385563&dopt=Abstract
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Estimated costs of false laboratory diagnoses of tuberculosis in three patients. Author(s): Northrup JM, Miller AC, Nardell E, Sharnprapai S, Etkind S, Driscoll J, McGarry M, Taber HW, Elvin P, Qualls NL, Braden CR. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1264-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453354&dopt=Abstract
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Estimation of the rate of unrecognized cross-contamination with mycobacterium tuberculosis in London microbiology laboratories. Author(s): Ruddy M, McHugh TD, Dale JW, Banerjee D, Maguire H, Wilson P, Drobniewski F, Butcher P, Gillespie SH. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4100-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409381&dopt=Abstract
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Estimation of tuberculosis incidence and mortality in Egypt using epidemiological models. Author(s): Wahdan IH, Sherif AA, Arafa M. Source: East Mediterr Health J. 2001 January-March; 7(1-2): 84-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12596956&dopt=Abstract
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Ethnic-specific genetic associations with pulmonary tuberculosis. Author(s): Delgado JC, Baena A, Thim S, Goldfeld AE. Source: The Journal of Infectious Diseases. 2002 November 15; 186(10): 1463-8. Epub 2002 October 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12404162&dopt=Abstract
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Etiology of pulmonary infections in predominantly HIV-infected adults with suspected tuberculosis, Botswana. Author(s): Lockman S, Hone N, Kenyon TA, Mwasekaga M, Villauthapillai M, Creek T, Zell E, Kirby A, Thacker WL, Talkington D, Moura IN, Binkin NJ, Clay L, Tappero JW. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 714-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921146&dopt=Abstract
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Evaluation of a commercially available serologic assay for antibodies against tuberculosis-associated glycolipid antigen. Author(s): Iinuma Y, Senda K, Takakura S, Ichiyama S, Tano M, Abe T, Yamamoto T, Nakashima K, Baba H, Hasegawa Y, Shimokata K. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 August; 40(8): 832-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12392314&dopt=Abstract
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Evaluation of a human immunodeficiency virus rule out tuberculosis critical pathway as an intervention to decrease nosocomial transmission of tuberculosis in the inpatient setting. Author(s): Jones SG. Source: Aids Patient Care and Stds. 2002 August; 16(8): 389-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12227989&dopt=Abstract
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Evaluation of a polymerase chain reaction amplification method for Mycobacterium tuberculosis complex on samples from different sources. Author(s): Cataloluk O, Karsligil T, Bayazit N. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(5): 329-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875521&dopt=Abstract
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Evaluation of a rapid bacteriophage-based method for the detection of Mycobacterium tuberculosis in clinical samples. Author(s): Marei AM, El-Behedy EM, Mohtady HA, Afify AF. Source: Journal of Medical Microbiology. 2003 April; 52(Pt 4): 331-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676872&dopt=Abstract
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Evaluation of a rapid immunochromatographic test for the serologic diagnosis of tuberculosis in Italy. Author(s): Bartoloni A, Strohmeyer M, Bartalesi F, Messeri D, Tortoli E, Farese A, Leoncini F, Nutini S, Righi R, Gabbuti A, Mazzotta F, Paradisi F. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2003 July; 9(7): 632-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925103&dopt=Abstract
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Evaluation of an amplified Mycobacterium tuberculosis direct test in clinical specimens. Author(s): Gurkan O, Acican T, Gulbay B. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 June; 6(6): 53841. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12068988&dopt=Abstract
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Evaluation of an in-house-developed radioassay kit for antibody detection in cases of pulmonary tuberculosis and tuberculous meningitis. Author(s): Kameswaran M, Shetty K, Ray MK, Jaleel MA, Kadival GV. Source: Clinical and Diagnostic Laboratory Immunology. 2002 September; 9(5): 987-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12204948&dopt=Abstract
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Evaluation of BACTEC MGIT 960 PZA medium for susceptibility testing of Mycobacterium tuberculosis to pyrazinamide (PZA): compared with the results of pyrazinamidase assay and Kyokuto PZA test. Author(s): Aono A, Hirano K, Hamasaki S, Abe C. Source: Diagnostic Microbiology and Infectious Disease. 2002 December; 44(4): 347-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543539&dopt=Abstract
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Evaluation of efficacy of community-based vs. institutional-based direct observed short-course treatment for the control of tuberculosis in Kilombero district, Tanzania. Author(s): Lwilla F, Schellenberg D, Masanja H, Acosta C, Galindo C, Aponte J, Egwaga S, Njako B, Ascaso C, Tanner M, Alonso P. Source: Tropical Medicine & International Health : Tm & Ih. 2003 March; 8(3): 204-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12631309&dopt=Abstract
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Evaluation of FASTPlaqueTB-RIF for determination of rifampicin resistance in Mycobacterium tuberculosis complex isolates. Author(s): Kisa O, Albay A, Bedir O, Baylan O, Doganci L. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 March; 7(3): 2848. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12661845&dopt=Abstract
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Evaluation of genotype MTBC assay for differentiation of clinical Mycobacterium tuberculosis complex isolates. Author(s): Richter E, Weizenegger M, Rusch-Gerdes S, Niemann S. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2672-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791901&dopt=Abstract
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Evaluation of outpatients with suspected pulmonary tuberculosis in a high HIV prevalence setting in Ethiopia: clinical, diagnostic and epidemiological characteristics. Author(s): Bruchfeld J, Aderaye G, Palme IB, Bjorvatn B, Britton S, Feleke Y, Kallenius G, Lindquist L. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(5): 331-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069014&dopt=Abstract
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Evaluation of PCR-based methods for the diagnosis of tuberculosis by identification of mycobacterial DNA in urine samples. Author(s): Kafwabulula M, Ahmed K, Nagatake T, Gotoh J, Mitarai S, Oizumi K, Zumla A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 August; 6(8): 732-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150487&dopt=Abstract
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Evaluation of serological tests for the diagnosis of tuberculosis. Author(s): Mathai E, Rajkumari R, Kuruvilla PJ, Kirubakaran H, Brahmadathan KN, Inbamalar U, Abraham OC. Source: Indian J Pathol Microbiol. 2002 July; 45(3): 303-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785171&dopt=Abstract
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Evaluation of sputum staining by modified cold method and comparison with ZiehlNeelsen and fluorochrome methods for the primary diagnosis of tuberculosis. Author(s): Tansuphasiri U, Kladphuang B. Source: Southeast Asian J Trop Med Public Health. 2002 March; 33(1): 128-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12118440&dopt=Abstract
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Evaluation of the BDProbeTec ET DTB assay(1) for direct detection of Mycobacterium tuberculosis complex from clinical samples. Author(s): Maugein J, Fourche J, Vacher S, Grimond C, Bebear C. Source: Diagnostic Microbiology and Infectious Disease. 2002 October; 44(2): 151-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458121&dopt=Abstract
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Evaluation of the BDProbeTec ET system for direct detection of Mycobacterium tuberculosis in pulmonary and extrapulmonary samples: a multicenter study. Author(s): Mazzarelli G, Rindi L, Piccoli P, Scarparo C, Garzelli C, Tortoli E. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1779-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682186&dopt=Abstract
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Evaluation of the concentration sputum smear technique for the laboratory diagnosis of pulmonary tuberculosis. Author(s): Gebre-Selassie S. Source: Trop Doct. 2003 July; 33(3): 160-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870603&dopt=Abstract
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Evaluation of the epidemiologic utility of secondary typing methods for differentiation of Mycobacterium tuberculosis isolates. Author(s): Kwara A, Schiro R, Cowan LS, Hyslop NE, Wiser MF, Roahen Harrison S, Kissinger P, Diem L, Crawford JT. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2683-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791904&dopt=Abstract
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Evaluation of the Idaho Technology LightCycler PCR for the direct detection of Mycobacterium tuberculosis in respiratory specimens. Author(s): Heginbothom ML, Magee JT, Flanagan PG. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 78-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701839&dopt=Abstract
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Evaluation of the phenol ammonium sulfate sedimentation smear microscopy method for diagnosis of pulmonary tuberculosis. Author(s): Selvakumar N, Rahman F, Garg R, Rajasekaran S, Mohan NS, Thyagarajan K, Sundaram V, Santha T, Frieden TR, Narayanan PR. Source: Journal of Clinical Microbiology. 2002 August; 40(8): 3017-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149368&dopt=Abstract
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Evaluation of the polymerase chain reaction in the diagnosis of miliary tuberculosis in bone marrow smear. Author(s): Escobedo-Jaimes L, Cicero-Sabido R, Criales-Cortez JL, Ramirez E, Romero M, Rivero V, Islas F, Olivera H, Gonzalez S, Escobar-Gutierrez A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 580-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797702&dopt=Abstract
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Evaluation of tuberculosis treatment results in Italy, report 1999. Author(s): Centis R, Migliori GB; Tuberculosis Study Group. National A.I.P.O. (Italian Association of Hospital Pneumologists); The SMIRA Group (Multicentre Italian Study on Drug Resistance); National Tuberculosis Project, Istituto Superiore di Sanita. Source: Monaldi Arch Chest Dis. 2002 October-December; 57(5-6): 297-305. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814046&dopt=Abstract
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Evaluation of tuberculosis trends in Spain, 1991-1999. Author(s): Caminero JA, Cayla JA, Lara N; Working Group on the Current Status of Tuberculosis in Spain. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 March; 7(3): 23642. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12661837&dopt=Abstract
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Evaluation of undergraduate training on tuberculosis at Istanbul Medical School. Author(s): Kilicaslan Z, Kiyan E, Erkan F, Gurgan M, Aydemir N, Arseven O. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 February; 7(2): 159-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588017&dopt=Abstract
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Evidence of endogenous reactivation of tuberculosis after a long period of latency. Author(s): Arend SM, van Dissel JT. Source: The Journal of Infectious Diseases. 2002 September 15; 186(6): 876-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12198629&dopt=Abstract
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Evolutionary relationships among strains of Mycobacterium tuberculosis with few copies of IS6110. Author(s): Dale JW, Al-Ghusein H, Al-Hashmi S, Butcher P, Dickens AL, Drobniewski F, Forbes KJ, Gillespie SH, Lamprecht D, McHugh TD, Pitman R, Rastogi N, Smith AT, Sola C, Yesilkaya H. Source: Journal of Bacteriology. 2003 April; 185(8): 2555-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12670980&dopt=Abstract
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Exacerbation of tuberculosis enteritis after treatment with infliximab. Author(s): Liberopoulos EN, Drosos AA, Elisaf MS. Source: The American Journal of Medicine. 2002 November; 113(7): 615. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12459414&dopt=Abstract
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Exogenous re-infection as a cause of recurrent tuberculosis in a low-incidence area. Author(s): de Boer AS, Borgdorff MW, Vynnycky E, Sebek MM, van Soolingen D. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 February; 7(2): 145-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588015&dopt=Abstract
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Experimental versus in silico fluorescent amplified fragment length polymorphism analysis of Mycobacterium tuberculosis: improved typing with an extended fragment range. Author(s): Sims EJ, Goyal M, Arnold C. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4072-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409377&dopt=Abstract
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Extrapulmonary and pulmonary tuberculosis in antananarivo (madagascar): high clustering rate in female patients. Author(s): Rasolofo Razanamparany V, Menard D, Auregan G, Gicquel B, Chanteau S. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 3964-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409359&dopt=Abstract
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Extra-pulmonary and pulmonary tuberculosis in Hong Kong. Author(s): Noertjojo K, Tam CM, Chan SL, Chan-Yeung MM. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 October; 6(10): 879-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12365574&dopt=Abstract
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Extrapulmonary tuberculosis in surgical specimens. Author(s): Talukder MS, Huq MH, Haque A, Sarker CB. Source: Mymensingh Med J. 2002 July; 11(2): 104-6. Erratum In: Mymensingh Med J. 2003 January; 12(1): 75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12395679&dopt=Abstract
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Facial paralysis caused by tuberculosis in a 2.5-month-old infant. Author(s): Dilber E, Yaris N, Aslan Y, Kalyoncu M, Ahmetoglu A, Okten A. Source: Annals of Tropical Paediatrics. 2003 March; 23(1): 51-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12648325&dopt=Abstract
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Factors associated with drug resistance in pulmonary tuberculosis. Author(s): Johnson J, Kagal A, Bharadwaj R. Source: Indian J Chest Dis Allied Sci. 2003 April-June; 45(2): 105-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12715932&dopt=Abstract
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Factors associated with humoral response to ESAT-6, 38 kDa and 14 kDa in patients with a spectrum of tuberculosis. Author(s): Silva VM, Kanaujia G, Gennaro ML, Menzies D. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 47884. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757050&dopt=Abstract
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Factors associated with patient and health system delays in the diagnosis of tuberculosis in South India. Author(s): Rajeswari R, Chandrasekaran V, Suhadev M, Sivasubramaniam S, Sudha G, Renu G. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 September; 6(9): 789-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12234134&dopt=Abstract
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Factors associated with the treatment of latent tuberculosis infection among healthcare workers at a midwestern teaching hospital. Author(s): Shukla SJ, Warren DK, Woeltje KF, Gruber CA, Fraser VJ. Source: Chest. 2002 November; 122(5): 1609-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12426260&dopt=Abstract
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Factors associated with time to sputum smear conversion in active pulmonary tuberculosis. Author(s): Dominguez-Castellano A, Muniain MA, Rodriguez-Bano J, Garcia M, Rios MJ, Galvez J, Perez-Cano R. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 432-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757043&dopt=Abstract
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Factors at first diagnosis of tuberculosis associated with compliance with the Directly Observed Therapy (DOT) in the Limpopo Province, South Africa. Author(s): Peltzer K, Onya H, Seoka P, Tladi FM, Malema RN. Source: Curationis. 2002 August; 25(3): 55-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12434639&dopt=Abstract
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Factors in tuberculosis contact investigations. Author(s): Bailey WC. Source: Jama : the Journal of the American Medical Association. 2002 June 12; 287(22): 2945. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052122&dopt=Abstract
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Factors in tuberculosis contact investigations. Author(s): Reichler M, Taylor Z, Castro KG. Source: Jama : the Journal of the American Medical Association. 2002 June 12; 287(22): 2944; Author Reply 2944-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052120&dopt=Abstract
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Factors influencing compliance in patients with tuberculosis on directly observed therapy at Ile-Ife, Nigeria. Author(s): Erhabor GE, Aghanwa HS, Yusuph M, Adebayo RA, Arogundade FA, Omidiora A. Source: East Afr Med J. 2000 May; 77(5): 235-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858912&dopt=Abstract
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Factors predicting persistent sputum smear positivity among pulmonary tuberculosis patients 2 months after treatment. Author(s): Singla R, Osman MM, Khan N, Al-Sharif N, Al-Sayegh MO, Shaikh MA. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 58-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701836&dopt=Abstract
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Failure of commercial ligase chain reaction to detect Mycobacterium tuberculosis DNA in sputum samples from a patient with smear-positive pulmonary tuberculosis due to a deletion of the target region. Author(s): Gilpin CM, Dawson DJ, O'Kane G, Armstrong JG, Coulter C. Source: Journal of Clinical Microbiology. 2002 June; 40(6): 2305-7. Erratum In: J Clin Microbiol 2002 October; 40(10): 3887. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12037118&dopt=Abstract
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False-positive Mycobacterium tuberculosis culture revealed by restriction fragment length polymorphism analysis. Author(s): Schoch OD, Pfyffer GE, Buhl D, Paky A. Source: Infection. 2003 June; 31(3): 189-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789481&dopt=Abstract
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False-positive mycobacterium tuberculosis cultures in 44 laboratories in The Netherlands (1993 to 2000): incidence, risk factors, and consequences. Author(s): de Boer AS, Blommerde B, de Haas PE, Sebek MM, Lambregts-van Weezenbeek KS, Dessens M, van Soolingen D. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4004-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409366&dopt=Abstract
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Fatal liver injury associated with rifampin-pyrazinamide treatment of latent tuberculosis infection. Author(s): Castro KG, Jereb JA, Koppaka VR, Cohn DL. Source: Chest. 2003 March; 123(3): 967. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628913&dopt=Abstract
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Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Author(s): Suarez PG, Floyd K, Portocarrero J, Alarcon E, Rapiti E, Ramos G, Bonilla C, Sabogal I, Aranda I, Dye C, Raviglione M, Espinal MA. Source: Lancet. 2002 June 8; 359(9322): 1980-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12076553&dopt=Abstract
Studies 225
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Field evaluation of a rapid immunochromatographic test for tuberculosis. Author(s): Gounder C, De Queiroz Mello FC, Conde MB, Bishai WR, Kritski AL, Chaisson RE, Dorman SE. Source: Journal of Clinical Microbiology. 2002 June; 40(6): 1989-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12037053&dopt=Abstract
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Fine mapping of a putative tuberculosis-susceptibility locus on chromosome 15q11-13 in African families. Author(s): Cervino AC, Lakiss S, Sow O, Bellamy R, Beyers N, Hoal-van Helden E, van Helden P, McAdam KP, Hill AV. Source: Human Molecular Genetics. 2002 July 1; 11(14): 1599-603. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12075004&dopt=Abstract
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Fine needle aspiration diagnosis of isolated pancreatic tuberculosis. A case report and review of literature. Author(s): D'Cruz S, Sachdev A, Kaur L, Handa U, Bhalla A, Lehl SS. Source: Jop [electronic Resource] : Journal of the Pancreas. 2003 July; 4(4): 158-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853684&dopt=Abstract
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Fitz-Hugh-Curtis syndrome as a result of genital tuberculosis: a report of three cases. Author(s): Sharma JB, Malhotra M, Arora R. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 March; 82(3): 295-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694129&dopt=Abstract
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Fixed-dose combination chemotherapy (Rifater/Rifinah) for active pulmonary tuberculosis in Taiwan: a two-year follow-up. Author(s): Su WJ, Perng RP. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 1029-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475151&dopt=Abstract
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Fixed-dose combination drugs for tuberculosis: application in standardised treatment regimens. Author(s): Blomberg B, Fourie B. Source: Drugs. 2003; 63(6): 535-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12656652&dopt=Abstract
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Fluoroquinolones, tuberculosis, and resistance. Author(s): Ginsburg AS, Grosset JH, Bishai WR. Source: The Lancet Infectious Diseases. 2003 July; 3(7): 432-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12837348&dopt=Abstract
226 Tuberculosis
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Follow-up of compliance with tuberculosis treatment in children: monitoring by urine tests. Author(s): Palanduz A, Gultekin D, Kayaalp N. Source: Pediatric Pulmonology. 2003 July; 36(1): 55-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12772224&dopt=Abstract
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Four-year experience of use of the Cobas Amplicor system for rapid detection of Mycobacterium tuberculosis complex in respiratory and nonrespiratory specimens in Greece. Author(s): Levidiotou S, Vrioni G, Galanakis E, Gesouli E, Pappa C, Stefanou D. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 June; 22(6): 349-56. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783277&dopt=Abstract
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French guidelines for diagnosis and treating latent and active tuberculosis in patients with RA treated with TNF blockers. Author(s): Mariette X, Salmon D. Source: Annals of the Rheumatic Diseases. 2003 August; 62(8): 791. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860745&dopt=Abstract
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From exposure to disease: the role of environmental factors in susceptibility to and development of tuberculosis. Author(s): Lienhardt C. Source: Epidemiologic Reviews. 2001; 23(2): 288-301. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12192738&dopt=Abstract
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From multidrug-resistant tuberculosis to DOTS expansion and beyond: making the most of a paradigm shift. Author(s): Kim JY, Mukherjee JS, Rich ML, Mate K, Bayona J, Becerra MC. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 59-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758190&dopt=Abstract
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Further investigations on the association of Mycobacterium tuberculosis with Eales' disease. Author(s): Madhavan HN, Therese KL, Doraiswamy K. Source: Indian J Ophthalmol. 2002 March; 50(1): 35-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12090085&dopt=Abstract
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Gallbladder tuberculosis: case report. Author(s): Yu R, Liu Y. Source: Chin Med J (Engl). 2002 August; 115(8): 1259-61. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515279&dopt=Abstract
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Gamma/delta T cell subsets in patients with active Mycobacterium tuberculosis infection and tuberculin anergy. Author(s): Szereday L, Baliko Z, Szekeres-Bartho J. Source: Clinical and Experimental Immunology. 2003 February; 131(2): 287-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562390&dopt=Abstract
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Gas chromatographic detection of Mycobacterium tuberculosis complex in pure cultures from respiratory specimens. Author(s): Dorneanu O, Wittmer A, Diculencu D, Pelz K. Source: Rev Med Chir Soc Med Nat Iasi. 2000 October-December; 104(4): 161-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12089947&dopt=Abstract
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Gastric tuberculosis with concomitant stromal tumour of stomach (GIST). Author(s): Khan S, Asghar RG, Mirza MH, Khan TN. Source: J Coll Physicians Surg Pak. 2003 January; 13(1): 48-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12685977&dopt=Abstract
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Gastrointestinal tuberculosis. Author(s): Sheer TA, Coyle WJ. Source: Current Gastroenterology Reports. 2003 August; 5(4): 273-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12864956&dopt=Abstract
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Genetic basis of tuberculosis susceptibility in India. Author(s): Shanmugalakshmi S, Pitchappan RM. Source: Indian J Pediatr. 2002 November; 69 Suppl 1: S25-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501922&dopt=Abstract
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Genetic biodiversity of Mycobacterium tuberculosis complex strains from patients with pulmonary tuberculosis in Cameroon. Author(s): Niobe-Eyangoh SN, Kuaban C, Sorlin P, Cunin P, Thonnon J, Sola C, Rastogi N, Vincent V, Gutierrez MC. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2547-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791879&dopt=Abstract
228 Tuberculosis
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Genetic susceptibility to tuberculosis. Author(s): Malik S, Schurr E. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 September; 40(9): 863-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435101&dopt=Abstract
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Genital tuberculosis in a menopausal woman. A case report. Author(s): Patacchiola F, Di Stefano L, Palermo P, Di Berardino C, Coppola G, Mascaretti G. Source: Minerva Ginecol. 2002 June; 54(3): 287-91. English, Italian. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12063445&dopt=Abstract
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Genitourinary manifestations of tuberculosis. Author(s): Wise GJ, Marella VK. Source: The Urologic Clinics of North America. 2003 February; 30(1): 111-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580563&dopt=Abstract
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Genitourinary tuberculosis: a review of 174 cases. Author(s): Gokce G, Kilicarslan H, Ayan S, Tas F, Akar R, Kaya K, Gultekin EY. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(5): 338-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069015&dopt=Abstract
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Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains. Author(s): Gutacker MM, Smoot JC, Migliaccio CA, Ricklefs SM, Hua S, Cousins DV, Graviss EA, Shashkina E, Kreiswirth BN, Musser JM. Source: Genetics. 2002 December; 162(4): 1533-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524330&dopt=Abstract
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Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis. Author(s): Hughes AL, Friedman R, Murray M. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1342-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453367&dopt=Abstract
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Genomic deletions suggest a phylogeny for the Mycobacterium tuberculosis complex. Author(s): Mostowy S, Cousins D, Brinkman J, Aranaz A, Behr MA. Source: The Journal of Infectious Diseases. 2002 July 1; 186(1): 74-80. Epub 2002 May 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12089664&dopt=Abstract
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Genomic study of Mycobacterium tuberculosis and its clinical applications. Author(s): Tyagi JS, Sharma D. Source: Indian J Pediatr. 2002 November; 69 Suppl 1: S29-38. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501923&dopt=Abstract
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Genomics and tuberculosis. Author(s): Bose M. Source: Indian J Chest Dis Allied Sci. 2002 October-December; 44(4): 221-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12437233&dopt=Abstract
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Genotype analysis of Mycobacterium tuberculosis isolates from a sentinel surveillance population. Author(s): Cowan LS, Crawford JT. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1294-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453359&dopt=Abstract
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Genotype frequencies of the +874T-->A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Author(s): Lio D, Marino V, Serauto A, Gioia V, Scola L, Crivello A, Forte GI, ColonnaRomano G, Candore G, Caruso C. Source: European Journal of Immunogenetics : Official Journal of the British Society for Histocompatibility and Immunogenetics. 2002 October; 29(5): 371-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12358843&dopt=Abstract
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Genotypic and phenotypic resistance of Mycobacterium tuberculosis to rifamycins and fluoroquinolones. Author(s): Yew WW, Chan E, Chan CY, Cheng AF. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 October; 6(10): 936-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12365583&dopt=Abstract
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Genotyping analyses of tuberculosis cases in U.S.- and foreign-born Massachusetts residents. Author(s): Sharnprapai S, Miller AC, Suruki R, Corkren E, Etkind S, Driscoll J, McGarry M, Nardell E. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1239-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453348&dopt=Abstract
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Genotyping of the Mycobacterium tuberculosis complex using MIRUs: association with VNTR and spoligotyping for molecular epidemiology and evolutionary genetics. Author(s): Sola C, Filliol I, Legrand E, Lesjean S, Locht C, Supply P, Rastogi N. Source: Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. 2003 July; 3(2): 125-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809807&dopt=Abstract
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Global drug-resistance patterns and the management of latent tuberculosis infection in immigrants to the United States. Author(s): Khan K, Muennig P, Behta M, Zivin JG. Source: The New England Journal of Medicine. 2002 December 5; 347(23): 1850-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466510&dopt=Abstract
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Global fund for AIDS, tuberculosis and malaria. Author(s): Nordstrom A. Source: Lancet. 2002 May 4; 359(9317): 1621-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12048001&dopt=Abstract
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Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs. Author(s): Tullius MV, Harth G, Horwitz MA. Source: Infection and Immunity. 2003 July; 71(7): 3927-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819079&dopt=Abstract
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Guidelines for the investigation and follow-up of individuals under medical surveillance for tuberculosis after arriving in Canada: a summary. Author(s): Heywood N, Kawa B, Long R, Njoo H, Panaro L, Wobeser W; Immigration subcommittee of the Canadian Tuberculosis Committee. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2003 June 10; 168(12): 1563-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796337&dopt=Abstract
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Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. Centers for Disease Control and Prevention. Author(s): Mazurek GH, Villarino ME; CDC. Source: Mmwr. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports / Centers for Disease Control. 2003 January 31; 52(Rr-2): 15-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583541&dopt=Abstract
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Hearing loss and nephrotoxicity in long-term aminoglycoside treatment in patients with tuberculosis. Author(s): de Jager P, van Altena R. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 July; 6(7): 622-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12102302&dopt=Abstract
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Hemophagocytic syndrome as an initial presentation of miliary tuberculosis without pulmonary findings. Author(s): Dilber E, Erduran E, Kalyoncu M, Aynaci FM, Okten A, Ahmetoglu A. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(9): 689-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12374364&dopt=Abstract
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Hemostatic changes in active pulmonary tuberculosis. Author(s): Turken O, Kunter E, Sezer M, Solmazgul E, Cerrahoglu K, Bozkanat E, Ozturk A, Ilvan A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 October; 6(10): 927-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12365581&dopt=Abstract
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Henoch-Schonlein purpura and pulmonary tuberculosis. Author(s): Islek I, Muslu A, Totan M, Gok F, Sanic A. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2002 October; 44(5): 545-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12225561&dopt=Abstract
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Hepatic tuberculosis--a case report. Author(s): Rahaman QM, Nath NC, Midya S. Source: J Indian Med Assoc. 2002 August; 100(8): 522-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12675187&dopt=Abstract
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Hepatic tuberculosis--a case report. Author(s): Sivaraman V. Source: J Indian Med Assoc. 2002 November; 100(11): 672; Author Reply 672. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797646&dopt=Abstract
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Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore. Author(s): Teleman MD, Chee CB, Earnest A, Wang YT. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 August; 6(8): 699-705. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150482&dopt=Abstract
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Heritability analysis of cytokines as intermediate phenotypes of tuberculosis. Author(s): Stein CM, Guwatudde D, Nakakeeto M, Peters P, Elston RC, Tiwari HK, Mugerwa R, Whalen CC. Source: The Journal of Infectious Diseases. 2003 June 1; 187(11): 1679-85. Epub 2003 May 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12751024&dopt=Abstract
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High plasma osteopontin level and its relationship with interleukin-12-mediated type 1 T helper cell response in tuberculosis. Author(s): Koguchi Y, Kawakami K, Uezu K, Fukushima K, Kon S, Maeda M, Nakamoto A, Owan I, Kuba M, Kudeken N, Azuma M, Yara S, Shinzato T, Higa F, Tateyama M, Kadota J, Mukae H, Kohno S, Uede T, Saito A. Source: American Journal of Respiratory and Critical Care Medicine. 2003 May 15; 167(10): 1355-9. Epub 2003 February 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574077&dopt=Abstract
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High risk for tuberculosis in hospital physicians, Peru. Author(s): Bonifacio N, Saito M, Gilman RH, Leung F, Cordova Chavez N, Chacaltana Huarcaya J, Vera Quispe C. Source: Emerging Infectious Diseases. 2002 July; 8(7): 747-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12095450&dopt=Abstract
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Highly active antiretroviral therapy and tuberculosis control in Africa: synergies and potential. Author(s): Harries AD, Hargreaves NJ, Chimzizi R, Salaniponi FM. Source: Bulletin of the World Health Organization. 2002; 80(6): 464-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12132003&dopt=Abstract
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Highly active antiretroviral therapy for HIV with tuberculosis: pardon the granuloma. Author(s): Judson MA. Source: Chest. 2002 August; 122(2): 399-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12171807&dopt=Abstract
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Highly active antiretroviral therapy for patients with tuberculosis: the solution or the problem? Author(s): Boix V, Merino E, Portilla J. Source: Aids (London, England). 2002 July 5; 16(10): 1436-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12131228&dopt=Abstract
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Hip dislocation revealing hip tuberculosis. A case report. Author(s): El Hassani S, Benbouazza K, Allali F, Bensabbah R, Attaibi A, HajjajHassouni N. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2002 December; 69(6): 607-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12537270&dopt=Abstract
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Historic and recent events contribute to the disease dynamics of Beijing-like Mycobacterium tuberculosis isolates in a high incidence region. Author(s): Richardson M, van Lill SW, van der Spuy GD, Munch Z, Booysen CN, Beyers N, van Helden PD, Warren RM. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 1001-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475147&dopt=Abstract
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Historical intensity of natural selection for resistance to tuberculosis. Author(s): Lipsitch M, Sousa AO. Source: Genetics. 2002 August; 161(4): 1599-607. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196403&dopt=Abstract
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HIV and tuberculosis in a rural hospital in Kenya. Author(s): Torrens JK. Source: East Afr Med J. 2000 April; 77(4): 185-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858900&dopt=Abstract
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HIV and tuberculosis in the former Soviet Union. Author(s): Schwalbe N, Harrington P. Source: Lancet. 2002 December; 360 Suppl: S19-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504488&dopt=Abstract
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HIV and tuberculosis: surveillance revisited. Author(s): Corbett EL. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 709. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921144&dopt=Abstract
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HIV infection in patients with tuberculosis in Baghdad (1996-98). Author(s): Abdul-Abbas AJ, al-Delami AM, Yousif TK. Source: East Mediterr Health J. 2000 September-November; 6(5-6): 1103-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12197334&dopt=Abstract
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HIV risk factors among patients with tuberculosis--Botswana 1999. Author(s): Talbot EA, Kenyon TA, Moeti TL, Hsin G, Dooley L, El-Halabi S, Binkin NJ. Source: International Journal of Std & Aids. 2002 May; 13(5): 311-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11972934&dopt=Abstract
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HIV-1 and tuberculosis infection. Author(s): Warren RM, van Helden PD. Source: Lancet. 2002 May 4; 359(9317): 1618-9; Author Reply 1619-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12047995&dopt=Abstract
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HIV-associated tuberculosis among a cohort of heterosexual discordant couples in Lusaka, Zambia. Author(s): Kennedy SB, Campbell J, Hester RA. Source: J Health Popul Nutr. 2002 December; 20(4): 289-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12659408&dopt=Abstract
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Hospital costs of high-burden diseases: malaria and pulmonary tuberculosis in a high HIV prevalence context in Zimbabwe. Author(s): Hongoro C, McPake B. Source: Tropical Medicine & International Health : Tm & Ih. 2003 March; 8(3): 242-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12631315&dopt=Abstract
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Hospital prevalence of pulmonary tuberculosis and co-infection with human immunodeficiency virus in Ilorin: a review of nine years (1991-1999). Author(s): Salami AK, Oluboyo PO. Source: West Afr J Med. 2002 January-March; 21(1): 24-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12081336&dopt=Abstract
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How can detection of infectious tuberculosis be improved? Experience in the Somali region of Ethiopia. Author(s): Lambert ML, Sugulle H, Seyoum D, Abdurahman S, Abdinasir A, Frieden M, Matthys F, Van der Stuyft P. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 485-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757051&dopt=Abstract
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How human immunodeficiency virus voluntary testing can contribute to tuberculosis control. Author(s): Godfrey-Faussett P, Maher D, Mukadi YD, Nunn P, Perriens J, Raviglione M. Source: Iapac Mon. 2003 March; 9(3): 54-60. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12744196&dopt=Abstract
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How human immunodeficiency virus voluntary testing can contribute to tuberculosis control. Author(s): Godfrey-Faussett P, Maher D, Mukadi YD, Nunn P, Perriens J, Raviglione M. Source: Bulletin of the World Health Organization. 2002; 80(12): 939-45. Epub 2003 January 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571721&dopt=Abstract
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Human dendritic cells presenting adenovirally expressed antigen elicit Mycobacterium tuberculosis--specific CD8+ T cells. Author(s): Lewinsohn DA, Lines RA, Lewinsohn DM. Source: American Journal of Respiratory and Critical Care Medicine. 2002 September 15; 166(6): 843-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12231495&dopt=Abstract
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Human eosinophil peroxidase induces surface alteration, killing, and lysis of Mycobacterium tuberculosis. Author(s): Borelli V, Vita F, Shankar S, Soranzo MR, Banfi E, Scialino G, Brochetta C, Zabucchi G. Source: Infection and Immunity. 2003 February; 71(2): 605-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540536&dopt=Abstract
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Human exposure following Mycobacterium tuberculosis infection of multiple animal species in a Metropolitan Zoo. Author(s): Oh P, Granich R, Scott J, Sun B, Joseph M, Stringfield C, Thisdell S, Staley J, Workman-Malcolm D, Borenstein L, Lehnkering E, Ryan P, Soukup J, Nitta A, Flood J. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1290-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453358&dopt=Abstract
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Human genetic susceptibility to tuberculosis and other mycobacterial diseases. Author(s): Hoal EG. Source: Iubmb Life. 2002 April-May; 53(4-5): 225-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12121000&dopt=Abstract
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Human immunity to M. tuberculosis: T cell subsets and antigen processing. Author(s): Boom WH, Canaday DH, Fulton SA, Gehring AJ, Rojas RE, Torres M. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 98-106. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758197&dopt=Abstract
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Human immunodeficiency virus and osteoarticular tuberculosis. Author(s): Jellis JE. Source: Clinical Orthopaedics and Related Research. 2002 May; (398): 27-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11964628&dopt=Abstract
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Human immunodeficiency virus infection in children hospitalised with tuberculosis. Author(s): Blusse van Oud-Alblas HJ, van Vliet ME, Kimpen JL, de Villiers GS, Schaaf HS, Donald PR. Source: Annals of Tropical Paediatrics. 2002 June; 22(2): 115-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12070946&dopt=Abstract
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Human immunodeficiency virus-1 RNA levels and CD4 lymphocyte counts, during treatment for active tuberculosis, in South African patients. Author(s): Morris L, Martin DJ, Bredell H, Nyoka SN, Sacks L, Pendle S, Page-Shipp L, Karp CL, Sterling TR, Quinn TC, Chaisson RE. Source: The Journal of Infectious Diseases. 2003 June 15; 187(12): 1967-71. Epub 2003 Jun 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792875&dopt=Abstract
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Human Th1 cell lines recognize the Mycobacterium tuberculosis ESAT-6 antigen and its peptides in association with frequently expressed HLA class II molecules. Author(s): Mustafa AS, Shaban FA, Al-Attiyah R, Abal AT, El-Shamy AM, Andersen P, Oftung F. Source: Scandinavian Journal of Immunology. 2003 February; 57(2): 125-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588658&dopt=Abstract
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Humoral immune response against 38-kDa and 16-kDa mycobacterial antigens in bone and joint tuberculosis. Author(s): Demkow U, Zielonka TM, Nowak-Misiak M, Filewska M, Bialas B, Strzalkowski J, Rapala K, Zwolska Z, Skopinska-Rozewska E. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 1023-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475150&dopt=Abstract
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Hyper-IgM syndrome with systemic tuberculosis. Author(s): Ito I, Ishida T, Hashimoto T, Arita M, Osawa M, Mishima M, Nonoyama S. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(4): 305-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12064697&dopt=Abstract
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Identification of novel Mycobacterium tuberculosis antigens with potential as diagnostic reagents or subunit vaccine candidates by comparative genomics. Author(s): Cockle PJ, Gordon SV, Lalvani A, Buddle BM, Hewinson RG, Vordermeier HM. Source: Infection and Immunity. 2002 December; 70(12): 6996-7003. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438379&dopt=Abstract
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Identifying the sources of tuberculosis in young children: a multistate investigation. Author(s): Sun SJ, Bennett DE, Flood J, Loeffler AM, Kammerer S, Ellis BA. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1216-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453345&dopt=Abstract
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IFN-alpha beta released by Mycobacterium tuberculosis-infected human dendritic cells induces the expression of CXCL10: selective recruitment of NK and activated T cells. Author(s): Lande R, Giacomini E, Grassi T, Remoli ME, Iona E, Miettinen M, Julkunen I, Coccia EM. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 February 1; 170(3): 1174-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538673&dopt=Abstract
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IL-18 production in human pulmonary and pleural tuberculosis. Author(s): Song CH, Lee JS, Nam HH, Kim JM, Suhr JW, Jung SS, Na MJ, Paik TH, Kim HJ, Park JK, Jo EK. Source: Scandinavian Journal of Immunology. 2002 December; 56(6): 611-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472673&dopt=Abstract
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Images in clinical medicine. Tuberculosis with atlantoaxial and craniovertebral Pott's disease. Author(s): Weber U, Scherubl H. Source: The New England Journal of Medicine. 2002 December 5; 347(23): 1849. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466509&dopt=Abstract
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Imaging findings of urinary tuberculosis on excretory urography and computerized tomography. Author(s): Wang LJ, Wu CF, Wong YC, Chuang CK, Chu SH, Chen CJ. Source: The Journal of Urology. 2003 February; 169(2): 524-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544301&dopt=Abstract
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Imaging in tuberculosis of the skull and skull-base: case report. Author(s): Sencer S, Sencer A, Aydin K, Hepgul K, Poyanli A, Minareci O. Source: Neuroradiology. 2003 March; 45(3): 160-3. Epub 2003 February 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12684719&dopt=Abstract
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Imaging of renal tuberculosis in eastern Taiwan: correlation with clinical course and different communities. Author(s): Leung TK, Lu CT, Ling CM, Lee CC, Chang PN, Lee SK, Yen PS, Chou SB. Source: Kaohsiung J Med Sci. 2003 June; 19(6): 271-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873035&dopt=Abstract
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Immune reactivation and paradoxical worsening in an HIV-infected tuberculosis patient. Author(s): de Lange WC. Source: Advances in Experimental Medicine and Biology. 2003; 531: 261-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916798&dopt=Abstract
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Immune response to tuberculosis: experimental animal models. Author(s): Kaufmann SH. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 107-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758198&dopt=Abstract
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Immune system stimulator shows promise against tuberculosis. Author(s): Orellana C. Source: The Lancet Infectious Diseases. 2002 December; 2(12): 711. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467673&dopt=Abstract
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Immunotherapy for tuberculosis: wave of the future or tilting at windmills? Author(s): Barnes PF. Source: American Journal of Respiratory and Critical Care Medicine. 2003 July 15; 168(2): 142-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851240&dopt=Abstract
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Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis. Author(s): Sterling TR, Lehmann HP, Frieden TR. Source: Bmj (Clinical Research Ed.). 2003 March 15; 326(7389): 574. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637401&dopt=Abstract
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Impact of enhanced notification of tuberculosis laboratory results to minimise treatment delay, Chiang Rai Hospital, Northern Thailand. Author(s): Uthaivoravit W, Yanai H, Tappero JW, Limpakarnjanarat K, Srismith R, Mastro TD, Mori T. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 46-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701834&dopt=Abstract
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Impact of genotyping of Mycobacterium tuberculosis on public health practice in Massachusetts. Author(s): Miller AC, Sharnprapai S, Suruki R, Corkren E, Nardell EA, Driscoll JR, McGarry M, Taber H, Etkind S. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1285-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453357&dopt=Abstract
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Impact of HIV on admissions and deaths in a tuberculosis hospital-recommendations for admission and discharge criteria. Author(s): Thanassi W, Post FA, Shean K, Bekker LG, Maartens G. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2003 June; 93(6): 463-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916389&dopt=Abstract
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Impact of human immunodeficiency virus 1 infection on clinical presentation, treatment outcome and survival in a cohort of Ethiopian children with tuberculosis. Author(s): Palme IB, Gudetta B, Bruchfeld J, Muhe L, Giesecke J. Source: The Pediatric Infectious Disease Journal. 2002 November; 21(11): 1053-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12442029&dopt=Abstract
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Impact of tuberculosis on HIV disease progression in persons with well-documented time of HIV seroconversion. Author(s): Del Amo J, Perez-Hoyos S, Hernandez Aguado I, Diez M, Castilla J, Porter K; Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) Collaboration. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2003 June 1; 33(2): 184-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794552&dopt=Abstract
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Impact of tuberculosis on HIV-1 replication, diversity, and disease progression. Author(s): Collins KR, Quinones-Mateu ME, Toossi Z, Arts EJ. Source: Aids Rev. 2002 July-September; 4(3): 165-76. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416451&dopt=Abstract
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Impaired neutrophil function in patients with pulmonary tuberculosis and its normalization in those undergoing specific treatment, except the HIV-coinfected cases. Author(s): Fiorenza G, Bottasso OA, Rateni L, Farroni MA, Dlugovitzky D. Source: Fems Immunology and Medical Microbiology. 2003 March 20; 35(2): 159-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628553&dopt=Abstract
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Implementation of proficiency testing in conjunction with a rechecking system for external quality assurance in tuberculosis laboratories in Mexico. Author(s): Martinez-Guarneros A, Balandrano-Campos S, Solano-Ceh MA, GonzalezDominguez F, Lipman HB, Ridderhof JC, Flisser A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 51621. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797692&dopt=Abstract
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Improve tuberculosis services for HIV patients, says WHO. Author(s): Ashraf H. Source: Lancet. 2003 July 19; 362(9379): 218. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885508&dopt=Abstract
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Improvement of differentiation and interpretability of spoligotyping for Mycobacterium tuberculosis complex isolates by introduction of new spacer oligonucleotides. Author(s): van der Zanden AG, Kremer K, Schouls LM, Caimi K, Cataldi A, Hulleman A, Nagelkerke NJ, van Soolingen D. Source: Journal of Clinical Microbiology. 2002 December; 40(12): 4628-39. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454164&dopt=Abstract
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Improving bacteriological diagnosis of tuberculosis. Author(s): Wattal C. Source: Indian J Pediatr. 2002 November; 69 Suppl 1: S11-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501920&dopt=Abstract
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Improving vaccines against tuberculosis. Author(s): Britton WJ, Palendira U. Source: Immunology and Cell Biology. 2003 February; 81(1): 34-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534944&dopt=Abstract
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In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis. Author(s): Rodriguez JC, Ruiz M, Lopez M, Royo G. Source: International Journal of Antimicrobial Agents. 2002 December; 20(6): 464-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458143&dopt=Abstract
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Incidence of cutaneous tuberculosis in patients with organ tuberculosis. Author(s): Kivanc-Altunay I, Baysal Z, Ekmekci TR, Koslu A. Source: International Journal of Dermatology. 2003 March; 42(3): 197-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653914&dopt=Abstract
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Incidence of multidrug-resistant tuberculosis in urban and rural India and implications for prevention. Author(s): Almeida D, Rodrigues C, Udwadia ZF, Lalvani A, Gothi GD, Mehta P, Mehta A. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 June 15; 36(12): E152-4. Epub 2003 Jun 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802779&dopt=Abstract
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Incidence of pulmonary disease caused by mycobacteria other than tuberculosis in British Columbia. Author(s): Elwood RK, Opazo Saez AM, Lentini V, Shadmani R. Source: Can Respir J. 2002 September-October; 9(5): 319-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410324&dopt=Abstract
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Increased incidence of the outbreak strain of Mycobacterium tuberculosis in the surrounding community after an outbreak in a jail. Author(s): Jones TF, Woodley CL, Fountain FF, Schaffner W. Source: Southern Medical Journal. 2003 February; 96(2): 155-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630640&dopt=Abstract
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Increased pleural fluid adenosine deaminase in brucellosis is difficult to differentiate from tuberculosis. Author(s): Dikensoy O, Namiduru M, Hocaoglu S, Ikidag B, Filiz A. Source: Respiration; International Review of Thoracic Diseases. 2002; 69(6): 556-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12457012&dopt=Abstract
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India makes poor tuberculosis progress in 2002. Author(s): Sharma DC. Source: The Lancet Infectious Diseases. 2003 May; 3(5): 265. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12726966&dopt=Abstract
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Induced sputum and bronchoscopy in the diagnosis of pulmonary tuberculosis. Author(s): McWilliams T, Wells AU, Harrison AC, Lindstrom S, Cameron RJ, Foskin E. Source: Thorax. 2002 December; 57(12): 1010-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454293&dopt=Abstract
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Influence of highly active anti-retroviral therapy (HAART) on the natural history of extra-pulmonary tuberculosis in HIV patients. Author(s): Garcia de Olalla P, Martinez-Gonzalez MA, Cayla JA, Jansa JM, Iglesias B, Guerrero R, Marco A, Gatell JM, Ocana I; Barcelona AIDS-TB Study Group. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1051-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546112&dopt=Abstract
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Influence of interleukin-12 receptor beta1 polymorphisms on tuberculosis. Author(s): Akahoshi M, Nakashima H, Miyake K, Inoue Y, Shimizu S, Tanaka Y, Okada K, Otsuka T, Harada M. Source: Human Genetics. 2003 March; 112(3): 237-43. Epub 2002 December 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12596048&dopt=Abstract
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Influence of Mycobacterium tuberculosis on differential activation of helper T-cells. Author(s): Talreja J, Bhatnagar A, Jindal SK, Ganguly NK. Source: Clinical and Experimental Immunology. 2003 February; 131(2): 292-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562391&dopt=Abstract
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Informatics tools to monitor progress and outcomes of patients with drug resistant tuberculosis in Peru. Author(s): Fraser HS, Jazayeri D, Mitnick CD, Mukherjee JS, Bayona J. Source: Proceedings / Amia. Annual Symposium. Amia Symposium. 2002; : 270-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12463829&dopt=Abstract
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Inhibition of IFN-gamma-induced class II transactivator expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: a potential mechanism for immune evasion. Author(s): Pai RK, Convery M, Hamilton TA, Boom WH, Harding CV. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 July 1; 171(1): 175-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816996&dopt=Abstract
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Inhibition of response to alpha interferon by Mycobacterium tuberculosis. Author(s): Prabhakar S, Qiao Y, Hoshino Y, Weiden M, Canova A, Giacomini E, Coccia E, Pine R. Source: Infection and Immunity. 2003 May; 71(5): 2487-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12704120&dopt=Abstract
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Inhibitory effect of NO-releasing ciprofloxacin (NCX 976) on Mycobacterium tuberculosis survival. Author(s): Ciccone R, Mariani F, Cavone A, Persichini T, Venturini G, Ongini E, Colizzi V, Colasanti M. Source: Antimicrobial Agents and Chemotherapy. 2003 July; 47(7): 2299-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821482&dopt=Abstract
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Initial defaulting in the National Tuberculosis Programme in Ho Chi Minh City, Vietnam: a survey of extent, reasons and alternative actions taken following default. Author(s): Buu TN, Lonnroth K, Quy HT. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 735-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921149&dopt=Abstract
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Initiative to unify control of HIV/AIDS and tuberculosis. Author(s): Paterson R. Source: The Lancet Infectious Diseases. 2003 March; 3(3): 119. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614714&dopt=Abstract
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Innate immunity to Mycobacterium tuberculosis. Author(s): van Crevel R, Ottenhoff TH, van der Meer JW. Source: Advances in Experimental Medicine and Biology. 2003; 531: 241-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916796&dopt=Abstract
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Integration of operational research into National Tuberculosis Control Programmes. Author(s): Harries AD. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 143-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758204&dopt=Abstract
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Interferon-gamma and interleukin-10 gene polymorphisms in pulmonary tuberculosis. Author(s): Lopez-Maderuelo D, Arnalich F, Serantes R, Gonzalez A, Codoceo R, Madero R, Vazquez JJ, Montiel C. Source: American Journal of Respiratory and Critical Care Medicine. 2003 April 1; 167(7): 970-5. Epub 2003 January 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531774&dopt=Abstract
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Interferon-gamma production in response to M. tuberculosis antigens in TB patients in Indonesia. Author(s): Subronto YW, van Meijgaarden KE, Geluk A, Arend SM, Sunardi T, Franken KL, Hisyam B, de Vries RR, Ottenhoff TH. Source: Advances in Experimental Medicine and Biology. 2003; 531: 249-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916797&dopt=Abstract
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Interleukin-10, polymorphism in SLC11A1 (formerly NRAMP1), and susceptibility to tuberculosis. Author(s): Awomoyi AA, Marchant A, Howson JM, McAdam KP, Blackwell JM, Newport MJ. Source: The Journal of Infectious Diseases. 2002 December 15; 186(12): 1808-14. Epub 2002 November 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12447767&dopt=Abstract
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Internalization of Mycobacterium tuberculosis by macropinocytosis in nonphagocytic cells. Author(s): Garcia-Perez BE, Mondragon-Flores R, Luna-Herrera J. Source: Microbial Pathogenesis. 2003 August; 35(2): 49-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901843&dopt=Abstract
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Interpreting the results of the amplified Mycobacterium tuberculosis direct test for detection of M. tuberculosis rRNA. Author(s): Middleton AM, Cullinan P, Wilson R, Kerr JR, Chadwick MV. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2741-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791919&dopt=Abstract
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Intestinal nematodes and pulmonary tuberculosis. Author(s): Tristao-Sa R, Ribeiro-Rodrigues R, Johnson LT, Pereira FE, Dietze R. Source: Revista Da Sociedade Brasileira De Medicina Tropical. 2002 September-October; 35(5): 533-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621678&dopt=Abstract
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Intractable hematochezia: an unusual presentation of intestinal tuberculosis. Author(s): Rabkin DG, Caiati JM, Allendorf JA, Treat M. Source: Surgery. 2003 May; 133(5): 592-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773991&dopt=Abstract
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Intraocular tuberculosis mimicking retinoblastoma: a case report. Author(s): Sen S, Kashyap S, Singh UB, NagaSuresh V, Chand M, Garg SP. Source: Diagnostic Cytopathology. 2003 February; 28(2): 107-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12561034&dopt=Abstract
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Invasion activity of a Mycobacterium tuberculosis peptide presented by the Escherichia coli AIDA autotransporter. Author(s): Casali N, Konieczny M, Schmidt MA, Riley LW. Source: Infection and Immunity. 2002 December; 70(12): 6846-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438361&dopt=Abstract
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Investigation of environmental and host-related risk factors for tuberculosis in Africa. I. Methodological aspects of a combined design. Author(s): Lienhardt C, Bennett S, Del Prete G, Bah-Sow O, Newport M, Gustafson P, Manneh K, Gomes V, Hill A, McAdam K. Source: American Journal of Epidemiology. 2002 June 1; 155(11): 1066-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12034586&dopt=Abstract
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Investigation of environmental and host-related risk factors for tuberculosis in Africa. II. Investigation of host genetic factors. Author(s): Bennett S, Lienhardt C, Bah-Sow O, Gustafson P, Manneh K, Del Prete G, Gomes V, Newport M, McAdam K, Hill A. Source: American Journal of Epidemiology. 2002 June 1; 155(11): 1074-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12034587&dopt=Abstract
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Investigation of the relationships between immune-mediated inhibition of mycobacterial growth and other potential surrogate markers of protective Mycobacterium tuberculosis immunity. Author(s): Hoft DF, Worku S, Kampmann B, Whalen CC, Ellner JJ, Hirsch CS, Brown RB, Larkin R, Li Q, Yun H, Silver RF. Source: The Journal of Infectious Diseases. 2002 November 15; 186(10): 1448-57. Epub 2002 October 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12404160&dopt=Abstract
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Investigation of the role of CD8+ T cells in bovine tuberculosis in vivo. Author(s): Villarreal-Ramos B, McAulay M, Chance V, Martin M, Morgan J, Howard CJ. Source: Infection and Immunity. 2003 August; 71(8): 4297-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874305&dopt=Abstract
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Involving private practitioners and chest physicians in the control of tuberculosis. Author(s): Caminero JA, Billo NE. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 148-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758205&dopt=Abstract
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Is Crohn's disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne's disease. Author(s): Greenstein RJ. Source: The Lancet Infectious Diseases. 2003 August; 3(8): 507-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901893&dopt=Abstract
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Is Mycobacterium africanum subtype II (Uganda I and Uganda II) a genetically welldefined subspecies of the Mycobacterium tuberculosis complex? Author(s): Sola C, Rastogi N, Gutierrez MC, Vincent V, Brosch R, Parsons L. Source: Journal of Clinical Microbiology. 2003 March; 41(3): 1345-6; Author Reply 13468. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624085&dopt=Abstract
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Is the DOTS strategy sufficient to achieve tuberculosis control in low- and middleincome countries? 1. Need for interventions in universities and medical schools. Author(s): Caminero JA. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 50915. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797691&dopt=Abstract
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Is the risk of occupational tuberculosis higher for young health care workers? Author(s): Raitio M, Helenius H, Tala E. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 55662. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797698&dopt=Abstract
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IS6110 fingerprinting of sensitive and resistant strains (1991-1992) of Mycobacterium tuberculosis in Colombia. Author(s): Gomez-Marin JE, Leon Franco CI, Inirida Guerrero M, Rigouts L, Portaels F. Source: Memorias Do Instituto Oswaldo Cruz. 2002 October; 97(7): 1005-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471428&dopt=Abstract
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IS6110-mediated deletion polymorphism in the direct repeat region of clinical isolates of Mycobacterium tuberculosis. Author(s): Sampson SL, Warren RM, Richardson M, Victor TC, Jordaan AM, van der Spuy GD, van Helden PD. Source: Journal of Bacteriology. 2003 May; 185(9): 2856-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700265&dopt=Abstract
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Isolated solitary vertebral body tuberculosis--study of seven cases. Author(s): Lolge S, Maheshwari M, Shah J, Patkar D, Chawla A. Source: Clinical Radiology. 2003 July; 58(7): 545-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12834638&dopt=Abstract
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Isolated tuberculosis of talus without ankle and subtalar joint involvement. Author(s): Anand A, Sood LK. Source: Med J Malaysia. 2002 September; 57(3): 371-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12440280&dopt=Abstract
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Isolation and evaluation of diagnostic value of two major secreted proteins of Mycobacterium tuberculosis. Author(s): Senthil Kumar KS, Uma Devi KR, Alamelu R. Source: Indian J Chest Dis Allied Sci. 2002 October-December; 44(4): 225-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12437234&dopt=Abstract
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Isoniazid for latent tuberculosis infection: approaching 40 and reaching its prime. Author(s): Nolan CM. Source: American Journal of Respiratory and Critical Care Medicine. 2003 August 15; 168(4): 412-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912731&dopt=Abstract
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Isoniazid prophylaxis for tuberculosis prevention among HIV infected police officers in Dar es Salaam. Author(s): Bakari M, Moshi A, Aris EA, Chale S, Josiah R, Magao P, Pallangyo N, Mugusi F, Sandstrom E, Biberfeld G, Mhalu F, Pallangyo K. Source: East Afr Med J. 2000 September; 77(9): 494-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12862141&dopt=Abstract
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Isotype-specific anti-38 and 27 kDa (mpt 51) response in pulmonary tuberculosis with human immunodeficiency virus coinfection. Author(s): Ramalingam B, Uma Devi KR, Raja A. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(4): 234-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839150&dopt=Abstract
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Keeping pulmonary tuberculosis at bay. Author(s): Eckler JA. Source: Nursing. 2002 December; 32(12): 70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512494&dopt=Abstract
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Labial tuberculosis: a unique cause of lip swelling complicating HIV infection. Author(s): Ilyas SE, Chen FF, Hodgson TA, Speight PM, Lacey CJ, Porter SR, Llyas SE. Source: Hiv Medicine. 2002 October; 3(4): 283-6. Erratum In: Hiv Med. 2003 April; 4(2): Following T of C. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12444947&dopt=Abstract
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Laboratory cross-contamination of Mycobacterium tuberculosis: an investigation and analysis of causes and consequences. Author(s): Poynten M, Andresen DN, Gottlieb T. Source: Internal Medicine Journal. 2002 November; 32(11): 512-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12412933&dopt=Abstract
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Laboratory methods for diagnosis and detection of drug resistant Mycobacterium tuberculosis complex with reference to developing countries: a review. Author(s): Githui WA. Source: East Afr Med J. 2002 May; 79(5): 242-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12638807&dopt=Abstract
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Lack of toxicity from concomitant directly observed disulfiram and isoniazidcontaining therapy for active tuberculosis. Author(s): Burman WJ, Terra M, Breese P, Cohn D, Reves R. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 September; 6(9): 839-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12234141&dopt=Abstract
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Laparoscopic bilateral hand-assisted nephrectomy: end-stage renal disease from tuberculosis, an unusual indication for nephrectomy before transplantation. Author(s): Casaccia M, Torelli P, Fontana I, Panaro F, Valente U. Source: Surgical Laparoscopy, Endoscopy & Percutaneous Techniques. 2003 February; 13(1): 59-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598763&dopt=Abstract
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Laryngeal tuberculosis masquerading as carcinoma. Author(s): Lin CJ, Kang BH, Wang HW. Source: Eur Arch Otorhinolaryngol. 2002 November;259(10):521-3. Epub 2002 June 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12434184&dopt=Abstract
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Laryngeal tuberculosis. Author(s): Porras Alonso E, Martin Mateos A, Perez-Requena J, Avalos Serrano E. Source: Rev Laryngol Otol Rhinol (Bord). 2002; 123(1): 47-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201001&dopt=Abstract
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Laryngeal tuberculosis: a report of 15 cases. Author(s): Nishiike S, Irifune M, Doi K, Sawada T, Kubo T. Source: The Annals of Otology, Rhinology, and Laryngology. 2002 October; 111(10): 9168. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12389861&dopt=Abstract
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Laryngeal tuberculosis: an often forgotten diagnosis. Author(s): Rizzo PB, Da Mosto MC, Clari M, Scotton PG, Vaglia A, Marchiori C. Source: International Journal of Infectious Diseases : Ijid : Official Publication of the International Society for Infectious Diseases. 2003 June; 7(2): 129-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839714&dopt=Abstract
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Latent tuberculosis in pregnancy: screening and treatment. Author(s): Bergeron KG, Bonebrake RG, Allen C, Gray CJ. Source: Curr Womens Health Rep. 2003 August; 3(4): 303-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12844453&dopt=Abstract
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Latent tuberculosis treatment. Author(s): Houston S, Long R, Hoeppner V. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2002 September 3; 167(5): 452-3; Author Reply 453-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12240804&dopt=Abstract
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Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection. Author(s): Tufariello JM, Chan J, Flynn JL. Source: The Lancet Infectious Diseases. 2003 September; 3(9): 578-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954564&dopt=Abstract
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Latent tuberculosis: models, mechanisms, and novel prospects for eradication. Author(s): Riska PF, Carleton S. Source: Seminars in Pediatric Infectious Diseases. 2002 October; 13(4): 263-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12491232&dopt=Abstract
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Lay workers in directly observed treatment (DOT) programmes for tuberculosis in high burden settings: Should they be paid? A review of behavioural perspectives. Author(s): Kironde S, Bajunirwe F. Source: Afr Health Sci. 2002 August; 2(2): 73-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789106&dopt=Abstract
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Leptin and energy metabolism in pulmonary tuberculosis. Author(s): Schwenk A, Hodgson L, Rayner CF, Griffin GE, Macallan DC. Source: The American Journal of Clinical Nutrition. 2003 February; 77(2): 392-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540399&dopt=Abstract
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Levels of interferon-gamma and interleukin-2 receptor-alpha for bronchoalveolar lavage fluid and serum were correlated with clinical grade and treatment of pulmonary tuberculosis. Author(s): Tsao TC, Huang CC, Chiou WK, Yang PY, Hsieh MJ, Tsao KC. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 August; 6(8): 720-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150485&dopt=Abstract
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Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population. Author(s): Lou HX, Shullo MA, McKaveney TP. Source: Pharmacotherapy. 2002 June; 22(6): 701-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12066961&dopt=Abstract
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Limited transmission of multidrug-resistant tuberculosis. Author(s): Spradling P, Ridzon R, Nitta AT, Kim J. Source: American Journal of Respiratory and Critical Care Medicine. 2003 February 1; 167(3): 473; Author Reply 473-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554633&dopt=Abstract
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Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area. Author(s): Supply P, Warren RM, Banuls AL, Lesjean S, Van Der Spuy GD, Lewis LA, Tibayrenc M, Van Helden PD, Locht C. Source: Molecular Microbiology. 2003 January; 47(2): 529-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519202&dopt=Abstract
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Localization of extrapulmonary tuberculosis in the synovial membrane, skin, and meninges in a patient with systemic lupus erythematosus and IgG deficiency. Author(s): Duzgun N, Peksari Y, Sonel B, Yucesan C, Erekul S, Duman M. Source: Rheumatology International. 2002 May; 22(1): 41-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12120911&dopt=Abstract
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Longitudinal analysis of Mycobacterium tuberculosis 19-kDa antigen-specific T cells in patients with pulmonary tuberculosis: association with disease activity and crossreactivity to a peptide from HIVenv gp120. Author(s): Hohn H, Kortsik C, Tully G, Nilges K, Necker A, Freitag K, Neukirch C, Galle P, Lohr H, Maeurer MJ. Source: European Journal of Immunology. 2003 June; 33(6): 1613-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12778479&dopt=Abstract
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Longitudinal study of tuberculosis outcomes among immunologically naive Ache natives of Paraguay. Author(s): Hurtado AM, Hill KR, Rosenblatt W, Bender J, Scharmen T. Source: American Journal of Physical Anthropology. 2003 June; 121(2): 134-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12740957&dopt=Abstract
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Long-term outcomes and risk factor analysis after pneumonectomy for active and sequela forms of pulmonary tuberculosis. Author(s): Kim YT, Kim HK, Sung SW, Kim JH. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2003 May; 23(5): 833-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12754042&dopt=Abstract
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Long-term tolerance and effectiveness of moxifloxacin therapy for tuberculosis: preliminary results. Author(s): Valerio G, Bracciale P, Manisco V, Quitadamo M, Legari G, Bellanova S. Source: Journal of Chemotherapy (Florence, Italy). 2003 February; 15(1): 66-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12678417&dopt=Abstract
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Loop-mediated isothermal amplification for direct detection of Mycobacterium tuberculosis complex, M. avium, and M. intracellulare in sputum samples. Author(s): Iwamoto T, Sonobe T, Hayashi K. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2616-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791888&dopt=Abstract
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Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti. Author(s): Pym AS, Brodin P, Brosch R, Huerre M, Cole ST. Source: Molecular Microbiology. 2002 November; 46(3): 709-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410828&dopt=Abstract
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Low access to a highly effective therapy: a challenge for international tuberculosis control. Author(s): Dye C, Watt CJ, Bleed D. Source: Bulletin of the World Health Organization. 2002; 80(6): 437-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12131999&dopt=Abstract
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Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive ethiopians. Author(s): Wolday D, Hailu B, Girma M, Hailu E, Sanders E, Fontanet AL. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 February; 7(2): 110-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588010&dopt=Abstract
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Low isoniazid concentrations and outcome of tuberculosis treatment with onceweekly isoniazid and rifapentine. Author(s): Weiner M, Burman W, Vernon A, Benator D, Peloquin CA, Khan A, Weis S, King B, Shah N, Hodge T; Tuberculosis Trials Consortium. Source: American Journal of Respiratory and Critical Care Medicine. 2003 May 15; 167(10): 1341-7. Epub 2003 January 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531776&dopt=Abstract
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Low level laser therapy for treating tuberculosis. Author(s): Vlassov VV, Pechatnikov LM, MacLehose HG. Source: Cochrane Database Syst Rev. 2002; (3): Cd003490. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12137698&dopt=Abstract
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Low level of compliance with tuberculosis treatment in children: monitoring by urine tests. Author(s): Palanduz A, Gultekin D, Erdem E, Kayaalp N. Source: Annals of Tropical Paediatrics. 2003 March; 23(1): 47-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12648324&dopt=Abstract
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Low plasma concentrations of rifampicin in tuberculosis patients in Indonesia. Author(s): van Crevel R, Alisjahbana B, de Lange WC, Borst F, Danusantoso H, van der Meer JW, Burger D, Nelwan RH. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 June; 6(6): 497502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12068982&dopt=Abstract
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Low prevalence and increased household clustering of Mycobacterium tuberculosis infection in high altitude villages in Peru. Author(s): Olender S, Saito M, Apgar J, Gillenwater K, Bautista CT, Lescano AG, Moro P, Caviedes L, Hsieh EJ, Gilman RH. Source: Am J Trop Med Hyg. 2003 June; 68(6): 721-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12887034&dopt=Abstract
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Low-stringency single-specific-primer PCR as a tool for detection of mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis. Author(s): Carvalho WS, Spindola de Miranda S, Costa KM, Araujo JG, Augusto CJ, Pesquero JB, Pesquero JL, Gomes MA. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 3384-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843099&dopt=Abstract
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Lupus miliaris disseminatus faciei and its debated link to tuberculosis. Author(s): Nino M, Barberio E, Delfino M. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2003 January; 17(1): 97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602984&dopt=Abstract
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Macrophages exposed to Mycobacterium tuberculosis release chemokines able to recruit selected leucocyte subpopulations: focus on gammadelta cells. Author(s): Ferrero E, Biswas P, Vettoretto K, Ferrarini M, Uguccioni M, Piali L, Leone BE, Moser B, Rugarli C, Pardi R. Source: Immunology. 2003 March; 108(3): 365-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603603&dopt=Abstract
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Management of a patient with active rheumatoid arthritis and suspected tuberculosis causing effusive-constrictive pericarditis. Author(s): Yildiz M, Erdogan O, Aktoz M, Gul C, Ozbay G. Source: International Journal of Cardiology. 2003 May; 89(1): 115-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727018&dopt=Abstract
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Management of multiple drug-resistant tuberculosis. Author(s): Hutchison DC, Drobniewski FA, Milburn HJ. Source: Respiratory Medicine. 2003 January; 97(1): 65-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556013&dopt=Abstract
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Managing the treatment of pulmonary tuberculosis. Author(s): Glyn-Jones J. Source: Nurs Times. 2002 October 1-8; 98(40): 48. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12382443&dopt=Abstract
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Mechanisms of cell recruitment in the immune response to Mycobacterium tuberculosis. Author(s): Peters W, Ernst JD. Source: Microbes and Infection / Institut Pasteur. 2003 February; 5(2): 151-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650773&dopt=Abstract
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Medical and social analysis of prisoners with tuberculosis in a Russian prison colony: an observational study. Author(s): Drobniewski F, Balabanova Y, Ruddy M, Fedorin I, Melentyev A, Mutovkin E, Kuznetzov S. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 January 15; 36(2): 234-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522759&dopt=Abstract
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Menstrual dysfunction in non-genital tuberculosis. Author(s): Sharma S. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2002 December; 79(3): 245-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445991&dopt=Abstract
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Method for inactivating and fixing unstained smear preparations of mycobacterium tuberculosis for improved laboratory safety. Author(s): Chedore P, Th'ng C, Nolan DH, Churchwell GM, Sieffert DE, Hale YM, Jamieson F. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4077-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409378&dopt=Abstract
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Methods used in the molecular epidemiology of tuberculosis. Author(s): Mostrom P, Gordon M, Sola C, Ridell M, Rastogi N. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2002 November; 8(11): 694-704. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445006&dopt=Abstract
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Microevolution of the direct repeat region of Mycobacterium tuberculosis: implications for interpretation of spoligotyping data. Author(s): Warren RM, Streicher EM, Sampson SL, van der Spuy GD, Richardson M, Nguyen D, Behr MA, Victor TC, van Helden PD. Source: Journal of Clinical Microbiology. 2002 December; 40(12): 4457-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454136&dopt=Abstract
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Miliary tuberculosis presenting as adult respiratory distress syndrome. Author(s): Dhall R, Kakar A. Source: J Assoc Physicians India. 2003 January; 51: 83-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693468&dopt=Abstract
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Miliary tuberculosis with bilateral pneumothorax: a rare complication. Author(s): Sharma N, Kumar P. Source: Indian J Chest Dis Allied Sci. 2002 April-June; 44(2): 125-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12026252&dopt=Abstract
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Miliary tuberculosis with positive acid-fast bacilli in a pediatric patient. Author(s): Fernandes SR, Homa MN, Igarashi A, Salles AL, Jaloretto AP, Freitas MS, Nogueira PC. Source: Sao Paulo Medical Journal = Revista Paulista De Medicina. 2003 May 5; 121(3): 125-7. Epub 2003 August 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920475&dopt=Abstract
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Modeling bacterial evolution with comparative-genome-based marker systems: application to Mycobacterium tuberculosis evolution and pathogenesis. Author(s): Alland D, Whittam TS, Murray MB, Cave MD, Hazbon MH, Dix K, Kokoris M, Duesterhoeft A, Eisen JA, Fraser CM, Fleischmann RD. Source: Journal of Bacteriology. 2003 June; 185(11): 3392-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12754238&dopt=Abstract
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Modern laboratory diagnosis of tuberculosis. Author(s): Drobniewski FA, Caws M, Gibson A, Young D. Source: The Lancet Infectious Diseases. 2003 March; 3(3): 141-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614730&dopt=Abstract
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Molecular analysis of rifampicin-resistant Mycobacterium tuberculosis isolated in Spain (1996-2001). Description of new mutations in the rpoB gene and review of the literature. Author(s): Herrera L, Jimenez S, Valverde A, Garcia-Aranda MA, Saez-Nieto JA. Source: International Journal of Antimicrobial Agents. 2003 May; 21(5): 403-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727071&dopt=Abstract
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Molecular and conventional epidemiology of tuberculosis in Hong Kong: a population-based prospective study. Author(s): Chan-Yeung M, Tam CM, Wong H, Leung CC, Wang J, Yew WW, Lam CW, Kam KM. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2706-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791911&dopt=Abstract
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Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical isolates in Lithuania. Author(s): Bakonyte D, Baranauskaite A, Cicenaite J, Sosnovskaja A, Stakenas P. Source: Antimicrobial Agents and Chemotherapy. 2003 June; 47(6): 2009-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12760887&dopt=Abstract
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Molecular detection of early appearance of drug resistance during Mycobacterium tuberculosis infection. Author(s): Victor TC, Lee H, Cho SN, Jordaan AM, van der Spuy G, van Helden PD, Warren R. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 September; 40(9): 876-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435103&dopt=Abstract
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Molecular differentiation of Mycobacterium tuberculosis strains without IS6110 insertions. Author(s): Lok KH, Benjamin WH Jr, Kimerling ME, Pruitt V, Lathan M, Razeq J, Hooper N, Cronin W, Dunlap NE. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1310-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453362&dopt=Abstract
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Molecular epidemiology and drug resistance of Mycobacterium tuberculosis isolates in the Archangel prison in Russia: predominance of the W-Beijing clone family. Author(s): Toungoussova OS, Mariandyshev A, Bjune G, Sandven P, Caugant DA. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 September 1; 37(5): 665-72. Epub 2003 August 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942398&dopt=Abstract
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Molecular epidemiology of multidrug-resistant tuberculosis, New York City, 19951997. Author(s): Munsiff SS, Bassoff T, Nivin B, Li J, Sharma A, Bifani P, Mathema B, Driscoll J, Kreiswirth BN. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1230-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453347&dopt=Abstract
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Molecular epidemiology of tuberculosis in a low- to moderate-incidence state: are contact investigations enough? Author(s): Cronin WA, Golub JE, Lathan MJ, Mukasa LN, Hooper N, Razeq JH, Baruch NG, Mulcahy D, Benjamin WH, Magder LS, Strickland GT, Bishai WR. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1271-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453355&dopt=Abstract
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Molecular epidemiology of tuberculosis in a rural area of high prevalence in South India: implications for disease control and prevention. Author(s): Narayanan S, Das S, Garg R, Hari L, Rao VB, Frieden TR, Narayanan PR. Source: Journal of Clinical Microbiology. 2002 December; 40(12): 4785-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454197&dopt=Abstract
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Molecular epidemiology of tuberculosis in a sentinel surveillance population. Author(s): Ellis BA, Crawford JT, Braden CR, McNabb SJ, Moore M, Kammerer S; National Tuberculosis Genotyping and Surveillance Network Work Group. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1197-209. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453343&dopt=Abstract
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Molecular epidemiology of tuberculosis. Author(s): Barnes PF, Cave MD. Source: The New England Journal of Medicine. 2003 September 18; 349(12): 1149-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679530&dopt=Abstract
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Molecular fingerprinting of isoniazid-resistant Mycobacterium tuberculosis isolates from chest diseases hospital in Kuwait. Author(s): Mokaddas E, Ahmad S, Abal AT. Source: Microbiol Immunol. 2002; 46(11): 767-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516773&dopt=Abstract
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Molecular mechanisms regulating persistent Mycobacterium tuberculosis infection. Author(s): Zahrt TC. Source: Microbes and Infection / Institut Pasteur. 2003 February; 5(2): 159-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650774&dopt=Abstract
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Molecular methods for Mycobacterium tuberculosis strain typing: a users guide. Author(s): Kanduma E, McHugh TD, Gillespie SH. Source: Journal of Applied Microbiology. 2003; 94(5): 781-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694442&dopt=Abstract
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Molecular typing of Mycobacterium tuberculosis strains with a common two-band IS6110 pattern. Author(s): Lok KH, Benjamin WH Jr, Kimerling ME, Pruitt V, Mulcahy D, Robinson N, Keenan NB, Dunlap NE. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1303-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453360&dopt=Abstract
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Monitoring socioeconomic inequalities in sexually transmitted infections, tuberculosis, and violence: geocoding and choice of area-based socioeconomic measures--the public health disparities geocoding project (US). Author(s): Krieger N, Waterman PD, Chen JT, Soobader MJ, Subramanian SV. Source: Public Health Reports (Washington, D.C. : 1974). 2003 May-June; 118(3): 240-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12766219&dopt=Abstract
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Monocytes and neutrophils from tuberculosis patients are insensitive to antiinflammatory effects triggered by the prototypic formyl peptide N-formyl-methionylleucyl-phenylalanine (FMLP). Author(s): Beigier-Bompadre M, Aleman M, Barrionuevo P, Franco MC, Rubel CJ, Sasiain Mdel C, Palermo MS, Abbate E, Isturiz MA. Source: Clinical and Experimental Immunology. 2003 August; 133(2): 267-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869034&dopt=Abstract
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Mortality due to silico-tuberculosis and lung cancer among 200 whetstone cutters. Author(s): Ogawa S, Imai H, Ikeda M. Source: Ind Health. 2003 July; 41(3): 231-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916753&dopt=Abstract
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MR imaging features of nasopharyngeal tuberculosis: report of three cases and literature review. Author(s): King AD, Ahuja AT, Tse GM, van Hasselt AC, Chan AB. Source: Ajnr. American Journal of Neuroradiology. 2003 February; 24(2): 279-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591649&dopt=Abstract
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Mtp-40 and alpha antigen gene fragment amplification for the detection of Mycobacterium tuberculosis in Colombian clinical specimens. Author(s): Alfonso R, Romero RE, Patarroyo ME, Murillo LA. Source: Memorias Do Instituto Oswaldo Cruz. 2002 December; 97(8): 1157-63. Epub 2003 January 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12563484&dopt=Abstract
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Multicenter evaluation of ethambutol susceptibility testing of mycobacterium tuberculosis by agar proportion and radiometric methods. Author(s): Madison B, Robinson-Dunn B, George I, Gross W, Lipman H, Metchock B, Sloutsky A, Washabaugh G, Mazurek G, Ridderhof J. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 3976-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409361&dopt=Abstract
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Multi-drug resistant tuberculosis in context of RNTCP. Author(s): Arora VK, Visalakshi P. Source: Indian J Chest Dis Allied Sci. 2003 July-September; 45(3): 215-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866642&dopt=Abstract
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Multidrug-resistant strains of Mycobacterium tuberculosis isolated from patients in Tehran belong to a genetically distinct cluster. Author(s): Feizabadi MM, Shahriari M, Safavi M, Gharavi S, Hamid M. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(1): 47-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12685884&dopt=Abstract
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Multidrug-resistant tuberculosis at Srinagarind Hospital, Khon Kaen, Thailand. Author(s): Reechaipichitkul W. Source: Southeast Asian J Trop Med Public Health. 2002 September; 33(3): 570-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693593&dopt=Abstract
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Multidrug-resistant tuberculosis in pregnancy: case report and review of the literature. Author(s): Lessnau KD, Qarah S. Source: Chest. 2003 March; 123(3): 953-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628902&dopt=Abstract
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Multifocal vertebral tuberculosis with the involvement of the ribs case report. Author(s): Amogne W, Abubaker A. Source: Ethiop Med J. 2002 October; 40(4): 397-405. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12596659&dopt=Abstract
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Multiple drug-resistant Mycobacterium tuberculosis: evidence for changing fitness following passage through human hosts. Author(s): Gillespie SH, Billington OJ, Breathnach A, McHugh TD. Source: Microbial Drug Resistance (Larchmont, N.Y.). 2002 Winter; 8(4): 273-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12523624&dopt=Abstract
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Multiple equilibria: tuberculosis transmission require unrealistic assumptions. Author(s): Lipsitch M, Murray MB. Source: Theoretical Population Biology. 2003 March; 63(2): 169-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615499&dopt=Abstract
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Musculoskeletal images. Knee-joint tuberculosis. Author(s): Waddell JP. Source: Canadian Journal of Surgery. Journal Canadien De Chirurgie. 2003 June; 46(3): 202-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12812243&dopt=Abstract
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Mycobacterium bovis BCG scar status and HLA class II alleles influence purified protein derivative-specific T-cell receptor V beta expression in pulmonary tuberculosis patients from southern India. Author(s): Shanmugalakshmi S, Dheenadhayalan V, Muthuveeralakshmi P, Arivarignan G, Pitchappan RM. Source: Infection and Immunity. 2003 August; 71(8): 4544-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874334&dopt=Abstract
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Mycobacterium bovis subsp. caprae caused one-third of human M. bovis-associated tuberculosis cases reported in Germany between 1999 and 2001. Author(s): Kubica T, Rusch-Gerdes S, Niemann S. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 3070-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843046&dopt=Abstract
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Mycobacterium tuberculosis chaperonin 10 heptamers self-associate through their biologically active loops. Author(s): Roberts MM, Coker AR, Fossati G, Mascagni P, Coates AR, Wood SP. Source: Journal of Bacteriology. 2003 July; 185(14): 4172-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12837792&dopt=Abstract
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Mycobacterium tuberculosis chaperonin 10 is secreted in the macrophage phagosome: is secretion due to dissociation and adoption of a partially helical structure at the membrane? Author(s): Fossati G, Izzo G, Rizzi E, Gancia E, Modena D, Moras ML, Niccolai N, Giannozzi E, Spiga O, Bono L, Marone P, Leone E, Mangili F, Harding S, Errington N, Walters C, Henderson B, Roberts MM, Coates AR, Casetta B, Mascagni P. Source: Journal of Bacteriology. 2003 July; 185(14): 4256-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12837802&dopt=Abstract
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Mycobacterium tuberculosis complex is not detected by DNA amplification assay in sputum specimens of patients with lung scars due to past pulmonary tuberculosis. Author(s): Rajalahti I, Vuorinen P, Jarvenpaa R, Nieminen MM. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 February; 7(2): 190-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588022&dopt=Abstract
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Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary. Author(s): Grosset J. Source: Antimicrobial Agents and Chemotherapy. 2003 March; 47(3): 833-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604509&dopt=Abstract
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Mycobacterium tuberculosis infection of a tophaceous pseudogout nodule. Author(s): Schumacher HR Jr. Source: The Journal of Rheumatology. 2003 March; 30(3): 637; Author Reply 638. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610833&dopt=Abstract
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Mycobacterium tuberculosis infection of a tophaceous pseudogout nodule. Author(s): Santos-Ocampo AS, Tupasi TE, Villanueva F, Roxas FK, Ramos CP. Source: The Journal of Rheumatology. 2002 May; 29(5): 1093-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12022329&dopt=Abstract
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Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro. Author(s): Hanekom WA, Mendillo M, Manca C, Haslett PA, Siddiqui MR, Barry C 3rd, Kaplan G. Source: The Journal of Infectious Diseases. 2003 July 15; 188(2): 257-66. Epub 2003 Jul 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854081&dopt=Abstract
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Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Author(s): Smith I. Source: Clinical Microbiology Reviews. 2003 July; 16(3): 463-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857778&dopt=Abstract
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Mycobacterium tuberculosis presenting as an infected pulmonary bulla. Author(s): Bull TM, Keith RL, Kraft M, Dempsy EC, Miller YE. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 504. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757057&dopt=Abstract
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Mycobacterium tuberculosis subverts the differentiation of human monocytes into dendritic cells. Author(s): Mariotti S, Teloni R, Iona E, Fattorini L, Giannoni F, Romagnoli G, Orefici G, Nisini R. Source: European Journal of Immunology. 2002 November; 32(11): 3050-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12385024&dopt=Abstract
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Mycobacterium tuberculosis transmission between cluster members with similar fingerprint patterns. Author(s): Ijaz K, Yang Z, Matthews HS, Bates JH, Cave MD. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1257-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453352&dopt=Abstract
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Mycobacterium tuberculosis uptake by recipient host macrophages is influenced by environmental conditions in the granuloma of the infectious individual and is associated with impaired production of interleukin-12 and tumor necrosis factor alpha. Author(s): Li YJ, Petrofsky M, Bermudez LE. Source: Infection and Immunity. 2002 November; 70(11): 6223-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379701&dopt=Abstract
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Mycobacterium tuberculosis-induced activation accelerates apoptosis in peripheral blood neutrophils from patients with active tuberculosis. Author(s): Aleman M, Garcia A, Saab MA, De La Barrera SS, Finiasz M, Abbate E, Sasiain MC. Source: American Journal of Respiratory Cell and Molecular Biology. 2002 November; 27(5): 583-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397018&dopt=Abstract
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Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis: a randomised placebo-controlled trial. Author(s): Mwinga A, Nunn A, Ngwira B, Chintu C, Warndorff D, Fine P, Darbyshire J, Zumla A; LUSKAR collaboration. Source: Lancet. 2002 October 5; 360(9339): 1050-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12383985&dopt=Abstract
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Mycobacterium vaccae immunotherapy for treating tuberculosis. Author(s): de Bruyn G, Garner P. Source: Cochrane Database Syst Rev. 2003; (1): Cd001166. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535403&dopt=Abstract
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Nasopharyngeal tuberculosis with massive cervical lymphadenopathy. Author(s): Unal M, Dusmez D, Gorur K, Aydin O, Talas DU. Source: The Journal of Otolaryngology. 2002 June; 31(3): 186-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12121028&dopt=Abstract
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National Tuberculosis Genotyping and Surveillance Network: design and methods. Author(s): Crawford JT, Braden CR, Schable BA, Onorato IM. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1192-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453342&dopt=Abstract
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Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis. Author(s): Soborg C, Andersen AB, Madsen HO, Kok-Jensen A, Skinhoj P, Garred P. Source: The Journal of Infectious Diseases. 2002 August 15; 186(4): 517-21. Epub 2002 July 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195379&dopt=Abstract
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Nearly 70% of tuberculosis cases remain undetected. Author(s): Ahmad K. Source: The Lancet Infectious Diseases. 2002 June; 2(6): 319. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12144883&dopt=Abstract
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Negative transcriptional regulation of the mce3 operon in Mycobacterium tuberculosis. Author(s): Santangelo MP, Goldstein J, Alito A, Gioffre A, Caimi K, Zabal O, Zumarraga M, Romano MI, Cataldi AA, Bigi F. Source: Microbiology (Reading, England). 2002 October; 148(Pt 10): 2997-3006. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368433&dopt=Abstract
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Neonatal tuberculosis associated with shock, disseminated intravascular coagulation, hemophagocytic syndrome, and hypercalcemia: a case report. Author(s): Okascharoen C, Nuntnarumit P, Sirinavin S. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 January; 23(1): 79-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556935&dopt=Abstract
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Nested polymerase chain reaction for Mycobacterium tuberculosis DNA detection in aqueous and vitreous of patients with uveitis. Author(s): Ortega-Larrocea G, Bobadilla-del-Valle M, Ponce-de-Leon A, SifuentesOsornio J. Source: Archives of Medical Research. 2003 March-April; 34(2): 116-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700006&dopt=Abstract
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Nested polymerase chain reaction in the diagnosis of negative Ziehl-Neelsen stained Mycobacterium tuberculosis fistula-in-ano: report of four cases. Author(s): Shan YS, Yan JJ, Sy ED, Jin YT, Lee JC. Source: Diseases of the Colon and Rectum. 2002 December; 45(12): 1685-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12473896&dopt=Abstract
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New drug targets for Mycobacterium tuberculosis. Author(s): Chopra P, Meena LS, Singh Y. Source: The Indian Journal of Medical Research. 2003 January; 117: 1-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866819&dopt=Abstract
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New vaccines for the prevention of tuberculosis. Author(s): von Reyn CF, Vuola JM. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 August 15; 35(4): 465-74. Epub 2002 July 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12145732&dopt=Abstract
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Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Author(s): Murray MF. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 February 15; 36(4): 453-60. Epub 2003 January 31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12567303&dopt=Abstract
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Nitric oxide and tuberculosis infection. Author(s): Escalante P, Cagle PT. Source: American Journal of Respiratory and Critical Care Medicine. 2003 June 15; 167(12): 1718; Author Reply 1718. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796058&dopt=Abstract
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Nitric oxide scavenging and detoxification by the Mycobacterium tuberculosis haemoglobin, HbN in Escherichia coli. Author(s): Pathania R, Navani NK, Gardner AM, Gardner PR, Dikshit KL. Source: Molecular Microbiology. 2002 September; 45(5): 1303-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12207698&dopt=Abstract
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No association between Helicobacter pylori and Mycobacterium tuberculosis infections among gastrointestinal clinic attendees in Lima, Peru. Author(s): Torres MA, Passaro DJ, Watanabe J, Parsonnet J, Small P, Miyagu J, Rodriquez C, Astete M, Gilman RH. Source: Epidemiology and Infection. 2003 February; 130(1): 87-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12613749&dopt=Abstract
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Non-adherence to tuberculosis treatment in the eastern Tarai of Nepal. Author(s): Wares DF, Singh S, Acharya AK, Dangi R. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 32735. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729337&dopt=Abstract
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Noncompliance with tuberculosis treatment by patients at a tuberculosis and AIDS reference hospital in midwestern Brazil. Author(s): Rabahi MF, Rodrigues AB, Queiroz de Mello F, de Almeida Netto JC, Kritski AL. Source: The Brazilian Journal of Infectious Diseases : an Official Publication of the Brazilian Society of Infectious Diseases. 2002 April; 6(2): 63-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11980606&dopt=Abstract
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Nonhealing ulcerative mass of the elbow: do not forget tuberculosis. Author(s): Ayhan S, Ozmen S, Uluoglu O, Demirtas Y, Boyacioglu M, Latifoglu O, Atabay K. Source: Annals of Plastic Surgery. 2002 May; 48(5): 557-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11981201&dopt=Abstract
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Non-tuberculous mycobacterial lung infection mimicking primary tuberculosis in non-immunocompromised children. Author(s): Levrey-Hadden H, Reix P, Louis D, Bellon G. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(6): 725-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12162613&dopt=Abstract
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Nosocomial outbreak of multidrug-resistant tuberculosis caused by a strain of Mycobacterium tuberculosis W-Beijing family in St. Petersburg, Russia. Author(s): Narvskaya O, Otten T, Limeschenko E, Sapozhnikova N, Graschenkova O, Steklova L, Nikonova A, Filipenko ML, Mokrousov I, Vyshnevskiy B. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2002 August; 21(8): 596602. Epub 2002 August 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12226690&dopt=Abstract
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NRAMP1 and susceptibility to tuberculosis. Author(s): Bellamy R. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 September; 6(9): 747. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12234128&dopt=Abstract
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NRAMP1 polymorphisms, susceptibility and clinical features of tuberculosis. Author(s): Abe T, Iinuma Y, Ando M, Yokoyama T, Yamamoto T, Nakashima K, Takagi N, Baba H, Hasegawa Y, Shimokata K. Source: The Journal of Infection. 2003 May; 46(4): 215-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799146&dopt=Abstract
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Nymphs of the Oriental cockroach (Blatta orientalis) as passive vectors of causal agents of avian tuberculosis and paratuberculosis. Author(s): Fischer OA, Matlova L, Dvorska L, Svastova P, Pavlik I. Source: Medical and Veterinary Entomology. 2003 June; 17(2): 145-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823831&dopt=Abstract
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Observation of body temperature and erythrocyte sedimentation rate in spinal tuberculosis patients with anterior interbody autograft and internal fixation. Author(s): Feng L, Qu DB, Jin DD, Chen JT. Source: Di Yi June Yi Da Xue Xue Bao. 2002 January; 22(1): 84-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390858&dopt=Abstract
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Occurrence of Pneumocystis carinii in HIV-positive patients with suspected pulmonary tuberculosis in Ethiopia. Author(s): Aderaye G, Bruchfeld J, Olsson M, Lindquist L. Source: Aids (London, England). 2003 February 14; 17(3): 435-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556698&dopt=Abstract
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Ocular disease in patients with tuberculosis and HIV presenting with fever in Africa. Author(s): Beare NA, Kublin JG, Lewis DK, Schijffelen MJ, Peters RP, Joaki G, Kumwenda J, Zijlstra EE. Source: The British Journal of Ophthalmology. 2002 October; 86(10): 1076-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12234881&dopt=Abstract
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Ocular tuberculosis. Author(s): Kuruvilla A. Source: Lancet. 2003 January 18; 361(9353): 260-1; Author Reply 261. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547573&dopt=Abstract
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Ofloxacin population pharmacokinetics in patients with tuberculosis. Author(s): Stambaugh JJ, Berning SE, Bulpitt AE, Hollender ES, Narita M, Ashkin D, Peloquin CA. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 June; 6(6): 503-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12068983&dopt=Abstract
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Olaf Scheel and Johannes Heimbeck: their contribution to understanding the pathogenesis and prevention of tuberculosis. Author(s): Bjartveit K. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 30611. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729334&dopt=Abstract
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On treatment of tuberculosis in heterogeneous populations. Author(s): Murphy BM, Singer BH, Kirschner D. Source: Journal of Theoretical Biology. 2003 August 21; 223(4): 391-404. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875819&dopt=Abstract
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Orbital tuberculosis with abscess. Author(s): Aggarwal D, Suri A, Mahapatra AK. Source: Journal of Neuro-Ophthalmology : the Official Journal of the North American Neuro-Ophthalmology Society. 2002 September; 22(3): 208-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12352584&dopt=Abstract
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Oropharyngeal tuberculosis causing severe odynophagia and dysphagia. Author(s): Caylan R, Aydin K, Caylan R. Source: European Archives of Oto-Rhino-Laryngology : Official Journal of the European Federation of Oto-Rhino-Laryngological Societies (Eufos) : Affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2002 May; 259(5): 229-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12107522&dopt=Abstract
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Outbreak of tuberculosis among homeless persons coinfected with human immunodeficiency virus. Author(s): McElroy PD, Southwick KL, Fortenberry ER, Levine EC, Diem LA, Woodley CL, Williams PM, McCarthy KD, Ridzon R, Leone PA. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 May 15; 36(10): 1305-12. Epub 2003 May 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746777&dopt=Abstract
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Outbreak of tuberculosis at a Newcastle public house: the role and effectiveness of contact screening. Author(s): Pettit S, Black A, Stenton C, Black N. Source: Commun Dis Public Health. 2002 March; 5(1): 48-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12070978&dopt=Abstract
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Outbreak of tuberculosis in a 2000-year-old Chinese population. Author(s): Fusegawa H, Wang BH, Sakurai K, Nagasawa K, Okauchi M, Nagakura K. Source: Kansenshogaku Zasshi. 2003 March; 77(3): 146-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708007&dopt=Abstract
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Outbreak of tuberculosis in a homeless men's shelter. Author(s): Morrow CB, Cibula DA, Novick LF. Source: American Journal of Preventive Medicine. 2003 May; 24(4 Suppl): 124-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12744992&dopt=Abstract
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Outcome in neurologically impaired patients with craniovertebral junction tuberculosis: results of combined anteroposterior surgery. Author(s): Arunkumar MJ, Rajshekhar V. Source: Journal of Neurosurgery. 2002 September; 97(2 Suppl): 166-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12296673&dopt=Abstract
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Outcome of directly observed therapy for tuberculosis in Yokohama City, Japan. Author(s): Tsuchida K, Koyanagi H. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 730-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921148&dopt=Abstract
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Outcome of patients with tuberculosis who transfer between reporting units in Malawi. Author(s): Meijnen S, Weismuller MM, Claessens NJ, Kwanjana JH, Salaniponi FM, Harries AD. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 August; 6(8): 666-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150477&dopt=Abstract
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Outcome of the treatment of culture negative tuberculosis (respiratory and nonrespiratory): Blackburn 1996-2000. Author(s): Ormerod LP, Green RM, Horsfield N. Source: The Journal of Infection. 2002 August; 45(2): 88-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217709&dopt=Abstract
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Outcome of treatment of pulmonary tuberculosis in Switzerland in 1996. Author(s): Helbling P, Medinger C, Altpeter E, Raeber PA, Beeli D, Zellweger JP. Source: Swiss Medical Weekly : Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology. 2002 September 7; 132(35-36): 517-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12506334&dopt=Abstract
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Outcome of tuberculosis treatment in Hamburg: a survey, 1997-2001. Author(s): Diel R, Niemann S. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 February; 7(2): 124-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588012&dopt=Abstract
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Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Author(s): Larsen MH, Vilcheze C, Kremer L, Besra GS, Parsons L, Salfinger M, Heifets L, Hazbon MH, Alland D, Sacchettini JC, Jacobs WR Jr. Source: Molecular Microbiology. 2002 October; 46(2): 453-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406221&dopt=Abstract
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Oxidative stress response genes in Mycobacterium tuberculosis: role of ahpC in resistance to peroxynitrite and stage-specific survival in macrophages. Author(s): Master SS, Springer B, Sander P, Boettger EC, Deretic V, Timmins GS. Source: Microbiology (Reading, England). 2002 October; 148(Pt 10): 3139-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368447&dopt=Abstract
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Paediatric tuberculosis. Author(s): Hoskyns W. Source: Postgraduate Medical Journal. 2003 May; 79(931): 272-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782773&dopt=Abstract
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Pancreatic tuberculosis. Author(s): Pramesh CS, Heroor AA, Shukla PJ, Jagannath PM, De Souza LJ. Source: Trop Gastroenterol. 2002 July-September; 23(3): 142-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693159&dopt=Abstract
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Pancreatic tuberculosis: still a histopathological diagnosis. Author(s): Chaudhary A, Negi SS, Sachdev AK, Gondal R. Source: Digestive Surgery. 2002; 19(5): 389-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435910&dopt=Abstract
270 Tuberculosis
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Para-aminosalicylic acid (PAS) desensitization review in a case of multidrug-resistant pulmonary tuberculosis. Author(s): Wilson JW, Kelkar P, Frigas E. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 493-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757053&dopt=Abstract
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Paradoxical response in patients with CNS tuberculosis. Author(s): Gupta M, Bajaj BK, Khwaja G. Source: J Assoc Physicians India. 2003 March; 51: 257-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839346&dopt=Abstract
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Pattern of active pulmonary tuberculosis in human immunodeficiency virus seropositive adult patients in University College Hospital, Ibadan, Nigeria. Author(s): Awoyemi OB, Ige OM, Onadeko BO. Source: Afr J Med Med Sci. 2002 March; 31(1): 25-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12518925&dopt=Abstract
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Pattern recognition technique in immunological antigenic tests to identify Mycobacterium tuberculosis infection. Author(s): Selvaraj R, Gopal G, Raja A, Kumaraswami V. Source: Tuberculosis (Edinburgh, Scotland). 2002; 82(6): 261-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623268&dopt=Abstract
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Paucibacillary tuberculosis--a retrospective study. Author(s): Dam T, Bose M. Source: J Indian Med Assoc. 2002 April; 100(4): 231-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405330&dopt=Abstract
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PCR diagnosis of tuberculosis--experience in India. Author(s): Singh UB, Seth P. Source: Indian J Pediatr. 2002 November; 69 Suppl 1: S20-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501921&dopt=Abstract
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PCR-based method to differentiate the subspecies of the Mycobacterium tuberculosis complex on the basis of genomic deletions. Author(s): Huard RC, de Oliveira Lazzarini LC, Butler WR, van Soolingen D, Ho JL. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1637-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682155&dopt=Abstract
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PCR-based methodology for detecting multidrug-resistant strains of Mycobacterium tuberculosis Beijing family circulating in Russia. Author(s): Mokrousov I, Otten T, Vyazovaya A, Limeschenko E, Filipenko ML, Sola C, Rastogi N, Steklova L, Vyshnevskiy B, Narvskaya O. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 June; 22(6): 342-8. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783278&dopt=Abstract
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Pediatric tuberculosis: time for a new approach. Author(s): Starke JR. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 208-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758213&dopt=Abstract
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Perforations and fistulae in gastrointestinal tuberculosis. Author(s): Nagi B, Lal A, Kochhar R, Bhasin DK, Thapa BR, Singh K. Source: Acta Radiologica (Stockholm, Sweden : 1987). 2002 September; 43(5): 501-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12423461&dopt=Abstract
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Performance assessment of two commercial amplification assays for direct detection of Mycobacterium tuberculosis complex from respiratory and extrapulmonary specimens. Author(s): Piersimoni C, Scarparo C, Piccoli P, Rigon A, Ruggiero G, Nista D, Bornigia S. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4138-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409387&dopt=Abstract
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Performance of the microscopic observation drug susceptibility assay in drug susceptibility testing for Mycobacterium tuberculosis. Author(s): Park WG, Bishai WR, Chaisson RE, Dorman SE. Source: Journal of Clinical Microbiology. 2002 December; 40(12): 4750-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454186&dopt=Abstract
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Peripheral nerve granuloma in a patient with tuberculosis. Author(s): Orrell RW, King RH, Bowler JV, Ginsberg L. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 December; 73(6): 76971. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438489&dopt=Abstract
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Peripheral neuropathy associated with treatment for multidrug-resistant tuberculosis. Author(s): Shin SS, Hyson AM, Castaneda C, Sanchez E, Alcantara F, Mitnick CD, Fawzi MC, Bayona J, Farmer PE, Kim JY, Furin JJ. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 34753. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729340&dopt=Abstract
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Peritoneal tuberculosis mimicking advanced ovarian cancer in a patient treated with methotrexate for chronic rheumatoid arthritis. Author(s): Huesler M, Ruef C, Pfyffer GE, Haller U, Fink D. Source: Journal of Obstetrics and Gynaecology : the Journal of the Institute of Obstetrics and Gynaecology. 2003 May; 23(3): 315-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12850870&dopt=Abstract
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Peritoneal tuberculosis with negative polymerase chain reaction results: report of two cases. Author(s): Schwake L, von Herbay A, Junghanss T, Stremmel W, Mueller M. Source: Scandinavian Journal of Gastroenterology. 2003 February; 38(2): 221-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12678341&dopt=Abstract
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Persistence of a highly resistant strain of tuberculosis in New York City during 19901999. Author(s): Munsiff SS, Nivin B, Sacajiu G, Mathema B, Bifani P, Kreiswirth BN. Source: The Journal of Infectious Diseases. 2003 August 1; 188(3): 356-63. Epub 2003 July 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870116&dopt=Abstract
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Polyclonal and compartmentalized infection by Mycobacterium tuberculosis in patients with both respiratory and extrarespiratory involvement. Author(s): Garcia de Viedma D, Marin M, Ruiz Serrano MJ, Alcala L, Bouza E. Source: The Journal of Infectious Diseases. 2003 February 15; 187(4): 695-9. Epub 2003 Feb 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12599090&dopt=Abstract
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Polymerase chain reaction based detection of Mycobacterium tuberculosis in tissues showing granulomatous inflammation without demonstrable acid-fast bacilli. Author(s): Hsiao PF, Tzen CY, Chen HC, Su HY. Source: International Journal of Dermatology. 2003 April; 42(4): 281-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694493&dopt=Abstract
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Polymorphic nucleotide within the promoter of nitrate reductase (NarGHJI) is specific for Mycobacterium tuberculosis. Author(s): Stermann M, Bohrssen A, Diephaus C, Maass S, Bange FC. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 3252-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843072&dopt=Abstract
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Port-site tuberculosis after laparoscopy: report of eight cases. Author(s): Ramesh H, Prakash K, Lekha V, Jacob G, Venugopal A, Venugopal B. Source: Surgical Endoscopy. 2003 June; 17(6): 930-2. Epub 2003 March 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12618936&dopt=Abstract
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Predicting tuberculosis among migrant groups. Author(s): Watkins RE, Plant AJ. Source: Epidemiology and Infection. 2002 December; 129(3): 623-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12558347&dopt=Abstract
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Predictors of adherence to treatment for latent tuberculosis infection in high-risk Latino adolescents: a behavioral epidemiological analysis. Author(s): Hovell M, Blumberg E, Gil-Trejo L, Vera A, Kelley N, Sipan C, Hofstetter CR, Marshall S, Berg J, Friedman L, Catanzaro A, Moser K. Source: Social Science & Medicine (1982). 2003 April; 56(8): 1789-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639595&dopt=Abstract
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Prehistoric tuberculosis in america: adding comments to a literature review. Author(s): Gomez i Prat J, de Souza SM. Source: Memorias Do Instituto Oswaldo Cruz. 2003; 98 Suppl 1: 151-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687776&dopt=Abstract
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Presence of a 88 kDa Eales protein in uveitis, tuberculosis, leprosy and rheumatoid arthritis. Author(s): Rajesh M, Sulochana KN, Sundaram AL, Krishnakumar S, Biswas J, Ramakrishnan S. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 February; 9(2): Cr95-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601295&dopt=Abstract
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Presumptive infection of a total hip prosthesis by Mycobacterium tuberculosis: a case report. Author(s): Fernandez-Valencia JA, Garcia S, Riba J. Source: Acta Orthop Belg. 2003 April; 69(2): 193-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12769022&dopt=Abstract
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Prevalence and pattern of acquired drug resistance in tuberculosis including MDRTB in Bihar. Author(s): Barat D, Kumar G. Source: J Assoc Physicians India. 2003 March; 51: 327-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839372&dopt=Abstract
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Prevalence of anti-mycolic acid antibodies in patients with pulmonary tuberculosis co-infected with HIV. Author(s): Schleicher GK, Feldman C, Vermaak Y, Verschoor JA. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 September; 40(9): 882-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435104&dopt=Abstract
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Prevalence of antineutrophil cytoplasmic autoantibodies in patients with tuberculosis. Author(s): Flores-Suarez LF, Cabiedes J, Villa AR, van der Woude FJ, Alcocer-Varela J. Source: Rheumatology (Oxford, England). 2003 February; 42(2): 223-9. Erratum In: Rheumatology (Oxford). 2003 May; 42(5): 711. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12595614&dopt=Abstract
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Prevalence of HIV-1 infection among patients with leprosy and pulmonary tuberculosis in a semi-arid region, Nigeria. Author(s): Moses AE, Adelowo KA, Ajayi BB. Source: J R Soc Health. 2003 June; 123(2): 117-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852197&dopt=Abstract
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Prevalence of pulmonary tuberculosis among HIV-infected persons in a home care program in Phnom Penh, Cambodia. Author(s): Kimerling ME, Schuchter J, Chanthol E, Kunthy T, Stuer F, Glaziou P, Ee O. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 988-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475145&dopt=Abstract
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Primary oral tuberculosis: a report of a case diagnosed by polymerase chain reaction. Author(s): Rivera H, Correa MF, Castillo-Castillo S, Nikitakis NG. Source: Oral Diseases. 2003 January; 9(1): 46-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617258&dopt=Abstract
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Primary skeletal muscle tuberculosis. Author(s): Bakshi G, Satish R, Shetty SV, Anjana J. Source: Orthopedics. 2003 March; 26(3): 327-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650328&dopt=Abstract
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Primary tuberculosis of the thyroid gland: report of three cases. Author(s): Pazaitou K, Chrisoulidou A, Ginikopoulou E, Angel J, Destouni C, Vainas I. Source: Thyroid : Official Journal of the American Thyroid Association. 2002 December; 12(12): 1137-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593728&dopt=Abstract
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Primary urethral tuberculosis masquerading as a urethral caruncle: a diagnostic curiosity! Author(s): Singh I, Hemal AK. Source: International Urology and Nephrology. 2002; 34(1): 101-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12549649&dopt=Abstract
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Priorities in tuberculosis research in India. Author(s): Ganguly NK, Walia K. Source: Indian J Pediatr. 2002 November; 69 Suppl 1: S50-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501926&dopt=Abstract
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Private doctors must improve their treatment of tuberculosis, says WHO. Author(s): Brown P. Source: Bmj (Clinical Research Ed.). 2002 December 7; 325(7376): 1320. Erratum In: Bmj 2002 Dec 14; 325(7377): 1381. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468471&dopt=Abstract
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Private tuberculosis care provision associated with poor treatment outcome: comparative study of a semi-private lung clinic and the NTP in two urban districts in Ho Chi Minh City, Vietnam. National Tuberculosis Programme. Author(s): Lonnroth K, Thuong LM, Lambregts K, Quy HT, Diwan VK. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 February; 7(2): 165-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588018&dopt=Abstract
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Procalcitonin as a diagnostic tool in lower respiratory tract infections and tuberculosis. Author(s): Polzin A, Pletz M, Erbes R, Raffenberg M, Mauch H, Wagner S, Arndt G, Lode H. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 June; 21(6): 939-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797485&dopt=Abstract
276 Tuberculosis
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Processing sputum specimens in a refrigerated centrifuge does not increase the rate of isolation of Mycobacterium tuberculosis. Author(s): Selvakumar N, Govindan D, Chandu NA, Frieden TR, Narayanan PR. Source: Journal of Clinical Microbiology. 2003 January; 41(1): 469-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517897&dopt=Abstract
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Profile of geriatric patients under DOTS in Revised National Tuberculosis Control Programme. Author(s): Arora VK, Singla N, Sarin R. Source: Indian J Chest Dis Allied Sci. 2003 October-December; 45(4): 231-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962456&dopt=Abstract
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Proinflammatory cytokines in the course of Mycobacterium tuberculosis-induced apoptosis in monocytes/macrophages. Author(s): Ciaramella A, Cavone A, Santucci MB, Amicosante M, Martino A, Auricchio G, Pucillo LP, Colizzi V, Fraziano M. Source: The Journal of Infectious Diseases. 2002 November 1; 186(9): 1277-82. Epub 2002 October 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12402197&dopt=Abstract
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Prolonged paradoxical reaction of tuberculosis in an HIV-infected patient after initiation of highly active antiretroviral therapy. Author(s): Ramos A, Asensio A, Perales I, Montero MC, Martin T. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 June; 22(6): 374-6. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774198&dopt=Abstract
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Prospects for a better vaccine against tuberculosis. Author(s): Reed SG, Alderson MR, Dalemans W, Lobet Y, Skeiky YA. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 213-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758214&dopt=Abstract
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Prospects for new vaccines against tuberculosis. Author(s): Brandt L, Orme I. Source: Biotechniques. 2002 November; 33(5): 1098, 1100, 1102. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12449388&dopt=Abstract
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Protein expression in Mycobacterium tuberculosis differs with growth stage and strain type. Author(s): Pheiffer C, Betts J, Lukey P, van Helden P. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 September; 40(9): 869-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435102&dopt=Abstract
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Pseudo tumoral laryngeal tuberculosis. Author(s): Singh K, Kaur G, Parmar TL. Source: Indian Pediatrics. 2003 January; 40(1): 49-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554919&dopt=Abstract
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Public health impact of targeted tuberculosis screening in public schools. Author(s): Chang S, Wheeler LS, Farrell KP. Source: American Journal of Public Health. 2002 December; 92(12): 1942-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453813&dopt=Abstract
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Pulmonary granulomatous inflammation: From sarcoidosis to tuberculosis. Author(s): Perez RL, Rivera-Marrero CA, Roman J. Source: Seminars in Respiratory Infections. 2003 March; 18(1): 23-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12652451&dopt=Abstract
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Pulmonary paragonimiasis misdiagnosed as tuberculosis: with special references on paragonimiasis. Author(s): Nagakura K, Oouchi M, Abe K, Araki K. Source: Tokai J Exp Clin Med. 2002 December; 27(4): 97-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713013&dopt=Abstract
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Pulmonary tuberculosis and diabetes mellitus--a study. Author(s): Ezung T, Devi NT, Singh NT, Singh TB. Source: J Indian Med Assoc. 2002 June; 100(6): 376, 378-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416670&dopt=Abstract
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Pulmonary tuberculosis in children with Hodgkin's lymphoma. Author(s): Karakas Z, Agaoglu L, Taravari B, Saribeyoglu E, Somer A, Guler N, Unuvar A, Anak S, Yalcin I, Devecioglu O. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2003; 4(1): 78-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692526&dopt=Abstract
278 Tuberculosis
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Pulmonary tuberculosis in the Taiwanese prison population. Author(s): Chiang CY, Hsu CJ, Hsu PK, Suo J, Lin TP. Source: J Formos Med Assoc. 2002 August; 101(8): 537-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12440082&dopt=Abstract
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Pulmonary tuberculosis presenting as community-acquired pneumonia. Author(s): Asnis DS, Cherian S, Sun T, Shrestha S, Santucci T Jr. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 December 15; 35(12): 1574-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471584&dopt=Abstract
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Purified protein derivative-activated type 1 cytokine-producing CD4+ T lymphocytes in the lung: a characteristic feature of active pulmonary and nonpulmonary tuberculosis. Author(s): Barry SM, Lipman MC, Bannister B, Johnson MA, Janossy G. Source: The Journal of Infectious Diseases. 2003 January 15; 187(2): 243-50. Epub 2002 December 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552448&dopt=Abstract
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Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. Author(s): McNeill L, Allen M, Estrada C, Cook P. Source: Chest. 2003 January; 123(1): 102-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527609&dopt=Abstract
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Quality assessment of Mycobacterium tuberculosis genotyping in a large laboratory network. Author(s): Braden CR, Crawford JT, Schable BA. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1210-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453344&dopt=Abstract
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Quality assurance studies in eight State tuberculosis laboratories in India. Author(s): Paramasivan CN, Venkataraman P, Vasanthan JS, Rahman F, Narayanan PR. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 522-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797693&dopt=Abstract
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Quality of anti-tuberculosis drugs offered to patients. Author(s): Arya SC. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 4034. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729350&dopt=Abstract
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Radiographic appearances of pulmonary tuberculosis in HIV-1 seropositive and seronegative adult patients. Author(s): Kawooya VK, Kawooya M, Okwera A. Source: East Afr Med J. 2000 June; 77(6): 303-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858928&dopt=Abstract
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Radiological patterns in HIV-associated pulmonary tuberculosis: comparison between HAART-treated and non-HAART-treated patients. Author(s): Busi Rizzi E, Schinina V, Palmieri F, Girardi E, Bibbolino C. Source: Clinical Radiology. 2003 June; 58(6): 469-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788316&dopt=Abstract
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Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis. Author(s): Johnson JL, Ssekasanvu E, Okwera A, Mayanja H, Hirsch CS, Nakibali JG, Jankus DD, Eisenach KD, Boom WH, Ellner JJ, Mugerwa RD; Uganda-Case Western Reserve University Research Collaboration. Source: American Journal of Respiratory and Critical Care Medicine. 2003 July 15; 168(2): 185-91. Epub 2003 April 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702550&dopt=Abstract
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Rapid and simple MTT method for rifampicin and isoniazid susceptibility testing of Mycobacterium tuberculosis. Author(s): Foongladda S, Roengsanthia D, Arjrattanakool W, Chuchottaworn C, Chaiprasert A, Franzblau SG. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1118-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546122&dopt=Abstract
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Rapid and specific detection of Mycobacterium tuberculosis from acid-fast bacillus smear-positive respiratory specimens and BacT/ALERT MP culture bottles by using fluorogenic probes and real-time PCR. Author(s): Miller N, Cleary T, Kraus G, Young AK, Spruill G, Hnatyszyn HJ. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4143-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409388&dopt=Abstract
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Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by enumeration of Mycobacterium tuberculosis-specific T cells. Author(s): Chapman AL, Munkanta M, Wilkinson KA, Pathan AA, Ewer K, Ayles H, Reece WH, Mwinga A, Godfrey-Faussett P, Lalvani A. Source: Aids (London, England). 2002 November 22; 16(17): 2285-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12441800&dopt=Abstract
280 Tuberculosis
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Rapid detection of multidrug-resistant Mycobacterium tuberculosis using the mycobacteria growth indicator tube (MGIT) system. Author(s): Telles MA, Bori A, Amorim AB, Cruz AF, Pini MI, Sato DN. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 2002 October; 35(10): 1127-31. Epub 2002 October 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12424483&dopt=Abstract
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Rapid detection of resistance against rifampicin in isolates of Mycobacterium tuberculosis from Brazilian patients using a reverse-phase hybridization assay. Author(s): de Oliveira MM, da Silva Rocha A, Cardoso Oelemann M, Gomes HM, Fonseca L, Werneck-Barreto AM, Valim AM, Rossetti ML, Rossau R, Mijs W, Vanderborght B, Suffys P. Source: Journal of Microbiological Methods. 2003 June; 53(3): 335-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12689711&dopt=Abstract
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Rapid detection of rifampin resistance in Mycobacterium tuberculosis isolates by heteroduplex analysis and determination of rifamycin cross-resistance in rifampinresistant isolates. Author(s): Saribas Z, Kocagoz T, Alp A, Gunalp A. Source: Journal of Clinical Microbiology. 2003 February; 41(2): 816-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574290&dopt=Abstract
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Rapid detection of rpoB gene mutations in rifampin-resistant Mycobacterium tuberculosis isolates in shanghai by using the amplification refractory mutation system. Author(s): Fan XY, Hu ZY, Xu FH, Yan ZQ, Guo SQ, Li ZM. Source: Journal of Clinical Microbiology. 2003 March; 41(3): 993-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624020&dopt=Abstract
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Rapid diagnosis of active tuberculosis by detecting antibodies from lymphocyte secretions. Author(s): Raqib R, Rahman J, Kamaluddin AK, Kamal SM, Banu FA, Ahmed S, Rahim Z, Bardhan PK, Andersson J, Sack DA. Source: The Journal of Infectious Diseases. 2003 August 1; 188(3): 364-70. Epub 2003 July 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870117&dopt=Abstract
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Rapid diagnosis of extrapulmonary tuberculosis by PCR: impact of sample preparation and DNA extraction. Author(s): Honore-Bouakline S, Vincensini JP, Giacuzzo V, Lagrange PH, Herrmann JL. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2323-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791844&dopt=Abstract
Studies 281
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Rapid diagnosis of Mycobacterium tuberculosis by multiplex polymerase chain reaction from clinical specimens. Author(s): Bindayna KM, Thani A, Baig B, Botta GA. Source: J Commun Dis. 2001 December; 33(4): 252-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12561502&dopt=Abstract
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Rapid dot sputum and serum assay in pulmonary tuberculosis. Author(s): Stavri H, Moldovan O, Mihaltan F, Banica D, Doyle RJ. Source: Journal of Microbiological Methods. 2003 March; 52(3): 285-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531497&dopt=Abstract
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Rapid identification and susceptibility testing of Mycobacterium tuberculosis from MGIT cultures with luciferase reporter mycobacteriophages. Author(s): Banaiee N, Bobadilla-del-Valle M, Riska PF, Bardarov S Jr, Small PM, Poncede-Leon A, Jacobs WR Jr, Hatfull GF, Sifuentes-Osornio J. Source: Journal of Medical Microbiology. 2003 July; 52(Pt 7): 557-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12808076&dopt=Abstract
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Rationale and methods for the National Tuberculosis Genotyping and Surveillance Network. Author(s): Castro KG, Jaffe HW. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1188-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453341&dopt=Abstract
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Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv. Author(s): Camus JC, Pryor MJ, Medigue C, Cole ST. Source: Microbiology (Reading, England). 2002 October; 148(Pt 10): 2967-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368430&dopt=Abstract
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Recent advances in the molecular diagnosis of tuberculosis. Author(s): Su WJ. Source: J Microbiol Immunol Infect. 2002 December; 35(4): 209-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12542245&dopt=Abstract
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Recent advances in tuberculosis research in India. Author(s): Tyagi AK, Dhar N. Source: Adv Biochem Eng Biotechnol. 2003; 84: 211-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12934938&dopt=Abstract
282 Tuberculosis
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Recent developments in the treatment of tuberculosis. Author(s): Davies PD, Yew WW. Source: Expert Opinion on Investigational Drugs. 2003 August; 12(8): 1297-312. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882618&dopt=Abstract
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Recent progress in the development and testing of vaccines against human tuberculosis. Author(s): McMurray DN. Source: International Journal for Parasitology. 2003 May; 33(5-6): 547-54. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782054&dopt=Abstract
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Recent trend in the radiological presentation of pulmonary tuberculosis in Pakistani adults. Author(s): Rao NA, Sadiq MA. Source: J Pak Med Assoc. 2002 November; 52(11): 501-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12585367&dopt=Abstract
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Recombinant gamma interferon stimulates signal transduction and gene expression in alveolar macrophages in vitro and in tuberculosis patients. Author(s): Condos R, Raju B, Canova A, Zhao BY, Weiden M, Rom WN, Pine R. Source: Infection and Immunity. 2003 April; 71(4): 2058-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654826&dopt=Abstract
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Recommendations about the prevention and management of tuberculosis in patients taking infliximab. Author(s): Salmon D; GTI and AFSSAPS. Groupe Tuberculose et infliximab. Agence Francaise de Securite Sanitaire de Produits de Sante. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2002 March; 69(2): 170-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12027307&dopt=Abstract
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Recommendations for the prevention and management of tuberculosis in patients taking infliximab. Author(s): Salmon-Ceron D; Groupe Recherche Anti-TNF et Infections Opportunistes; Agence Francaise de Securite Sanitaire des Produits de Sante. Source: Annales De Medecine Interne. 2002 November; 153(7): 429-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598827&dopt=Abstract
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Recommendations for the screening and prevention of tuberculosis in patients with HIV and the screening for HIV in tuberculosis patients and their contacts. Author(s): Canadian Tuberculosis Committee. Source: Can Commun Dis Rep. 2002 December 15; 28: 1-6. English, French. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12501746&dopt=Abstract
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Recrudescence of pulmonary tuberculosis: radiological and CT features in an asymptomatic Southern Italian young population. Author(s): Cappabianca S, Barbieri A, Del Vecchio W, Sergi D, Grassi R. Source: Radiol Med (Torino). 2002 November-December; 104(5-6): 404-11. English, Italian. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589261&dopt=Abstract
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Recruitment of antigen-specific Th1-like responses to the human lung following bronchoscopic segmental challenge with purified protein derivative of Mycobacterium tuberculosis. Author(s): Silver RF, Zukowski L, Kotake S, Li Q, Pozuelo F, Krywiak A, Larkin R. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 July; 29(1): 117-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821447&dopt=Abstract
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Recurrence in tuberculosis: relapse or reinfection? Author(s): Lambert ML, Hasker E, Van Deun A, Roberfroid D, Boelaert M, Van der Stuyft P. Source: The Lancet Infectious Diseases. 2003 May; 3(5): 282-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12726976&dopt=Abstract
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Reduction of the rate of false-positive cultures of Mycobacterium tuberculosis in a laboratory with a high culture positivity rate. Author(s): Carroll NM, Richardson M, Engelke E, de Kock M, Lombard C, van Helden PD. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 September; 40(9): 888-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435105&dopt=Abstract
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Re-emergence of tuberculosis and its variants: implications for dentistry. Author(s): Samaranayake P. Source: Int Dent J. 2002 October; 52(5): 330-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12418601&dopt=Abstract
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Relationship between whole-blood interferon-gamma production and extent of radiographic disease in patients with pulmonary tuberculosis. Author(s): Inokuchi N, Sugahara K, Soda H, Usui T, Hirakata Y, Fukushima K, Yamada Y, Kohno S, Kamihira S. Source: Diagnostic Microbiology and Infectious Disease. 2003 June; 46(2): 109-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12812714&dopt=Abstract
284 Tuberculosis
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Renal amyloidosis secondary to tuberculosis of cecum. Author(s): El-Hennawy AS, Goldstein M, Nicastri A. Source: Nephron. 2002; 92(3): 708-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372961&dopt=Abstract
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Renal tuberculosis mimicking xanthogranulomatous pyelonephritis: ultrasonography, computed tomography and magnetic resonance imaging findings. Author(s): Izbudak-Oznur I, Sozen S, Isik S. Source: Turk J Pediatr. 2002 April-June; 44(2): 168-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12026210&dopt=Abstract
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Report from the Tenth Retrovirus Conference. Tuberculosis. Author(s): Friedland G. Source: Aids Clin Care. 2003 April; 15(4): 32. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12712945&dopt=Abstract
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Report identifies states with highest rate of tuberculosis. Author(s): Ann Intern Med. 2002 Oct 15;137(8):I32 Source: Health Care Financing Review. 2001 Summer; 22(4): 205-6. /entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12379094
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Resistance patterns of Mycobacterium tuberculosis complex isolates in the Turkish Army from 1998 to 2000. Author(s): Saracli MA, Albay A, Guney C, Alpt A, Ciftci F, Doganci L. Source: Military Medicine. 2003 January; 168(1): 24-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546241&dopt=Abstract
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Resistance to anti-tuberculosis drugs among smear-positive cases in Thai prisons 2 years after the implementation of the DOTS strategy. Author(s): Pleumpanupat W, Jittimanee S, Akarasewi P, Rienthong S, Jittimanee S, Chiewlian Y, Phunpruk S, Malainual C, Ngamtrairai N, Adedipe A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 472-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757049&dopt=Abstract
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Resistance to anti-tuberculosis drugs and practices in drug susceptibility testing in Moldova, 1995-1999. Author(s): Crudu V, Arnadottir T, Laticevschi D. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 33642. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729338&dopt=Abstract
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Restoration of antigen-specific CD4 T-cell response against Mycobacterium tuberculosis in HIV-infected people. Author(s): Nomdedeu M, Soriano A, Plana M. Source: Chest. 2003 July; 124(1): 412-3; Author Reply 413. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853557&dopt=Abstract
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Results of a 12-month regimen for drug-resistant pulmonary tuberculosis. Author(s): Perez-Guzman C, Vargas MH, Martinez-Rossier LA, Torres-Cruz A, Villarreal-Velarde H. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1102-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546119&dopt=Abstract
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Results of an extended tuberculosis screening programme among sixth formers in a London school--more questions than answers. Author(s): Roberts CM, Musiska M. Source: Commun Dis Public Health. 2003 April; 6(1): 22-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736967&dopt=Abstract
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Rethinking the socioeconomics and geography of tuberculosis among foreign-born residents of New Jersey, 1994-1999. Author(s): Davidow AL, Mangura BT, Napolitano EC, Reichman LB. Source: American Journal of Public Health. 2003 June; 93(6): 1007-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773369&dopt=Abstract
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Retroperitoneoscopic extirpation for adult multicystic calcified dysplastic kidneys with contralateral ureteral abnormalities mimicking genitourinary tuberculosis. Author(s): Hemal AK, Nabi G, Hemal U. Source: Journal of Endourology / Endourological Society. 2002 April; 16(3): 161-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12028625&dopt=Abstract
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Reversible myelofibrosis induced by tuberculosis. Author(s): Viallard JF, Parrens M, Boiron JM, Texier J, Mercie P, Pellegrin JL. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 June 15; 34(12): 1641-3. Epub 2002 May 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032901&dopt=Abstract
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Reversible segmental portal hypertension--an unusual presentation of abdominal tuberculosis in a renal transplant recipient. Author(s): Varma PP, Seth AK, Kumar RS. Source: J Assoc Physicians India. 2003 February; 51: 218-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725273&dopt=Abstract
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Rifampin- and multidrug-resistant tuberculosis in Russian civilians and prison inmates: dominance of the beijing strain family. Author(s): Drobniewski F, Balabanova Y, Ruddy M, Weldon L, Jeltkova K, Brown T, Malomanova N, Elizarova E, Melentyey A, Mutovkin E, Zhakharova S, Fedorin I. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1320-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453364&dopt=Abstract
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Rifampin and pyrazinamide for treatment of latent tuberculosis infection: is it safe? Author(s): Jasmer RM, Daley CL. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 15; 167(6): 809-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623855&dopt=Abstract
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Rifamycin treatment of tuberculosis in a patient receiving atenolol: less interaction with rifabutin than with rifampin. Author(s): Goldberg SV, Hanson D, Peloquin CA. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 August 15; 37(4): 607-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905149&dopt=Abstract
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Risk factors and clinical features for tuberculosis among patients with systemic lupus erythematosus in Hong Kong. Author(s): Tam LS, Li EK, Wong SM, Szeto CC. Source: Scandinavian Journal of Rheumatology. 2002; 31(5): 296-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12455821&dopt=Abstract
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Risk factors for drug resistant tuberculosis in Leicestershire--poor adherence to treatment remains an important cause of resistance. Author(s): Pritchard AJ, Hayward AC, Monk PN, Neal KR. Source: Epidemiology and Infection. 2003 June; 130(3): 481-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12825732&dopt=Abstract
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Risk factors for hepatotoxicity associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection: experience from three public health tuberculosis clinics. Author(s): Lee AM, Mennone JZ, Jones RC, Paul WS. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 995-1000. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475146&dopt=Abstract
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Risk factors for tuberculosis infection and disease. Author(s): Ponticiello A, Mazzarella G, Gilli M, Pisanti C, Sanduzzi A. Source: Monaldi Arch Chest Dis. 2002 June-August; 57(3-4): 169-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619376&dopt=Abstract
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Risk factors for tuberculosis infection in children in contact with infectious tuberculosis cases in the Gambia, West Africa. Author(s): Lienhardt C, Sillah J, Fielding K, Donkor S, Manneh K, Warndorff D, Bennett S, McAdam K. Source: Pediatrics. 2003 May; 111(5 Pt 1): E608-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728119&dopt=Abstract
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Risk factors for tuberculosis infection in sub-Saharan Africa: a contact study in The Gambia. Author(s): Lienhardt C, Fielding K, Sillah J, Tunkara A, Donkor S, Manneh K, Warndorff D, McAdam KP, Bennett S. Source: American Journal of Respiratory and Critical Care Medicine. 2003 August 15; 168(4): 448-55. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773322&dopt=Abstract
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Risk of Mycobacterium tuberculosis infection and disease among health care workers, Chiang Rai, Thailand. Author(s): Yanai H, Limpakarnjanarat K, Uthaivoravit W, Mastro TD, Mori T, Tappero JW. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 36-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701833&dopt=Abstract
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Role of gallium arsenide laser irradiation at 890 nm as an adjunctive to antituberculosis drugs in the treatment of pulmonary tuberculosis. Author(s): Puri MM, Arora VK. Source: Indian J Chest Dis Allied Sci. 2003 January-March; 45(1): 19-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12683708&dopt=Abstract
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Role of isoniazid in once-weekly rifapentine treatment of pulmonary tuberculosis. Author(s): Mitchison DA. Source: American Journal of Respiratory and Critical Care Medicine. 2003 May 15; 167(10): 1298-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738593&dopt=Abstract
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Role of posterior stabilisation in the management of tuberculosis of the dorsal and lumbar spine. Author(s): Sundararaj GD, Behera S, Ravi V, Venkatesh K, Cherian VM, Lee V. Source: The Journal of Bone and Joint Surgery. British Volume. 2003 January; 85(1): 1006. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12585586&dopt=Abstract
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Role of surgery in pulmonary tuberculosis. Author(s): Freixinet JG, Rivas JJ, Rodriguez De Castro F, Caminero JA, Rodriguez P, Serra M, de la Torre M, Santana N, Canalis E. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 December; 8(12): Cr782-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503035&dopt=Abstract
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Safety and efficacy of isoniazid chemoprophylaxis administered during liver transplant candidacy for the prevention of posttransplant tuberculosis. Author(s): Singh N, Wagener MM, Gayowski T. Source: Transplantation. 2002 September 27; 74(6): 892-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12364876&dopt=Abstract
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Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis. Author(s): Stout JE, Engemann JJ, Cheng AC, Fortenberry ER, Hamilton CD. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 15; 167(6): 824-7. Epub 2002 November 21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12446275&dopt=Abstract
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Scaling up the response to tuberculosis in the WHO European Region. Author(s): Zaleskis R, Magnusson G. Source: European Journal of Public Health. 2003 March; 13(1): 96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12678326&dopt=Abstract
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Screening for pulmonary tuberculosis among military conscripts in Taiwan. Author(s): Chiang CY, Suo J, Yu MC, Yang SL, Lin TP. Source: J Formos Med Assoc. 2002 December; 101(12): 841-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12632817&dopt=Abstract
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Screening for tuberculosis in pregnancy. Author(s): Navarro-Alvarez S, Bobadilla del Valle M, Kato-Maeda M. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2002 December; 79(3): 251-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445993&dopt=Abstract
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Screening Latino adolescents for latent tuberculosis infection (LTBI). Author(s): Sipan C, Blumberg E, Hovell M, Kelley N, Moser K, Ocana M, Friedman L, Acosta J, Vera A, Adams M. Source: Public Health Reports (Washington, D.C. : 1974). 2003 September-October; 118(5): 425-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941855&dopt=Abstract
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Second-line treatment for chronic tuberculosis. Author(s): Mohapatra PR, Janmeja AK, Saini V, Das SK, Deb A. Source: Lancet. 2002 November 2; 360(9343): 1430. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12424025&dopt=Abstract
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Selecting the components for a safe and efficient tuberculosis subunit vaccine--recent progress and post-genomic insights. Author(s): Okkels LM, Doherty TM, Andersen P. Source: Current Pharmaceutical Biotechnology. 2003 February; 4(1): 69-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12570683&dopt=Abstract
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Selective depression of interferon-gamma and granulysin production with increase of proliferative response by Vgamma9/Vdelta2 T cells in children with tuberculosis. Author(s): Dieli F, Sireci G, Caccamo N, Di Sano C, Titone L, Romano A, Di Carlo P, Barera A, Accardo-Palumbo A, Krensky AM, Salerno A. Source: The Journal of Infectious Diseases. 2002 December 15; 186(12): 1835-9. Epub 2002 November 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12447771&dopt=Abstract
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Selective identification of new therapeutic targets of Mycobacterium tuberculosis by IVIAT approach. Author(s): Deb DK, Dahiya P, Srivastava KK, Srivastava R, Srivastava BS. Source: Tuberculosis (Edinburgh, Scotland). 2002; 82(4-5): 175-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464489&dopt=Abstract
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Sensitivity of acid-fast staining for Mycobacterium tuberculosis in formalin-fixed tissue. Author(s): Fukunaga H, Murakami T, Gondo T, Sugi K, Ishihara T. Source: American Journal of Respiratory and Critical Care Medicine. 2002 October 1; 166(7): 994-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12359660&dopt=Abstract
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Serial surveys of the tuberculosis nursing and support provision in the high incidence districts of England and Wales. Author(s): Ormerod LP; Joint Tuberculosis Committee of the British Thoracic Society. Source: Commun Dis Public Health. 2002 December; 5(4): 336-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12564255&dopt=Abstract
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Serodiagnosis of tuberculosis: comparison of immunoglobulin A (IgA) response to sulfolipid I with IgG and IgM responses to 2,3-diacyltrehalose, 2,3,6-triacyltrehalose, and cord factor antigens. Author(s): Julian E, Matas L, Perez A, Alcaide J, Laneelle MA, Luquin M. Source: Journal of Clinical Microbiology. 2002 October; 40(10): 3782-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12354881&dopt=Abstract
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Serologic diagnosis of tuberculosis using a simple commercial multiantigen assay. Author(s): Perkins MD, Conde MB, Martins M, Kritski AL. Source: Chest. 2003 January; 123(1): 107-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527610&dopt=Abstract
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Serum adenosine deaminase activity and its isoenzyme in patients treated for tuberculosis. Author(s): Rokayan SA. Source: J Coll Physicians Surg Pak. 2003 January; 13(1): 11-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12685967&dopt=Abstract
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Serum cytokine concentrations do not parallel Mycobacterium tuberculosis-induced cytokine production in patients with tuberculosis. Author(s): Vankayalapati R, Wizel B, Weis SE, Klucar P, Shams H, Samten B, Barnes PF. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 January 1; 36(1): 24-8. Epub 2002 December 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12491197&dopt=Abstract
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Severe acute respiratory syndrome: Threat of tuberculosis persists. Author(s): Davies PD. Source: Bmj (Clinical Research Ed.). 2003 June 21; 326(7403): 1396. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816841&dopt=Abstract
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Shifting the focus of tuberculosis research in India. Author(s): Narayanan PR, Garg R, Santha T, Kumaran PP. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 135-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758203&dopt=Abstract
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Shifts of T4/T8 T lymphocytes from BAL fluid and peripheral blood by clinical grade in patients with pulmonary tuberculosis. Author(s): Tsao TC, Chen CH, Hong JH, Hsieh MJ, Tsao KC, Lee CH. Source: Chest. 2002 October; 122(4): 1285-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12377854&dopt=Abstract
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Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Author(s): Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo J, Vittinghoff E, King MD, Kawamura LM, Hopewell PC; Short-Course Rifampin and Pyrazinamide for Tuberculosis Infection (SCRIPT) Study Investigators. Source: Annals of Internal Medicine. 2002 October 15; 137(8): 640-7. Summary for Patients In: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379063&dopt=Abstract
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Short-course rifamycin and pyrazinamide treatment for latent tuberculosis infection in patients with HIV infection: the 2-year experience of a comprehensive communitybased program in Broward County, Florida. Author(s): Narita M, Kellman M, Franchini DL, McMillan ME, Hollender ES, Ashkin D. Source: Chest. 2002 October; 122(4): 1292-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12377855&dopt=Abstract
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Should bronchoscopy be performed in the evaluation of suspected pediatric pulmonary tuberculosis? Author(s): Bibi H, Mosheyev A, Shoseyov D, Feigenbaum D, Kurzbart E, Weiller Z. Source: Chest. 2002 November; 122(5): 1604-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12426259&dopt=Abstract
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Simultaneous identification of Mycobacterium genus and Mycobacterium tuberculosis complex in clinical samples by 5'-exonuclease fluorogenic PCR. Author(s): Garcia-Quintanilla A, Gonzalez-Martin J, Tudo G, Espasa M, Jimenez de Anta MT. Source: Journal of Clinical Microbiology. 2002 December; 40(12): 4646-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454166&dopt=Abstract
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Skin tuberculosis with atypical mycobacteria 8 years after combined pancreas-kidney transplantation. Author(s): Schmekal B, Janko O, Zazgornik J, Schinko H, Bogner S, Syre G, Biesenbach G. Source: American Journal of Nephrology. 2002 September-December; 22(5-6): 566-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12381960&dopt=Abstract
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Skin-test screening and tuberculosis transmission among the homeless. Author(s): Kong PM, Tapy J, Calixto P, Burman WJ, Reves RR, Yang Z, Cave MD. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1280-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453356&dopt=Abstract
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Skip lesions in intestinal tuberculosis. Author(s): Shah SI, Khan I, Khan A. Source: J Coll Physicians Surg Pak. 2003 April; 13(4): 233-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12718784&dopt=Abstract
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Smoking and mortality from tuberculosis and other diseases in India: retrospective study of 43000 adult male deaths and 35000 controls. Author(s): Gajalakshmi V, Peto R, Kanaka TS, Jha P. Source: Lancet. 2003 August 16; 362(9383): 507-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12932381&dopt=Abstract
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Smoking and tuberculosis: an association overlooked. Author(s): Maurya V, Vijayan VK, Shah A. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 November; 6(11): 942-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475139&dopt=Abstract
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Solitary choroidal tuberculoma in a patient with chest wall tuberculosis. Author(s): Ohta K, Yamamoto Y, Arai J, Komurasaki Y, Yoshimura N. Source: The British Journal of Ophthalmology. 2003 June; 87(6): 795. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12770992&dopt=Abstract
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Solitary cystic tuberculosis of long tubular bones in children. Author(s): Eren A, Atay EF, Omeroglu H, Altintas F. Source: Journal of Pediatric Orthopaedics. Part B / European Paediatric Orthopaedic Society, Pediatric Orthopaedic Society of North America. 2003 January; 12(1): 72-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12488777&dopt=Abstract
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Specific lytic activity against mycobacterial antigens is inversely correlated with the severity of tuberculosis. Author(s): De La Barrera SS, Finiasz M, Frias A, Aleman M, Barrionuevo P, Fink S, Franco MC, Abbate E, del C Sasiain M. Source: Clinical and Experimental Immunology. 2003 June; 132(3): 450-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780692&dopt=Abstract
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Specificity and diversity of antibodies to Mycobacterium tuberculosis arabinomannan. Author(s): Navoa JA, Laal S, Pirofski LA, McLean GR, Dai Z, Robbins JB, Schneerson R, Casadevall A, Glatman-Freedman A. Source: Clinical and Diagnostic Laboratory Immunology. 2003 January; 10(1): 88-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522045&dopt=Abstract
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Spectrum of MR imaging findings in spinal tuberculosis. Author(s): Moorthy S, Prabhu NK. Source: Ajr. American Journal of Roentgenology. 2002 October; 179(4): 979-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239050&dopt=Abstract
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Spinal tuberculosis. Author(s): Kishore D, Singh NN, Verma R, Chauhan SS, Verma A, Potluri N, Misra S. Source: J Assoc Physicians India. 2002 October; 50: 1332-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568229&dopt=Abstract
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Spinal tuberculosis: report of an atypical presentation. Author(s): Hasegawa K, Murata H, Naitoh K, Nagano A. Source: Clinical Orthopaedics and Related Research. 2002 October; (403): 100-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12360014&dopt=Abstract
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Spirometry and tuberculosis in Ecuador. Author(s): Begin P. Source: Can Respir J. 2003 January-February; 10(1): 15. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624617&dopt=Abstract
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Spoligologos: a bioinformatic approach to displaying and analyzing Mycobacterium tuberculosis data. Author(s): Driscoll JR, Bifani PJ, Mathema B, McGarry MA, Zickas GM, Kreiswirth BN, Taber HW. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1306-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453361&dopt=Abstract
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Stability of variable-number tandem repeats of mycobacterial interspersed repetitive units from 12 loci in serial isolates of Mycobacterium tuberculosis. Author(s): Savine E, Warren RM, van der Spuy GD, Beyers N, van Helden PD, Locht C, Supply P. Source: Journal of Clinical Microbiology. 2002 December; 40(12): 4561-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454152&dopt=Abstract
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Staphylococcal sepsis delaying diagnosis and treatment of vertebral tuberculosis. Author(s): Baussano I, Cazzadori A, Danzi C, Scardigli A, Concia E. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(6-7): 436. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12953968&dopt=Abstract
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Stevens' cure for tuberculosis. Author(s): Maynard RL. Source: Journal of the Royal Society of Medicine. 2002 November; 95(11): 575. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12411632&dopt=Abstract
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Stop tuberculosis! Author(s): Heininger U. Source: Archives of Disease in Childhood. 2003 January; 88(1): 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495950&dopt=Abstract
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Structure of Mycobacterium tuberculosis methionine sulfoxide reductase A in complex with protein-bound methionine. Author(s): Taylor AB, Benglis DM Jr, Dhandayuthapani S, Hart PJ. Source: Journal of Bacteriology. 2003 July; 185(14): 4119-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12837786&dopt=Abstract
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Structure of Mycobacterium tuberculosis single-stranded DNA-binding protein. Variability in quaternary structure and its implications. Author(s): Saikrishnan K, Jeyakanthan J, Venkatesh J, Acharya N, Sekar K, Varshney U, Vijayan M. Source: Journal of Molecular Biology. 2003 August 8; 331(2): 385-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888346&dopt=Abstract
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Study of drug resistance in previously treated tuberculosis patients in Gujarat, India. Author(s): Shah AR, Agarwal SK, Shah KV. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1098-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546118&dopt=Abstract
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Successful treatment of disseminated tuberculosis and acquired immunodeficiency syndrome in an 81-y-old woman. Author(s): Laszlo A, Gianelli S, Laurencet F, Krause KH, Janssens JP. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(6-7): 420-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12953961&dopt=Abstract
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Suggested guidelines for screening and management of tuberculosis in patients taking oral glucocorticoids--an important but often neglected issue. Author(s): Chan YC, Yosipovitch G. Source: Journal of the American Academy of Dermatology. 2003 July; 49(1): 91-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12833015&dopt=Abstract
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Sulfolipid deficiency does not affect the virulence of Mycobacterium tuberculosis H37Rv in mice and guinea pigs. Author(s): Rousseau C, Turner OC, Rush E, Bordat Y, Sirakova TD, Kolattukudy PE, Ritter S, Orme IM, Gicquel B, Jackson M. Source: Infection and Immunity. 2003 August; 71(8): 4684-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874349&dopt=Abstract
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Superficial fungal infection of the skin during treatment of tuberculosis. Author(s): Yew WW, Chau CH, Lee J. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1132. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546127&dopt=Abstract
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Surgical management of abdominal tuberculosis. Author(s): Hassan I, Brilakis ES, Thompson RL, Que FG. Source: Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract. 2002 November-December; 6(6): 862-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504225&dopt=Abstract
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Surgical treatment of thoracic and lumbar tuberculosis by anterior interbody fusion and posterior instrumentation. Author(s): Mukhtar AM, Farghaly MM, Ahmed SH. Source: Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre. 2003 April-June; 12(2): 92-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634463&dopt=Abstract
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Surveillance of drug-resistant Mycobacterium tuberculosis in The Gambia. Author(s): Adegbola RA, Hill P, Baldeh I, Otu J, Sarr R, Sillah J, Lienhardt C, Corrah T, Manneh K, Drobniewski F, McAdam KP. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 3903. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729346&dopt=Abstract
296 Tuberculosis
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Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1. Author(s): Sly LM, Hingley-Wilson SM, Reiner NE, McMaster WR. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 January 1; 170(1): 430-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12496428&dopt=Abstract
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Susceptibility testing with the manual mycobacteria growth indicator tube (MGIT) and the MGIT 960 system provides rapid and reliable verification of multidrugresistant tuberculosis. Author(s): Adjers-Koskela K, Katila ML. Source: Journal of Clinical Microbiology. 2003 March; 41(3): 1235-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624056&dopt=Abstract
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Susceptibility to tuberculosis--the importance of the pathogen as well as the host. Author(s): McShane H. Source: Clinical and Experimental Immunology. 2003 July; 133(1): 20-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823273&dopt=Abstract
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Sustainable tuberculosis control. Author(s): Tannenbaum TN. Source: Can Respir J. 2002 November-December; 9(6): 387-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522483&dopt=Abstract
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Sustained release drug delivery systems in management of tuberculosis. Author(s): Khuller GK, Pandey R. Source: Indian J Chest Dis Allied Sci. 2003 October-December; 45(4): 229-30. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962455&dopt=Abstract
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SWR mice are highly susceptible to pulmonary infection with Mycobacterium tuberculosis. Author(s): Turner OC, Keefe RG, Sugawara I, Yamada H, Orme IM. Source: Infection and Immunity. 2003 September; 71(9): 5266-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933873&dopt=Abstract
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Symptoms in patients attending services for diagnosis of pulmonary tuberculosis in Sudan. Author(s): El-Sony AI, Mustafa SA, Khamis AH, Sobhi S, Enarson DA, Baraka OZ, Bjune G. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 550-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797697&dopt=Abstract
Studies 297
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T lymphocyte phenotypic profile in lung segments affected by cavitary and noncavitary tuberculosis. Author(s): Mazzarella G, Bianco A, Perna F, D'Auria D, Grella E, Moscariello E, Sanduzzi A. Source: Clinical and Experimental Immunology. 2003 May; 132(2): 283-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12699418&dopt=Abstract
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TB or Not TB: how Mycobacterium tuberculosis may evade drug treatment. Author(s): Friedberg EC, Fischhaber PL. Source: Cell. 2003 April 18; 113(2): 139-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12705860&dopt=Abstract
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T-cell responses to CD1-presented lipid antigens in humans with Mycobacterium tuberculosis infection. Author(s): Ulrichs T, Moody DB, Grant E, Kaufmann SH, Porcelli SA. Source: Infection and Immunity. 2003 June; 71(6): 3076-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761085&dopt=Abstract
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Ten years of extrapulmonary tuberculosis in a Danish university clinic. Author(s): Ebdrup L, Storgaard M, Jensen-Fangel S, Obel N. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(4): 244-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839152&dopt=Abstract
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The CD14 receptor does not mediate entry of Mycobacterium tuberculosis into human mononuclear phagocytes. Author(s): Shams H, Wizel B, Lakey DL, Samten B, Vankayalapati R, Valdivia RH, Kitchens RL, Griffith DE, Barnes PF. Source: Fems Immunology and Medical Microbiology. 2003 May 15; 36(1-2): 63-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727367&dopt=Abstract
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The challenge of tuberculosis. Author(s): Davies PD. Source: Journal of the Royal Society of Medicine. 2003 June; 96(6): 262-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782688&dopt=Abstract
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The clearance of theophylline is increased during the initial period of tuberculosis treatment. Author(s): Ahn HC, Lee YC. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 58791. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797703&dopt=Abstract
298 Tuberculosis
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The Cobas Amplicor MTB test for detection of Mycobacterium tuberculosis complex from respiratory and non-respiratory clinical specimens. Author(s): Jonsson B, Ridell M. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(6-7): 372-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12953947&dopt=Abstract
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The effect of decentralisation on tuberculosis services in three states of Sudan. Author(s): El-Sony AI, Mustafa SA, Khamis AH, Enarson DA, Baraka OZ, Bjune G. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 44550. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757045&dopt=Abstract
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The effect of pulmonary rehabilitation in patients with post-tuberculosis lung disorder. Author(s): Ando M, Mori A, Esaki H, Shiraki T, Uemura H, Okazawa M, Sakakibara H. Source: Chest. 2003 June; 123(6): 1988-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796179&dopt=Abstract
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The high value of high-resolution computed tomography in predicting the activity of pulmonary tuberculosis. Author(s): Wang YH, Lin AS, Lai YF, Chao TY, Liu JW, Ko SF. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 563-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797699&dopt=Abstract
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The impact of HIV on transmission of tuberculosis in Tanzania. Author(s): Egwaga SM. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 66-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758191&dopt=Abstract
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The Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated HLA-DR and Fc gamma R1 on human macrophages through Toll-like receptor 2. Author(s): Gehring AJ, Rojas RE, Canaday DH, Lakey DL, Harding CV, Boom WH. Source: Infection and Immunity. 2003 August; 71(8): 4487-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874328&dopt=Abstract
Studies 299
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The production of tumour necrosis factor-alpha is decreased in peripheral blood mononuclear cells from multidrug-resistant tuberculosis patients following stimulation with the 30-kDa antigen of Mycobacterium tuberculosis. Author(s): Lee JS, Song CH, Lim JH, Kim HJ, Park JK, Paik TH, Kim CH, Kong SJ, Shon MH, Jung SS, Jo EK. Source: Clinical and Experimental Immunology. 2003 June; 132(3): 443-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780691&dopt=Abstract
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The role of adherence in tuberculosis HIV-positive patients treated in ambulatory regimen. Author(s): Rocha M, Pereira S, Ferreira L, Barros H. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 May; 21(5): 785-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765421&dopt=Abstract
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The role of the community in the control of tuberculosis. Author(s): Maher D. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 177-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758209&dopt=Abstract
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The role of the nurse in the community-based treatment of multidrug-resistant tuberculosis (MDR-TB). Author(s): Palacios E, Guerra D, Llaro K, Chalco K, Sapag R, Furin J. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 April; 7(4): 3436. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729339&dopt=Abstract
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The senX3-regX3 two-component regulatory system of Mycobacterium tuberculosis is required for virulence. Author(s): Parish T, Smith DA, Roberts G, Betts J, Stoker NG. Source: Microbiology (Reading, England). 2003 June; 149(Pt 6): 1423-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777483&dopt=Abstract
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The Singapore Tuberculosis Elimination Programme: the first five years. Author(s): Chee CB, James L. Source: Bulletin of the World Health Organization. 2003; 81(3): 217-21. Epub 2003 May 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12764518&dopt=Abstract
300 Tuberculosis
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The use of medication monitors to evaluate compliance among tuberculosis patients in Haiti. Author(s): Olle-Goig JE. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 98; Author Reply 98-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701842&dopt=Abstract
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The validity of HIV testing using sputum from suspected tuberculosis patients, Botswana, 2001. Author(s): Talbot EA, Hone NM, Moffat HJ, Lee EJ, Moeti TL, Mokobela K, Mbulawa M, Binkin NJ, Wells CD, Kenyon TA. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 710-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921145&dopt=Abstract
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TNF-alpha blockade and tuberculosis: better look before you leap. Author(s): Arend SM, Breedveld FC, van Dissel JT. Source: The Netherlands Journal of Medicine. 2003 April; 61(4): 111-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852719&dopt=Abstract
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Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter activesurveillance report. Author(s): Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD; BIOBADASER Group. Source: Arthritis and Rheumatism. 2003 August; 48(8): 2122-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905464&dopt=Abstract
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Treatment of tuberculosis. Author(s): American Thoracic Society; CDC; Infectious Diseases Society of America. Source: Mmwr. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports / Centers for Disease Control. 2003 June 20; 52(Rr-11): 1-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12836625&dopt=Abstract
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Tuberculosis active case-finding in a mother-to-child HIV transmission prevention programme in Soweto, South Africa. Author(s): Nachega J, Coetzee J, Adendorff T, Msandiwa R, Gray GE, McIntyre JA, Chaisson RE. Source: Aids (London, England). 2003 June 13; 17(9): 1398-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799565&dopt=Abstract
Studies 301
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Tuberculosis among never-jailed drug abusers. Author(s): Askarian M, Karmi A, Sadeghi-Hassanabadi A. Source: East Mediterr Health J. 2001 May; 7(3): 461-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690767&dopt=Abstract
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Tuberculosis and Pott's disease. Author(s): Laiho K, Kauppi M, Soini I. Source: The New England Journal of Medicine. 2003 April 10; 348(15): 1501; Author Reply 1501. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691067&dopt=Abstract
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Tuberculosis and vitamin D deficiency. Author(s): Bhattacharyya AK. Source: J Assoc Physicians India. 2003 March; 51: 325-6; Author Reply 327. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839370&dopt=Abstract
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Tuberculosis chemotherapy: still a double-edged sword. Author(s): Chaisson RE. Source: American Journal of Respiratory and Critical Care Medicine. 2003 June 1; 167(11): 1461-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12770849&dopt=Abstract
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Tuberculosis control in China. Author(s): Zhao F, Zhao Y, Liu X. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 15-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758184&dopt=Abstract
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Tuberculosis control in India. Author(s): Udwadia ZF. Source: The Lancet Infectious Diseases. 2003 September; 3(9): 535-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954558&dopt=Abstract
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Tuberculosis control in India. Author(s): Granich R, Wares F, Suvanand S, Chauhan LS. Source: The Lancet Infectious Diseases. 2003 September; 3(9): 535. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954557&dopt=Abstract
302 Tuberculosis
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Tuberculosis control: current status, challenges and barriers ahead in 22 high endemic countries. Author(s): Ibrahim KM, Khan S, Laaser U. Source: J Ayub Med Coll Abbottabad. 2002 October-December; 14(4): 11-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12688094&dopt=Abstract
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Tuberculosis control: past 10 years and future progress. Author(s): Frieden TR, Driver CR. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 82-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758194&dopt=Abstract
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Tuberculosis due to Mycobacterium bovis after alemtuzumab administration. Author(s): Abad S, Gyan E, Moachon L, Bouscary D, Sicard D, Dreyfus F, Blanche P. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 July 15; 37(2): E27-8. Epub 2003 Jul 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856232&dopt=Abstract
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Tuberculosis following therapy with infliximab may be refractory to antibiotic therapy. Author(s): Taylor JC, Orkin R, Lanham J. Source: Rheumatology (Oxford, England). 2003 July; 42(7): 901-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826707&dopt=Abstract
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Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 2001. Author(s): Lumb R, Bastian I, Dawson D, Gilpin C, Haverkort F, James G, Sievers A; Australian Mycobacterium Reference Laboratory Network. Source: Commun Dis Intell. 2003; 27(2): 173-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926732&dopt=Abstract
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Tuberculosis in children at the Royal Hospital for Sick Children, Glasgow. January 1995-April 1998. Author(s): Bland RM, Corrigan DL, Chapman JP, Paton JY. Source: Health Bull (Edinb). 2000 March; 58(2): 102-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12813837&dopt=Abstract
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Tuberculosis in Egyptian kidney transplant recipients: study of clinical course and outcome. Author(s): el-Agroudy AE, Refaie AF, Moussa OM, Ghoneim MA. Source: Journal of Nephrology. 2003 May-June; 16(3): 404-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832742&dopt=Abstract
Studies 303
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Tuberculosis in health care workers in a central hospital in Malawi. Author(s): Kanyerere HS, Salaniponi FM. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 May; 7(5): 48992. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757052&dopt=Abstract
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Tuberculosis in the cytokine era: what rheumatologists need to know. Author(s): Hamilton CD. Source: Arthritis and Rheumatism. 2003 August; 48(8): 2085-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905459&dopt=Abstract
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Tuberculosis is common in Ukrainian AIDS patients. Author(s): Vovk AD, Tchentsova NP, Maximenok EV, Kislykh EN, Antonyak SN, Shapiro AV, Shcherbinskaya A, Poddubny VF. Source: Aids Read. 1999 May-June; 9(3): 211. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728908&dopt=Abstract
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Tuberculosis of pancreas and peripancreatic lymph nodes in immunocompetent patients: experience from China. Author(s): Xia F, Poon RT, Wang SG, Bie P, Huang XQ, Dong JH. Source: World Journal of Gastroenterology : Wjg. 2003 June; 9(6): 1361-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800257&dopt=Abstract
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Tuberculosis of the lymph glands of the neck: a limited role for surgery. Author(s): Ammari FF, Bani Hani AH, Ghariebeh KI. Source: Otolaryngology and Head and Neck Surgery. 2003 April; 128(4): 576-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707664&dopt=Abstract
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Tuberculosis of the pituitary and sellar region. Author(s): Freda PU. Source: Pituitary. 2002; 5(3): 147-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12812304&dopt=Abstract
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Tuberculosis of the skull: a case report. Author(s): Lokere P, Boelaert JR, Van Landuyt H, Gordts B. Source: Acta Clin Belg. 2003 March-April; 58(2): 123-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12836496&dopt=Abstract
304 Tuberculosis
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Tuberculosis outbreak investigation of a U.S. Navy amphibious ship crew and the Marine expeditionary unit aboard, 1998. Author(s): Lamar JE 2nd, Malakooti MA. Source: Military Medicine. 2003 July; 168(7): 523-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901459&dopt=Abstract
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Tuberculosis peritonitis with clear fluid accompanying systemic disseminated tuberculosis in a CAPD patient. Author(s): Ogutmen B, Tuglular S, Al Ahdab H, Akoglu E, Ozener Q. Source: Perit Dial Int. 2003 January-February; 23(1): 95-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691518&dopt=Abstract
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Tuberculosis risk varies with the duration of HIV infection: a prospective study of European drug users with known date of HIV seroconversion. Author(s): van Asten L, Langendam M, Zangerle R, Hernandez Aguado I, Boufassa F, Schiffer V, Brettle RP, Robertson JR, Fontanet A, Coutinho RA, Prins M. Source: Aids (London, England). 2003 May 23; 17(8): 1201-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819522&dopt=Abstract
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Tuberculosis screening in dialysis patients--is the tuberculin test effective? Author(s): Poduval RD, Hammes MD. Source: Clinical Nephrology. 2003 June; 59(6): 436-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12834175&dopt=Abstract
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Tuberculosis screening in the federal prison system: an opportunity to treat and prevent tuberculosis in foreign-born populations. Author(s): Saunders DL, Olive DM, Wallace SB, Lacy D, Leyba R, Kendig NE. Source: Public Health Reports (Washington, D.C. : 1974). 2001 May-June; 116(3): 210-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12034910&dopt=Abstract
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Tuberculosis services need to improve for those living with HIV. Author(s): Das P. Source: The Lancet Infectious Diseases. 2003 September; 3(9): 530. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968625&dopt=Abstract
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Tuberculosis trends in the United States, 1992-2001. Author(s): Schneider E, Castro KG. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 21-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758185&dopt=Abstract
Studies 305
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Tuberculosis vaccines: the past, present and future. Author(s): Wang J, Xing Z. Source: Expert Rev Vaccines. 2002 October; 1(3): 341-54. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901573&dopt=Abstract
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Tuberculosis. Author(s): Rinaggio J. Source: Dent Clin North Am. 2003 July; 47(3): 449-65, V. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848459&dopt=Abstract
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Tuberculosis: looking beyond BCG vaccines. Author(s): Mustafa Abu S, Al-Attiyah R. Source: Journal of Postgraduate Medicine. 2003 April-June; 49(2): 134-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867689&dopt=Abstract
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Tuberculosis-related deaths in Queensland, Australia, 1989-1998: characteristics and risk factors. Author(s): Walpola HC, Siskind V, Patel AM, Konstantinos A, Derhy P. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 742-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921150&dopt=Abstract
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Tumour necrosis factor-alpha inhibitors and the reactivation of latent tuberculosis infection. Author(s): Long R, Gardam M. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2003 April 29; 168(9): 1153-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12719321&dopt=Abstract
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Typing of drug resistant isolates of Mycobacterium tuberculosis from India using the IS6110 element reveals substantive polymorphism. Author(s): Siddiqi N, Shamim M, Amin A, Chauhan DS, Das R, Srivastava K, Singh D, Sharma VD, Katoch VM, Sharma SK, Hanief M, Hasnain SE. Source: Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. 2001 December; 1(2): 109-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798025&dopt=Abstract
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Ultrasound for the diagnosis of HIV-associated tuberculosis. Author(s): Hudson CP, Wood R. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2003 June; 93(6): 440-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916381&dopt=Abstract
306 Tuberculosis
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Ultrastructure of the interaction between mycobacterium tuberculosis- H37Rvcontaining phagosomes and the lysosomal compartment in human alveolar macrophages. Author(s): Borelli V, Vita F, Soranzo MR, Banfi E, Zabucchi G. Source: Experimental and Molecular Pathology. 2002 October; 73(2): 128-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12231214&dopt=Abstract
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Unrecognized tuberculosis in a nursing home causing death with spread of tuberculosis to the community. Author(s): Ijaz K, Dillaha JA, Yang Z, Cave MD, Bates JH. Source: Journal of the American Geriatrics Society. 2002 July; 50(7): 1213-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12133015&dopt=Abstract
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Unusual case of cutaneous tuberculosis associated with rheumatoid arthritis: a case report and literature review. Author(s): Faghihi G, Yoosefi A. Source: International Journal of Dermatology. 2002 December; 41(12): 913-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492987&dopt=Abstract
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Unusual clinical features of cutaneous tuberculosis in an immune compromised patient. Author(s): Tanaka A, Kato Y, Arai K, Oh-i T, Koga M. Source: The Journal of Dermatology. 2002 April; 29(4): 226-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12027088&dopt=Abstract
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Unusual manifestations of osteoarticular tuberculosis. Author(s): Babhulkar SS, Pande SK. Source: Clinical Orthopaedics and Related Research. 2002 May; (398): 114-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11964639&dopt=Abstract
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Unusual MR presentation of cerebral parenchymal tuberculosis. Author(s): Daniel RT, Henry PT, Rajshekhar V. Source: Neurology India. 2002 June; 50(2): 210-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12134192&dopt=Abstract
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Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003. Author(s): Centers for Disease Control and Prevention (CDC); American Thoracic Society. Source: Mmwr. Morbidity and Mortality Weekly Report. 2003 August 8; 52(31): 735-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904741&dopt=Abstract
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Upper respiratory tract tuberculosis; rare but clinically important infectious disease. Author(s): Hojo M. Source: Intern Med. 2002 August; 41(8): 606-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12211525&dopt=Abstract
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Urging health system research: identifying gaps and fortifying tuberculosis control in Pakistan. Author(s): Khan IM, Yassin KM, Hurrelmann K, Laaser U. Source: Croatian Medical Journal. 2002 August; 43(4): 480-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12187528&dopt=Abstract
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Urinary neopterin measurement as a non-invasive diagnostic method in pulmonary tuberculosis. Author(s): Yuksekol I, Ozkan M, Akgul O, Tozkoparan E, Al-Rashed M, Balkan A, Hatipoglu K, Bilgic H, Erbil K, Demirci N. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 771-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921154&dopt=Abstract
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Use of an arrayed promoter-probe library for the identification of macrophageregulated genes in Mycobacterium tuberculosis. Author(s): Hobson RJ, McBride AJ, Kempsell KE, Dale JW. Source: Microbiology (Reading, England). 2002 May; 148(Pt 5): 1571-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11988532&dopt=Abstract
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Use of DNA extracts from Ziehl-Neelsen-stained slides for molecular detection of rifampin resistance and spoligotyping of Mycobacterium tuberculosis. Author(s): Van Der Zanden AG, Te Koppele-Vije EM, Vijaya Bhanu N, Van Soolingen D, Schouls LM. Source: Journal of Clinical Microbiology. 2003 March; 41(3): 1101-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624036&dopt=Abstract
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Use of DNA fingerprinting to investigate a multiyear, multistate tuberculosis outbreak. Author(s): McElroy PD, Sterling TR, Driver CR, Kreiswirth B, Woodley CL, Cronin WA, Hardge DX, Shilkret KL, Ridzon R. Source: Emerging Infectious Diseases. 2002 November; 8(11): 1252-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453351&dopt=Abstract
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Use of equivocal zone in interpretation of results of the amplified mycobacterium tuberculosis direct test for diagnosis of tuberculosis. Author(s): Kerleguer A, Koeck JL, Fabre M, Gerome P, Teyssou R, Herve V. Source: Journal of Clinical Microbiology. 2003 April; 41(4): 1783-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682187&dopt=Abstract
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Use of isoniazid for latent tuberculosis infection in a public health clinic. Author(s): LoBue PA, Moser KS. Source: American Journal of Respiratory and Critical Care Medicine. 2003 August 15; 168(4): 443-7. Epub 2003 May 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746255&dopt=Abstract
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Use of molecular methods to identify the Mycobacterium tuberculosis complex (MTBC) and other mycobacterial species and to detect rifampin resistance in MTBC isolates following growth detection with the BACTEC MGIT 960 system. Author(s): Somoskovi A, Song Q, Mester J, Tanner C, Hale YM, Parsons LM, Salfinger M. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 2822-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843007&dopt=Abstract
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Use of molecular techniques to distinguish between treatment failure and exogenous reinfection with Mycobacterium tuberculosis. Author(s): Kruuner A, Pehme L, Ghebremichael S, Koivula T, Hoffner SE, Mikelsaar M. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 July 15; 35(2): 146-55. Epub 2002 June 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12087520&dopt=Abstract
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Use of multiepitope polyproteins in serodiagnosis of active tuberculosis. Author(s): Houghton RL, Lodes MJ, Dillon DC, Reynolds LD, Day CH, McNeill PD, Hendrickson RC, Skeiky YA, Sampaio DP, Badaro R, Lyashchenko KP, Reed SG. Source: Clinical and Diagnostic Laboratory Immunology. 2002 July; 9(4): 883-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12093690&dopt=Abstract
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Use of PCR and culture for detection of Mycobacterium tuberculosis in specimens from patients with normal and slow responses to chemotherapy. Author(s): Velayati AA, Bakayev VV, Bahrmand AR. Source: Scandinavian Journal of Infectious Diseases. 2002; 34(3): 163-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12030386&dopt=Abstract
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Use of receiver operating characteristic curves to assess the performance of a microdilution assay for determination of drug susceptibility of clinical isolates of Mycobacterium tuberculosis. Author(s): Luna-Herrera J, Martinez-Cabrera G, Parra-Maldonado R, Enciso-Moreno JA, Torres-Lopez J, Quesada-Pascual F, Delgadillo-Polanco R, Franzblau SG. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 January; 22(1): 21-7. Epub 2003 January 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12582740&dopt=Abstract
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Use of spoligotyping for accurate classification of recurrent tuberculosis. Author(s): Warren RM, Streicher EM, Charalambous S, Churchyard G, van der Spuy GD, Grant AD, van Helden PD, Victor TC. Source: Journal of Clinical Microbiology. 2002 October; 40(10): 3851-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12354898&dopt=Abstract
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Use of the bovine model of tuberculosis for the development of improved vaccines and diagnostics. Author(s): Hewinson RG, Vordermeier HM, Buddle BM. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 119-30. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758201&dopt=Abstract
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Use of the urine color test to monitor compliance with isoniazid treatment of latent tuberculosis infection. Author(s): Eidlitz-Markus T, Zeharia A, Baum G, Mimouni M, Amir J. Source: Chest. 2003 March; 123(3): 736-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628871&dopt=Abstract
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Useful clues to the presence of smear-negative pulmonary tuberculosis in a West African city. Author(s): Bah B, Massari V, Sow O, Siriwardana M, Camara LM, Larouze B, Murray JF. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 July; 6(7): 592-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12102298&dopt=Abstract
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Usefulness of a new mycobacteriophage-based technique for rapid diagnosis of pulmonary tuberculosis. Author(s): Alcaide F, Gali N, Dominguez J, Berlanga P, Blanco S, Orus P, Martin R. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 2867-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843014&dopt=Abstract
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Uterine granulomas: tuberculosis, an important cause. Author(s): Mishra K, Wadhwa N. Source: American Journal of Clinical Pathology. 2002 December; 118(6): 966-7; Author Reply 967. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472289&dopt=Abstract
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Utility of an in-house mycobacteriophage-based assay for rapid detection of rifampin resistance in Mycobacterium tuberculosis clinical isolates. Author(s): Gali N, Dominguez J, Blanco S, Prat C, Quesada MD, Matas L, Ausina V. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2647-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791894&dopt=Abstract
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Utility of polymerase chain reaction for detecting Mycobacterium tuberculosis in specimens from percutaneous transthoracic needle aspiration. Author(s): Kang EY, Choi JA, Seo BK, Oh YW, Lee CK, Shim JJ. Source: Radiology. 2002 October; 225(1): 205-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12355006&dopt=Abstract
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Value of tuberculin skin test to diagnose tuberculosis among patients with respiratory systems in a chest clinic. Author(s): Agarwal BP. Source: J Assoc Physicians India. 2002 July; 50: 988-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12126369&dopt=Abstract
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Variable-number tandem repeat typing of Mycobacterium tuberculosis isolates with low copy numbers of IS6110 by using mycobacterial interspersed repetitive units. Author(s): Cowan LS, Mosher L, Diem L, Massey JP, Crawford JT. Source: Journal of Clinical Microbiology. 2002 May; 40(5): 1592-602. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11980927&dopt=Abstract
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Variants of the human NRAMP1 gene and susceptibility to tuberculosis in Morocco. Author(s): El Baghdadi J, Remus N, Benslimane A, El Annaz H, Chentoufi M, Abel L, Schurr E. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 June; 7(6): 599602. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797705&dopt=Abstract
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Variations in the NRAMP1 gene and susceptibility of tuberculosis in Taiwanese. Author(s): Liaw YS, Tsai-Wu JJ, Wu CH, Hung CC, Lee CN, Yang PC, Luh KT, Kuo SH. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 May; 6(5): 45460. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019922&dopt=Abstract
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Variations in the occurrence of the S315T mutation within the katG gene in isoniazidresistant clinical Mycobacterium tuberculosis isolates from Kuwait. Author(s): Abal AT, Ahmad S, Mokaddas E. Source: Microbial Drug Resistance (Larchmont, N.Y.). 2002 Summer; 8(2): 99-105. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12118524&dopt=Abstract
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View box case-8. Ilio-cecal tuberculosis. Author(s): Masroor I, Hashmi R. Source: J Pak Med Assoc. 2002 August; 52(8): 382. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12481683&dopt=Abstract
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Vitamin A status of patients presenting with pulmonary tuberculosis and asymptomatic HIV-infected individuals, Dar es Salaam, Tanzania. Author(s): Mugusi FM, Rusizoka O, Habib N, Fawzi W. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 August; 7(8): 804-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921158&dopt=Abstract
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Vitamin D deficiency and tuberculosis: need for vitamin D food fortification. Author(s): Joshi SR, Joshi SS. Source: J Assoc Physicians India. 2003 March; 51: 326. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839371&dopt=Abstract
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Voluntary counselling, HIV testing and adjunctive cotrimoxazole reduces mortality in tuberculosis patients in Thyolo, Malawi. Author(s): Zachariah R, Spielmann MP, Chinji C, Gomani P, Arendt V, Hargreaves NJ, Salaniponi FM, Harries AD. Source: Aids (London, England). 2003 May 2; 17(7): 1053-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12700456&dopt=Abstract
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Voluntary counselling, HIV testing and sexual behaviour among patients with tuberculosis in a rural district of Malawi. Author(s): Zachariah R, Spielmann MP, Harries AD, Salaniponi FL. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 January; 7(1): 65-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701837&dopt=Abstract
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Vulval tuberculosis: an unusual case. Author(s): Tripathi R, Prakash A, Rathore A, Saran S. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 August; 82(8): 769. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848651&dopt=Abstract
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What about GPs in the fight against tuberculosis? Author(s): Singh S. Source: Journal of the Royal Society of Medicine. 2003 August; 96(8): 424. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12893872&dopt=Abstract
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What can we learn by following the development of tuberculosis from one generation to another? 1930. Author(s): Andvord KF, Wijsmuller G, Blomberg B. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 July; 6(7): 562-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12102293&dopt=Abstract
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What is the diagnosis? Addison's disease caused by tuberculosis. Author(s): Mori Y. Source: Ann Nucl Med. 2002 December; 16(8): 582, Front Cover. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593426&dopt=Abstract
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What is the limit to case detection under the DOTS strategy for tuberculosis control? Author(s): Dye C, Watt CJ, Bleed DM, Williams BG. Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 35-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758187&dopt=Abstract
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What is the optimal approach for using a direct amplification test in the routine diagnosis of pulmonary tuberculosis? A preliminary assessment. Author(s): Lim TK, Zhu D, Gough A, Lee KH, Kumarasinghe G. Source: Respirology (Carlton, Vic.). 2002 December; 7(4): 351-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12421244&dopt=Abstract
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What's new in tuberculosis vaccines? Author(s): Ginsberg AM. Source: Bulletin of the World Health Organization. 2002; 80(6): 483-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12132007&dopt=Abstract
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WHO report calls for free anti-tuberculosis drugs for AIDS patients. Author(s): Fleck F. Source: Bmj (Clinical Research Ed.). 2003 July 19; 327(7407): 124. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869443&dopt=Abstract
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Whole blood bactericidal activity during treatment of pulmonary tuberculosis. Author(s): Wallis RS, Vinhas SA, Johnson JL, Ribeiro FC, Palaci M, Peres RL, Sa RT, Dietze R, Chiunda A, Eisenach K, Ellner JJ. Source: The Journal of Infectious Diseases. 2003 January 15; 187(2): 270-8. Epub 2003 Jan 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552451&dopt=Abstract
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Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. Author(s): Fleischmann RD, Alland D, Eisen JA, Carpenter L, White O, Peterson J, DeBoy R, Dodson R, Gwinn M, Haft D, Hickey E, Kolonay JF, Nelson WC, Umayam LA, Ermolaeva M, Salzberg SL, Delcher A, Utterback T, Weidman J, Khouri H, Gill J, Mikula A, Bishai W, Jacobs Jr WR Jr, Venter JC, Fraser CM. Source: Journal of Bacteriology. 2002 October; 184(19): 5479-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12218036&dopt=Abstract
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Widespread occurrence of Mycobacterium tuberculosis DNA from 18th-19th century Hungarians. Author(s): Fletcher HA, Donoghue HD, Holton J, Pap I, Spigelman M. Source: American Journal of Physical Anthropology. 2003 February; 120(2): 144-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12541332&dopt=Abstract
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Widespread pyrazinamide-resistant Mycobacterium tuberculosis family in a lowincidence setting. Author(s): Nguyen D, Brassard P, Westley J, Thibert L, Proulx M, Henry K, Schwartzman K, Menzies D, Behr MA. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 2878-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843016&dopt=Abstract
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Will tuberculosis become resistant to all antibiotics? Author(s): Dye C, Espinal MA. Source: Proceedings of the Royal Society of London. Series B. Biological Sciences. 2001 January 7; 268(1462): 45-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12123297&dopt=Abstract
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World Bank approves loan to help Russia tackle HIV/AIDS and tuberculosis. Author(s): Webster P. Source: Lancet. 2003 April 19; 361(9366): 1355. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711479&dopt=Abstract
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Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Author(s): Glynn JR, Whiteley J, Bifani PJ, Kremer K, van Soolingen D. Source: Emerging Infectious Diseases. 2002 August; 8(8): 843-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12141971&dopt=Abstract
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Yield of sputum induction in the diagnosis of pleural tuberculosis. Author(s): Conde MB, Loivos AC, Rezende VM, Soares SL, Mello FC, Reingold AL, Daley CL, Kritski AL. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 1; 167(5): 723-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598215&dopt=Abstract
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CHAPTER 2. NUTRITION AND TUBERCULOSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and tuberculosis.
Finding Nutrition Studies on Tuberculosis The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “tuberculosis” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
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Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following is a typical result when searching for recently indexed consumer information on tuberculosis: •
Impact of nutritional deficiencies on resistance to experimental pulmonary tuberculosis. Author(s): Texas A&M University Health Science Center, USA. Source: McMurray, D N Nutr-Revolume 1998 January; 56(1 Pt 2): S147-52 0029-6643
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Mechanisms underlying the increased susceptibility of aged mice to tuberculosis. Author(s): College of Veterinary Medicine and Biomedical Sciences at Colorado State University, Fort Collins 80523, USA. Source: Orme, I Nutr-Revolume 1995 April; 53(4 Pt 2): S35-8; discussion S38-40 00296643
The following information is typical of that found when using the “Full IBIDS Database” to search for “tuberculosis” (or a synonym): •
A case series: initial outcome of persons with multidrug-resistant tuberculosis after treatment with the WHO standard retreatment regimen in Ho Chi Minh City, Vietnam. Author(s): Pham Ngoc Thach Tuberculosis and Lung Diseases Center, Ho Chi Minh City, Vietnam. Source: Lan NTN Lademarco, M F Binkin, N J Tung, L B Quy, H T Cj, N V Int-J-TubercLung-Dis. 2001 June; 5(6): 575-8 1027-3719
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A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users. Author(s): Department of Psychiatry, State University of New York Upstate Medical University, 750 East Adams St., Syracuse 13210, USA.
[email protected] Source: Batki, Steven L Gruber, Valerie A Bradley, Julia Moon Bradley, Mark Delucchi, Kevin Drug-Alcohol-Depend. 2002 May 1; 66(3): 283-93 0376-8716
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A parallel intraphagosomal survival strategy shared by mycobacterium tuberculosis and Salmonella enterica. Author(s): Department of Pathology, University of California, San Diego, La Jolla, CA 92093-0640, USA.
[email protected] Source: Buchmeier, N Blanc Potard, A Ehrt, S Piddington, D Riley, L Groisman, E A Mol-Microbiol. 2000 March; 35(6): 1375-82 0950-382X
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Activation of peripheral blood neutrophils from patients with active advanced tuberculosis. Author(s): Departamento de Inmunologia, Academia Nacional de Medicina, Buenos Aires, Argentina. Source: Aleman, M Beigier Bompadre, M Borghetti, C de la Barrera, S Abbate, E Isturiz, M Sasiain, M C Clin-Immunol. 2001 July; 100(1): 87-95 1521-6616
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ahpC, a gene involved in isoniazid resistance of the Mycobacterium tuberculosis complex. Source: Wilson, T.M. Collins, D.M. Mol-microbiol. Oxford : Blackwell Scientific Publications,. March 1996. volume 19 (5) page 1025-1034. 0950-382X
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Antimicrobial susceptibility testing of Mycobacterium tuberculosis to first-line drugs: comparisons of the MGIT 960 and BACTEC 460 systems. Author(s): Section of Microbiology and Infectious Diseases, Kaohsiung Veterans General Hospital, Taiwan, Republic of China.
[email protected]
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Source: Huang, T S Tu, H Z Lee, S S Huang, W K Liu, Y C Ann-Clin-Lab-Sci. 2002 Spring; 32(2): 142-7 0091-7370 •
Arylamine N-acetyltransferase of Mycobacterium tuberculosis is a polymorphic enzyme and a site of isoniazid metabolism. Author(s): Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
[email protected] Source: Upton, A M Mushtaq, A Victor, T C Sampson, S L Sandy, J Smith, D M van Helden, P V Sim, E Mol-Microbiol. 2001 October; 42(2): 309-17 0950-382X
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Attitudes regarding tuberculosis among Samoans. Author(s): University of Hawaii John a. Burns School of Medicine, 1960 East-West Road, Honolulu, HI 96822 Source: AhChing, L P Sapolu, M Yamada, S Pac-Health-Dialog. 2001 March; 8(1): 15-9 1015-7867
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Bacteriological conversion in twenty urinary tuberculosis patients treated with ofloxacin, rifampin and isoniazid: a 10-year follow-up study. Author(s): Microbiologia, Hospital del Rio Hortega, 47010 Valladolid, Spain.
[email protected] Source: Castineiras, A A Perez Pascual, P Zarranz, J E Della Latta, P Herreras, A IntMicrobiol. 2002 September; 5(3): 139-44 1139-6709
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Characteristics of drug resistance and HIV among tuberculosis patients in Mozambique. Author(s): National Tuberculosis and Leprosy Control Programme, Ministry of Health of Mozambique, Maputo.
[email protected] Source: Mac Arthur, A Gloyd, S Perdigao, P Noya, A Sacarlal, J Kreiss, J Int-J-TubercLung-Dis. 2001 October; 5(10): 894-902 1027-3719
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Chemotherapy of tuberculosis--antitubercular activity of Ocimum sanctum leafy extract. Source: Reddi, G. Shukla, N.P. Singh, K.V. Fitoterapia. Milano : Inverni della Beffa. 1986. volume 57 (2) page 114-116. 0367-326X
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Clinical microbiological case: poor radiologic evolution of pulmonary tuberculosis in a heart transplant patient. Author(s): Reina Sofia University Hospital, Cordoba, Spain. Source: Gavilan, F Torre Cisneros, J Vizcaino, M A Arizon, J M Lama, R Lopez Rubio, F Sanchez Guijo, P Clin-Microbiol-Infect. 2001 July; 7(7): 367-8, 399-401 1198-743X
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Clinical practice. Latent tuberculosis infection. Author(s): Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, San Francisco, CA 94110, USA.
[email protected] Source: Jasmer, R M Nahid, P Hopewell, P C N-Engl-J-Med. 2002 December 5; 347(23): 1860-6 1533-4406
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Compliance to treatment of latent tuberculosis infection in a region of Israel. Author(s): Department of Pediatrics, Barzilai Medical Center, Ashkelon, Israel.
[email protected] Source: Bibi, H Weiler Ravell, D Shoseyov, D Feigin, I Arbelli, Y Chemtob, D Isr-MedAssoc-J. 2002 January; 4(1): 13-6 1565-1088
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Congenital tuberculosis: a rare manifestation of a common infection. Author(s): The University of Texas-Houston Medical School, Houston, Texas 77030, USA.
[email protected] Source: Smith, Kim Connelly Curr-Opin-Infect-Dis. 2002 June; 15(3): 269-74 0951-7375
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Corticosteroids for tuberculosis? Author(s): Baylor College of Medicine, Houston, USA. Source: Varon, J Marik, P Postgrad-Med. 2000 April; 107(4): 102-3 0032-5481
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Cost-effectiveness of tuberculosis screening and observed preventive therapy for active drug injectors at a syringe-exchange program. Author(s): Beth Israel Medical Center, First Avenue at 16th Street, New York City, NY 10003, USA.
[email protected] Source: Perlman, D C Gourevitch, M N Trinh, C Salomon, N Horn, L Des Jarlais, D C JUrban-Health. 2001 September; 78(3): 550-67 1099-3460
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Crystal structure of Rv2118c: an AdoMet-dependent methyltransferase from Mycobacterium tuberculosis H37Rv. Author(s): Molecular and Structural Biology Division, Central Drug Research Institute, Chattar Manzil Palace, Mahatma Gandhi Marg, Lucknow 226001, India. Source: Gupta, A KuMarch, P H Dineshkumar, T K Varshney, U Subramanya, H S JMol-Biol. 2001 Sep14; 312(2): 381-91 0022-2836
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Design of regimens for treating tuberculosis in patients with HIV infection, with particular reference to sub-Saharan Africa. Author(s): National Tuberculosis Control Programme, Ministry of Health, Lilongwe, Malawi.
[email protected] Source: Harries, A D Hargreaves, N J Salaniponi, F M Int-J-Tuberc-Lung-Dis. 2001 December; 5(12): 1109-15 1027-3719
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Differential regulation of MMP-1/9 and TIMP-1 secretion in human monocytic cells in response to Mycobacterium tuberculosis. Author(s): Department of Infectious Diseases, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
[email protected] Source: Friedland, J S Shaw, T C Price, N M Dayer, J M Matrix-Biol. 2002 January; 21(1): 103-10 0945-053X
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Drug resistance of Mycobacterium tuberculosis strains isolated from patients with pulmonary tuberculosis in Archangels, Russia. Author(s): Department of International Health, the Faculty of Medicine, University of Oslo, Blindern, Norway.
[email protected] Source: Toungoussova, S Caugant, D A Sandven, P Mariandyshev, A O Bjune, G Int-JTuberc-Lung-Dis. 2002 May; 6(5): 406-14 1027-3719
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Drug resistance of strains of Mycobacterium tuberculosis isolated in Brazil. Author(s): Departamento de Patologia, Universidade Federal do (FURG), Rio Grande, Brazil.
[email protected] Source: Almeida da Silva, P E Osorio, M Reinhardt, M C de Souza Fonseca, L Dellagostin, O A Microbes-Infect. 2001 November; 3(13): 1111-3 1286-4579
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Effect of preoperative chemotherapy on the outcome of surgical treatment of vertebral tuberculosis: retrospective analysis of 434 cases. Author(s): Department of Orthopedics, Dokuz Eylul University Hospital, Izmir, Turkey. Source: Alici, E Akcali, O Tatari, H Gunal, I Arch-Orthop-Trauma-Surg. 2001; 121(1-2): 65-6 0936-8051
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Efficacy of common antiseptics against multidrug-resistant Mycobacterium tuberculosis. Author(s): Department of Internal Medicine, Kurume University School of Medicine, Japan.
[email protected]
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Source: Rikimaru, T Kondo, M Kajimura, K Hashimoto, K Oyamada, K Miyazaki, S Sagawa, K Aizawa, H Oizumi, K Int-J-Tuberc-Lung-Dis. 2002 September; 6(9): 763-70 1027-3719 •
Emergent immunoregulatory properties of combined glucocorticoid and antiglucocorticoid steroids in a model of tuberculosis. Author(s): Department of Pathology, Instituto Nacional de la Nutricion, Salvador Zubiran, Mexico City. Source: Hernandez Pando, R de la Luz Streber, M Orozco, H Arriaga, K Pavon, L Marti, O Lightman, S L Rook, G A QJM. 1998 November; 91(11): 755-66 1460-2725
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Evidence for a partial redundancy of the fibronectin-binding proteins for the transfer of mycoloyl residues onto the cell wall arabinogalactan termini of Mycobacterium tuberculosis. Author(s): Institut de Pharmacologie et de Biologie Structurale, Unite Mixte de Recherche du Centre de National de Recherche Scientifique et de l'Universite Paul Sabatier (UMR 5089), 205, Route de Narbonne, 31077 Toulouse cedex 04, France. Source: Puech, Virginie Guilhot, Christophe Perez, Esther Tropis, Marielle Armitige, Lisa Y Gicquel, Brigitte Daffe, Mamadou Mol-Microbiol. 2002 May; 44(4): 1109-22 0950382X
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Familial outbreak of disseminated multidrug-resistant tuberculosis and meningitis. Author(s): Department of Respiratory Disease, University of Naples Federico II, Italy. Source: Sofia, M Maniscalco, M Honore, N Molino, A Mormile, M Heym, B Cole, S T IntJ-Tuberc-Lung-Dis. 2001 June; 5(6): 551-8 1027-3719
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Immune mediated 'HAART' attack during treatment for tuberculosis. Highly active antiretroviral therapy. Author(s): Department of Medical Microbiology and Immunology, University of Alberta, Canada.
[email protected] Source: Kunimoto, D Y Chui, L Nobert, E Houston, S Int-J-Tuberc-Lung-Dis. 1999 October; 3(10): 944-7 1027-3719
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Influence of antimicrobial chemotherapy and smoking status on the plasma concentrations of vitamin C, vitamin E, beta-carotene, acute phase reactants, iron and lipid peroxides in patients with pulmonary tuberculosis. Author(s): Department of Immunology, University of Pretoria, South Africa. Source: Plit, M L Theron, A J Fickl, H van Rensburg, C E Pendel, S Anderson, R Int-JTuberc-Lung-Dis. 1998 July; 2(7): 590-6 1027-3719
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Influence of anti-tuberculosis drug resistance on the treatment outcome of pulmonary tuberculosis patients receiving DOTS in Riyadh, Saudi Arabia. Author(s): Department of Tuberculosis and Chest Diseases, Sahary Hospital, Riyadh, Kingdom of Saudi Arabia.
[email protected] Source: Singla, R Al Sharif, N Al Sayegh, M O Osman, M M Shaikh, M A Int-J-TubercLung-Dis. 2002 July; 6(7): 585-91 1027-3719
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Lack of toxicity from concomitant directly observed disulfiram and isoniazidcontaining therapy for active tuberculosis. Author(s): Denver Public Health Department, Colorado 80204, USA.
[email protected] Source: Burman, W J Terra, M Breese, P Cohn, D Reves, R Int-J-Tuberc-Lung-Dis. 2002 September; 6(9): 839-42 1027-3719
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Local perceptions of tuberculosis in a rural district in Malawi. Author(s): National Tuberculosis Control Programme, Community Health Science Unit, Lilongwe, Malawi.
[email protected] Source: Banerjee, A Harries, A D Nyirenda, T Salaniponi, F M Int-J-Tuberc-Lung-Dis. 2000 November; 4(11): 1047-51 1027-3719
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Low dose (1 microg) adrenocorticotropin stimulation test in the evaluation of hypothalamo-pituitary-adrenal axis in patients with active pulmonary tuberculosis. Author(s): Department of Endocrinology, Erciyes University, Medical School, Kayseri, Turkey. Source: Kelestimur, F Goktas, Z Gulmez, I Unluhizarci, K Bayram, F Ozesmi, M Guven, M Tutus, A J-Endocrinol-Invest. 2000 April; 23(4): 235-9 0391-4097
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Massive hepatosplenomegaly, jaundice and pancytopenia in miliary tuberculosis. Author(s): Department of Medicine & Infectious Diseases, University Hospital of Wales, Cardiff, UK. Source: Evans, R H Evans, M Harrison, N K Price, D E Freedman, A R J-Infect. 1998 March; 36(2): 236-9 0163-4453
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Metronidazole has no antibacterial effect in Cornell model murine tuberculosis. Author(s): Department of Medical Microbiology, St George's Hospital Medical School, London, UK. Source: Dhillon, J Allen, B W Hu, Y M Coates, A R Mitchison, D A Int-J-Tuberc-LungDis. 1998 September; 2(9): 736-42 1027-3719
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Miliary sarcoidosis following miliary tuberculosis. Author(s): Department of Pneumonology, Medical School, University of Crete, Heraklion, Greece.
[email protected] Source: Hatzakis, K Siafakas, N M Bouros, D Respiration. 2000; 67(2): 219-22 0025-7931
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Noncompliance with tuberculosis treatment by patients at a tuberculosis and AIDS reference hospital in midwestern Brazil. Author(s): Anuar Auad Hospital for Tropical Diseases (HDTAA) / SES Goiania, Goias, Brazil.
[email protected] Source: Rabahi, M F Rodrigues, A B Queiroz de Mello, F de Almeida Netto, J C Kritski, A L Braz-J-Infect-Dis. 2002 April; 6(2): 63-73 1413-8670
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Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Author(s): Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Source: Larsen, M H Vilcheze, C Kremer, L Besra, G S Parsons, L Salfinger, M Heifets, L Hazbon, M H Alland, D Sacchettini, J C Jacobs, W R Jr Mol-Microbiol. 2002 October; 46(2): 453-66 0950-382X
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Pattern of mycobacterial resistance to four anti-tuberculosis drugs in pulmonary tuberculosis patients in the state of Qatar after the implementation of DOTS and a limited expatriate screening programme. Author(s): Qatar Armed Forces Medical Services, Pulmonary, Sleep and Critical Care Medicine, Hamad General Hospital, Doha, Arabian Gulf.
[email protected] Source: Al Marri, M R Int-J-Tuberc-Lung-Dis. 2001 December; 5(12): 1116-21 1027-3719
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Pattern of some haematological indices in newly diagnosed pulmonary tuberculosis cases in Iwo, Nigeria: diagnostic and therapeutic implications. Author(s): Department of Medicine, Respiratory Unit, Faculty of Health Sciences, University of Ilorin, Nigeria, P.O. Box 29, Ilorin, Kwara State, Nigeria.
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Source: Dosumu, E A Niger-J-Med. 2001 Jan-March; 10(1): 18-20 1115-2613 •
Perianal ulceration in a “healthy” Chinese man with disseminated tuberculosis. Author(s): Social Hygiene Service, Department of Health, Hong Kong. Source: Ho, Man Hon Lee, King Chung Chong, Lai Yin J-Dermatol. 2002 June; 29(6): 36670 0385-2407
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Population pharmacokinetics of ethionamide in patients with tuberculosis. Author(s): Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA. Source: Zhu, M Namdar, R Stambaugh, J J Starke, J R Bulpitt, A E Berning, S E Peloquin, C A Tuberculosis-(Edinb). 2002; 82(2-3): 91-6 1472-9792
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Primary lingual tuberculosis: a case report with review of literature. Author(s): Department of Oral Medicine and Radiology, College of Dental Surgery, Kassturba Medical College, Manipal, India.
[email protected] Source: Carnelio, Sunitha Rodrigues, Gabriel J-Oral-Sci. 2002 March; 44(1): 55-7 13434934
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Primary nasal tuberculosis. Author(s): Dept. of Pulmonology, Medical Centre Alkmaar, The Netherlands. Source: Hup, A K Haitjema, T de Kuijper, G Rhinology. 2001 March; 39(1): 47-8 03000729
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Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Reference Laboratory Network: five rounds of proficiency testing, 1994-1998. Author(s): Laboratory Centre for Disease Control, Health Canada, Ottawa.
[email protected] Source: Laszlo, A Rahman, M Espinal, M Raviglione, M Int-J-Tuberc-Lung-Dis. 2002 September; 6(9): 748-56 1027-3719
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Rapid indication of multidrug-resistant tuberculosis from liquid cultures using FASTPlaqueTB-RIF, a manual phage-based test. Author(s): Biotec Laboratories Ltd., Johannesburg, South Africa.
[email protected] Source: Albert, H Trollip, A P Mole, R J Hatch, S J Blumberg, L Int-J-Tuberc-Lung-Dis. 2002 June; 6(6): 523-8 1027-3719
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Reactivity studies of the tyrosyl radical in ribonucleotide reductase from Mycobacterium tuberculosis and Arabidopsis thaliana--comparison with Escherichia coli and mouse. Author(s): Laboratoire de Chimie et Biochimie des Centres Redox Biologiques, DBMSCEA/CNRS/Universite Joseph Fourier, Grenoble, France. Source: Elleingand, E Gerez, C Un, S Knupling, M Lu, G Salem, J Rubin, H Sauge Merle, S Laulhere, J P Fontecave, M Eur-J-Biochem. 1998 December 1; 258(2): 485-90 0014-2956
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Rifampin and isoniazid resistance associated mutations in Mycobacterium tuberculosis clinical isolates in Seville, Spain. Author(s): Department of Microbiology, University of Seville School of Medicine, Spain.
[email protected] Source: Torres, M J Criado, A Gonzalez, N Palomares, J C Aznar, J Int-J-Tuberc-LungDis. 2002 February; 6(2): 160-3 1027-3719
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Rurality and tuberculosis incidence trends in North and South Carolina, 1980 to 1992. Source: Millard, P.S. Cegielski, J.P. Wing, S. Silver, A. J-rural-health. Kansas City, Mo. : National Rural Health Association. Fall 1994. volume 10 (4) page 226-236. 0890-765X
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Screening childhood contacts of patients with smear-positive pulmonary tuberculosis in Malawi. Author(s): Academic Medical Centre, University of Amsterdam, The Netherlands. Source: Claessens, N J Gausi, F F Meijnen, S Weismuller, M M Salaniponi, F M Harries, A D Int-J-Tuberc-Lung-Dis. 2002 April; 6(4): 362-4 1027-3719
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Should tuberculosis programmes invest in second-line treatments for multidrugresistant tuberculosis (MDR-TB)? Author(s): World Health Organization. Source: Gupta, R Raviglione, M C Espinal, M A Int-J-Tuberc-Lung-Dis. 2001 December; 5(12): 1078-9 1027-3719
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Side-effects of drugs used in directly observed treatment short-course in newly diagnosed pulmonary tuberculosis subjects in Nigerians: a controlled clinical study. Author(s): Department of Medicine, Respiratory Unit, Faculty of Health Sciences, University of Ilorin, Nigeria. Source: Dosumu, E A Niger-Postgrad-Med-J. 2002 March; 9(1): 34-7 1117-1936
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Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis. Author(s): Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128, USA. Source: Sharma, V Sharma, S Hoener zu Bentrup, K McKinney, J D Russell, D G Jacobs, W R Sacchettini, J C Nat-Struct-Biol. 2000 August; 7(8): 663-8 1072-8368
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Surveillance of Mycobacterium tuberculosis drug resistance in Hong Kong, 1986-1999, after the implementation of directly observed treatment. Author(s): Tuberculosis Reference Laboratory, Yung Fung Shee Memorial Center, Department of Health, Kwun Tong, Kowloon, Hong Kong.
[email protected] Source: Kam, K M Yip, C W Int-J-Tuberc-Lung-Dis. 2001 September; 5(9): 815-23 10273719
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The early bactericidal activity of amikacin in pulmonary tuberculosis. Author(s): Department of Paediatrics, University of Stellenbosch, Cape Town, South Africa. Source: Donald, P R Sirgel, F A Venter, A Smit, E Parkin, D P Van de Wal, B W Mitchison, D A Int-J-Tuberc-Lung-Dis. 2001 June; 5(6): 533-8 1027-3719
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The methyl-branched fortifications of Mycobacterium tuberculosis. Author(s): School of Biosciences, The University of Birmingham, Edgbaston, B15 2TT, Birmingham, United Kingdom.
[email protected] Source: Minnikin, D E Kremer, L Dover, L G Besra, G S Chem-Biol. 2002 May; 9(5): 54553 1074-5521
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Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture for drug users in methadone maintenance. Author(s): Department of Medicine, Yale University School of Medicine, New Haven, CT 06520-8025, USA. Source: O'Connor, P G Shi, J M Henry, S Durante, A J Friedman, L Selwyn, P A Addiction. 1999 July; 94(7): 1071-5 0965-2140
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Tuberculosis patients and practitioners in private clinics in India. Author(s): Foundation for Research in Community Health, Worli, Mumbai, India. Source: Uplekar, M Juvekar, S Morankar, S Rangan, S Nunn, P Int-J-Tuberc-Lung-Dis. 1998 April; 2(4): 324-9 1027-3719
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Use of molecular techniques to distinguish between treatment failure and exogenous reinfection with Mycobacterium tuberculosis. Author(s): Institute of Microbiology, Tartu University, Estonia.
[email protected] Source: Kruuner, Annika Pehme, Lea Ghebremichael, Solomon Koivula, Tuija Hoffner, Sven E Mikelsaar, Marika Clin-Infect-Dis. 2002 July 15; 35(2): 146-55 1537-6591
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Variations in the occurrence of the S315T mutation within the katG gene in isoniazidresistant clinical Mycobacterium tuberculosis isolates from Kuwait. Author(s): Department of Medicine, Faculty of Medicine, Kuwait University, Safat. Source: Abal, A T Ahmad, S Mokaddas, E Microb-Drug-Resist. 2002 Summer; 8(2): 99105 1076-6294
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Yield of continued monthly sputum evaluation among tuberculosis patients after culture conversion. Author(s): New York City Department of Health, Tuberculosis Control Program, New York 10007, USA. Source: Sundaram, V Fujiwara, P I Driver, C R Osahan, S S Munsiff, S S Int-J-TubercLung-Dis. 2002 March; 6(3): 238-45 1027-3719
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
The following is a specific Web list relating to tuberculosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
Vitamins Niacin Source: Integrative Medicine Communications; www.drkoop.com Pyridoxine Alternative names: Vitamin B6 (Pyridoxine) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B3 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 (Niacin) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B6 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B6 (Pyridoxine) Alternative names: Pyridoxine Source: Integrative Medicine Communications; www.drkoop.com Vitamin D Alternative names: Calciferol, Calcitrol, Cholecalciferol, Erocalciferol Source: Integrative Medicine Communications; www.drkoop.com Vitamin D Source: Prima Communications, Inc.www.personalhealthzone.com
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Minerals Iodine Source: Integrative Medicine Communications; www.drkoop.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND TUBERCULOSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to tuberculosis. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to tuberculosis and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “tuberculosis” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to tuberculosis: •
(+)-Totarol from Chamaecyparis nootkatensis and activity against Mycobacterium tuberculosis. Author(s): Constantine GH, Karchesy JJ, Franzblau SG, LaFleur LE. Source: Fitoterapia. 2001 June; 72(5): 572-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11429259&dopt=Abstract
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A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Author(s): Karyadi E, West CE, Schultink W, Nelwan RH, Gross R, Amin Z, Dolmans WM, Schlebusch H, van der Meer JW. Source: The American Journal of Clinical Nutrition. 2002 April; 75(4): 720-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11916759&dopt=Abstract
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A model of bovine tuberculosis control in domesticated cattle herds. Author(s): Kao RR, Roberts MG, Ryan TJ. Source: Proceedings of the Royal Society of London. Series B. Biological Sciences. 1997 July 22; 264(1384): 1069-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9263472&dopt=Abstract
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A randomised placebo-controlled trial of the efficacy of beta-sitosterol and its glucoside as adjuvants in the treatment of pulmonary tuberculosis. Author(s): Donald PR, Lamprecht JH, Freestone M, Albrecht CF, Bouic PJ, Kotze D, van Jaarsveld PP. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1997 December; 1(6): 518-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9487449&dopt=Abstract
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Absence of antimycobacterial synergism between garlic extract and antituberculosis drugs. Author(s): Abbruzzese MR, Delaha EC, Garagusi VF. Source: Diagnostic Microbiology and Infectious Disease. 1987 October; 8(2): 79-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3123123&dopt=Abstract
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Activation of human neutrophils by Mycobacterium tuberculosis H37Ra involves phospholipase C gamma 2, Shc adapter protein, and p38 mitogen-activated protein kinase. Author(s): Perskvist N, Zheng L, Stendahl O. Source: Journal of Immunology (Baltimore, Md. : 1950). 2000 January 15; 164(2): 959-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10623845&dopt=Abstract
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Activation of phospholipase D is tightly coupled to the phagocytosis of Mycobacterium tuberculosis or opsonized zymosan by human macrophages. Author(s): Kusner DJ, Hall CF, Schlesinger LS. Source: The Journal of Experimental Medicine. 1996 August 1; 184(2): 585-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8760812&dopt=Abstract
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Activity against multidrug-resistant Mycobacterium tuberculosis in Mexican plants used to treat respiratory diseases. Author(s): Jimenez-Arellanes A, Meckes M, Ramirez R, Torres J, Luna-Herrera J. Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 903-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680821&dopt=Abstract
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Activity against Mycobacterium tuberculosis of alkaloid constituents of Angostura bark, Galipea officinalis. Author(s): Houghton PJ, Woldemariam TZ, Watanabe Y, Yates M.
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Source: Planta Medica. 1999 April; 65(3): 250-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10232071&dopt=Abstract •
Activity of bromhexine and ambroxol, semi-synthetic derivatives of vasicine from the Indian shrub Adhatoda vasica, against Mycobacterium tuberculosis in vitro. Author(s): Grange JM, Snell NJ. Source: Journal of Ethnopharmacology. 1996 January; 50(1): 49-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8778507&dopt=Abstract
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Agelasine F from a Philippine Agelas sp. sponge exhibits in vitro antituberculosis activity. Author(s): Mangalindan GC, Talaue MT, Cruz LJ, Franzblau SG, Adams LB, Richardson AD, Ireland CM, Concepcion GP. Source: Planta Medica. 2000 May; 66(4): 364-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10865457&dopt=Abstract
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An incentive in tuberculosis preventive therapy for an inner city population. Author(s): Mangura BT, Passannante MR, Reichman LB. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1997 December; 1(6): 576-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9487458&dopt=Abstract
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Anti-Kp 90 IgA antibodies in the diagnosis of active tuberculosis. Author(s): Arikan S, Tuncer S, Us D, Unal S, Ustacelebi S. Source: Chest. 1998 November; 114(5): 1253-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9823997&dopt=Abstract
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Anti-tuberculosis activity of quassinoids. Author(s): Rahman S, Fukamiya N, Okano M, Tagahara K, Lee KH. Source: Chemical & Pharmaceutical Bulletin. 1997 September; 45(9): 1527-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9332005&dopt=Abstract
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Appearances on computed tomography following thoracoplasty for pulmonary tuberculosis. Author(s): Moore NR, Phillips MS, Shneerson JM, Smith ML, Flower CD, Dixon AK. Source: The British Journal of Radiology. 1988 July; 61(727): 573-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3261611&dopt=Abstract
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Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis. Author(s): Schon T, Elias D, Moges F, Melese E, Tessema T, Stendahl O, Britton S, Sundqvist T.
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Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 March; 21(3): 483-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12662006&dopt=Abstract •
Attitudes regarding tuberculosis among Samoans. Author(s): AhChing LP, Sapolu M, Samifua M, Yamada S. Source: Pac Health Dialog. 2001 March; 8(1): 15-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12017816&dopt=Abstract
•
Attitudes toward Tuberculosis in Vietnamese Immigrants. Author(s): Nguyen L, Yamada S, Matsunaga DS, Caballero J. Source: Asian Am Pac Isl J Health. 2000 Winter; 8(1): 69-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11567514&dopt=Abstract
•
Auditory disorder in central nervous system miliary tuberculosis: case report. Author(s): Stach BA, Westerberg BD, Roberson JB Jr. Source: Journal of the American Academy of Audiology. 1998 August; 9(4): 305-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9733241&dopt=Abstract
•
Bacillary disease and health seeking behavior among Filipinos with symptoms of tuberculosis: implications for control. Author(s): Tupasi TE, Radhakrishna S, Co VM, Villa ML, Quelapio MI, Mangubat NV, Sarol JN, Rivera AB, Pascual ML, Reyes AC, Sarmiento A, Solon M, Solon FS, Burton L, Mantala MJ. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2000 December; 4(12): 1126-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11144454&dopt=Abstract
•
Biflavonoids as novel antituberculosis agents. Author(s): Lin YM, Flavin MT, Cassidy CS, Mar A, Chen FC. Source: Bioorganic & Medicinal Chemistry Letters. 2001 August 20; 11(16): 2101-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11514148&dopt=Abstract
•
Can stress cause disease? Revisiting the tuberculosis research of Thomas Holmes, 1949-1961. Author(s): Lerner BH. Source: Annals of Internal Medicine. 1996 April 1; 124(7): 673-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8607596&dopt=Abstract
•
Can we control tuberculosis in high HIV prevalence settings? Author(s): Godfrey-Faussett P, Ayles H.
Alternative Medicine 331
Source: Tuberculosis (Edinburgh, Scotland). 2003; 83(1-3): 68-76. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758192&dopt=Abstract •
Care seeking behaviour and diagnostic processes in patients with smear-positive pulmonary tuberculosis in Malawi. Author(s): Salaniponi FM, Harries AD, Banda HT, Kang'ombe C, Mphasa N, Mwale A, Upindi B, Nyirenda TE, Banerjee A, Boeree MJ. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2000 April; 4(4): 32732. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10777081&dopt=Abstract
•
Community tuberculosis care through “TB clubs” in rural North Ethiopia. Author(s): Demissie M, Getahun H, Lindtjorn B. Source: Social Science & Medicine (1982). 2003 May; 56(10): 2009-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12697193&dopt=Abstract
•
Conceptions of tuberculosis and therapeutic choices in Highland Chiapas, Mexico. Author(s): Menegoni L. Source: Med Anthropol Q. 1996 September; 10(3): 381-401. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8873025&dopt=Abstract
•
Contribution of 'TB clubs' to tuberculosis control in a rural district in Ethiopia. Author(s): Getahun H, Maher D. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2000 February; 4(2): 174-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10694097&dopt=Abstract
•
Contribution of traditional healers to a rural tuberculosis control programme in Hlabisa, South Africa. Author(s): Colvin M, Gumede L, Grimwade K, Maher D, Wilkinson D. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 September; 7(9 Suppl 1): S86-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12971659&dopt=Abstract
•
Cultural meanings of tuberculosis in Aceh Province, Sumatra. Author(s): Caprara A, Abdulkadir N, Idawani C, Asmara H, Lever P, De Virgilio G. Source: Medical Anthropology. 2000 July; 19(1): 65-89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11833971&dopt=Abstract
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Delay in tuberculosis case-finding and treatment in Mwanza, Tanzania. Author(s): Wandwalo ER, Morkve O. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2000 February; 4(2): 133-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10694091&dopt=Abstract
•
Dietary phytate reduction improves zinc absorption in Malawian children recovering from tuberculosis but not in well children. Author(s): Manary MJ, Hotz C, Krebs NF, Gibson RS, Westcott JE, Arnold T, Broadhead RL, Hambidge KM. Source: The Journal of Nutrition. 2000 December; 130(12): 2959-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11110854&dopt=Abstract
•
Different tuberculosis in men and women: beliefs from focus groups in Vietnam. Author(s): Long NH, Johansson E, Diwan VK, Winkvist A. Source: Social Science & Medicine (1982). 1999 September; 49(6): 815-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10459892&dopt=Abstract
•
Differential regulation of MMP-1/9 and TIMP-1 secretion in human monocytic cells in response to Mycobacterium tuberculosis. Author(s): Friedland JS, Shaw TC, Price NM, Dayer JM. Source: Matrix Biology : Journal of the International Society for Matrix Biology. 2002 January; 21(1): 103-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11827797&dopt=Abstract
•
Diminished adherence and/or ingestion of virulent Mycobacterium tuberculosis by monocyte-derived macrophages from patients with tuberculosis. Author(s): Zabaleta J, Arias M, Maya JR, Garcia LF. Source: Clinical and Diagnostic Laboratory Immunology. 1998 September; 5(5): 690-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9729537&dopt=Abstract
•
Direct ex vivo analysis of antigen-specific IFN-gamma-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment. Author(s): Pathan AA, Wilkinson KA, Klenerman P, McShane H, Davidson RN, Pasvol G, Hill AV, Lalvani A. Source: Journal of Immunology (Baltimore, Md. : 1950). 2001 November 1; 167(9): 521725. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11673535&dopt=Abstract
•
Directly observed therapy, short-course: the best way to prevent multidrug-resistant tuberculosis. Author(s): Yew WW.
Alternative Medicine 333
Source: Chemotherapy. 1999; 45 Suppl 2: 26-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10449895&dopt=Abstract •
DOTS and beyond: towards a holistic approach to the conquest of tuberculosis. Author(s): Gangadharam PR. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1998 November; 2(11): 943-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9848619&dopt=Abstract
•
DOTS and beyond: towards a holistic approach to the conquest of tuberculosis. Author(s): Grange JM. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1997 August; 1(4): 293-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9432381&dopt=Abstract
•
Effect of iron supplementation on mild to moderate anaemia in pulmonary tuberculosis. Author(s): Das BS, Devi U, Mohan Rao C, Srivastava VK, Rath PK, Das BS. Source: The British Journal of Nutrition. 2003 September; 90(3): 541-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13129459&dopt=Abstract
•
First-line tuberculosis therapy and drug-resistant Mycobacterium tuberculosis in prisons. Author(s): Coninx R, Mathieu C, Debacker M, Mirzoev F, Ismaelov A, de Haller R, Meddings DR. Source: Lancet. 1999 March 20; 353(9157): 969-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10459906&dopt=Abstract
•
Fluoroquinolones and tuberculosis. Author(s): Bryskier A, Lowther J. Source: Expert Opinion on Investigational Drugs. 2002 February; 11(2): 233-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11829714&dopt=Abstract
•
Health culture and the clinical encounter: Vietnamese refugees' responses to preventive drug treatment of inactive tuberculosis. Author(s): Ito KL. Source: Med Anthropol Q. 1999 September; 13(3): 338-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10509313&dopt=Abstract
•
History of tuberculosis among Aborigines. Author(s): Metcalf C, Yach D.
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Source: The Medical Journal of Australia. 1989 July 17; 151(2): 116. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2661979&dopt=Abstract •
HIV-related tuberculosis in British Columbia: indications of a rise in prevalence and a change in risk groups. Author(s): Blenkush MF, Korzeniewska-Kozela M, Elwood RK, Black W, FitzGerald JM. Source: Clinical and Investigative Medicine. Medecine Clinique Et Experimentale. 1996 August; 19(4): 271-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8853575&dopt=Abstract
•
Identification of acidic, alkaline, and neutral sphingomyelinase activities in Mycobacterium tuberculosis. Author(s): Vargas-Villarreal J, Mata-C rdenas BD, Deslauriers M, Quinn FD, CastroGarza J, Martinez-Rodriguez HG, Said-Fernandez S. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 June; 9(6): Br224-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824945&dopt=Abstract
•
Identification of an elastolytic protease in stationary phase culture filtrates of M. tuberculosis. Author(s): Rowland SS, Ruckert JL, Burall BN Jr. Source: Fems Microbiology Letters. 1997 June 1; 151(1): 59-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9198282&dopt=Abstract
•
Identification of Mycobacterium tuberculosis and Mycobacterium avium-M. intracellulare directly from primary BACTEC cultures by using acridinium-esterlabeled DNA probes. Author(s): Evans KD, Nakasone AS, Sutherland PA, de la Maza LM, Peterson EM. Source: Journal of Clinical Microbiology. 1992 September; 30(9): 2427-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1401010&dopt=Abstract
•
Implications of agricultural and wildlife policy on management and eradication of bovine tuberculosis and brucellosis in free-ranging wood bison of northern Canada. Author(s): Nishi JS, Stephen C, Elkin BT. Source: Annals of the New York Academy of Sciences. 2002 October; 969: 236-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12381598&dopt=Abstract
•
In vitro experiments with Centella asiatica: investigation to elucidate the effect of an indigenously prepared powder of this plant on the acid-fastness and viability of M. tuberculosis. Author(s): Herbert D, Paramasivan CN, Prabhakar R, Swaminathan G.
Alternative Medicine 335
Source: Indian J Lepr. 1994 January-March; 66(1): 65-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7983394&dopt=Abstract •
In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by ethnobotanically selected South African plants. Author(s): Lall N, Meyer JJ. Source: Journal of Ethnopharmacology. 1999 September; 66(3): 347-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10473184&dopt=Abstract
•
Influence of dietary (n-3)-polyunsaturated fatty acids on leukotriene B4 and prostaglandin E2 synthesis and course of experimental tuberculosis in guinea pigs. Author(s): Mayatepek E, Paul K, Leichsenring M, Pfisterer M, Wagner D, Domann M, Sonntag HG, Bremer HJ. Source: Infection. 1994 March-April; 22(2): 106-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8070921&dopt=Abstract
•
Influence of n-6 and n-3 polyunsaturated fatty acids on the resistance to experimental tuberculosis. Author(s): Paul KP, Leichsenring M, Pfisterer M, Mayatepek E, Wagner D, Domann M, Sonntag HG, Bremer HJ. Source: Metabolism: Clinical and Experimental. 1997 June; 46(6): 619-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9186295&dopt=Abstract
•
Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Author(s): Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M, Davidson RN. Source: Lancet. 2000 February 19; 355(9204): 618-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10696983&dopt=Abstract
•
Inhibition of drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis by diospyrin, isolated from Euclea natalensis. Author(s): Lall N, Meyer JJ. Source: Journal of Ethnopharmacology. 2001 December; 78(2-3): 213-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11694367&dopt=Abstract
•
Inhibition of Mycobacterium tuberculosis growth by saringosterol from Lessonia nigrescens. Author(s): Wachter GA, Franzblau SG, Montenegro G, Hoffmann JJ, Maiese WM, Timmermann BN. Source: Journal of Natural Products. 2001 November; 64(11): 1463-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11720535&dopt=Abstract
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Inhibitory effect of sterols from Ruprechtia triflora and diterpenes from Calceolaria pinnifolia on the growth of Mycobacterium tuberculosis. Author(s): Woldemichael GM, Franzblau SG, Zhang F, Wang Y, Timmermann BN. Source: Planta Medica. 2003 July; 69(7): 628-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898418&dopt=Abstract
•
Interleukin-8 secretion from Mycobacterium tuberculosis-infected monocytes is regulated by protein tyrosine kinases but not by ERK1/2 or p38 mitogen-activated protein kinases. Author(s): Ameixa C, Friedland JS. Source: Infection and Immunity. 2002 August; 70(8): 4743-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12117995&dopt=Abstract
•
Intracellular expression of Mycobacterium tuberculosis-specific 10-kDa antigen down-regulates macrophage B7.1 expression and nitric oxide release. Author(s): Singh B, Singh G, Trajkovic V, Sharma P. Source: Clinical and Experimental Immunology. 2003 October; 134(1): 70-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974757&dopt=Abstract
•
Involuntary confinement for tuberculosis control: the Jewish view. Author(s): Rosner F. Source: The Mount Sinai Journal of Medicine, New York. 1996 January; 63(1): 44-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8935848&dopt=Abstract
•
Involvement of antilipoarabinomannan antibodies in classical complement activation in tuberculosis. Author(s): Hetland G, Wiker HG, Hogasen K, Hamasur B, Svenson SB, Harboe M. Source: Clinical and Diagnostic Laboratory Immunology. 1998 March; 5(2): 211-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9521145&dopt=Abstract
•
Is vitamin B6 supplementation of isoniazid therapy useful in childhood tuberculosis. Author(s): Mbala L, Matendo R, Nkailu R. Source: Trop Doct. 1998 April; 28(2): 103-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9594683&dopt=Abstract
•
Knowledge and practice pattern of non-allopathic indigenous medical practitioners regarding tuberculosis in a rural area of India. Author(s): Anandhi CL, Nagaraj VK, Kumar R. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 June; 6(6): 553-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12068991&dopt=Abstract
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•
Local perceptions of tuberculosis in a rural district in Malawi. Author(s): Banerjee A, Harries AD, Nyirenda T, Salaniponi FM. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2000 November; 4(11): 1047-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11092717&dopt=Abstract
•
Malnutrition among tuberculosis patients in Harrow, England. Author(s): Onwubalili JK. Source: European Journal of Clinical Nutrition. 1988 April; 42(4): 363-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3396528&dopt=Abstract
•
Medical and social consequences of tuberculosis in rural Ethiopia. Author(s): Getahun H. Source: Ethiop Med J. 1999 July; 37(3): 147-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11957311&dopt=Abstract
•
Metal ions modulate the plastic nature of Mycobacterium tuberculosis chaperonin-10. Author(s): Taneja B, Mande SC. Source: Protein Engineering. 2001 June; 14(6): 391-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11477217&dopt=Abstract
•
Miliary tuberculosis with acute respiratory failure and histiocytic hemophagocytosis. Successful treatment with extracorporeal lung support and epipodophyllotoxin VP 16-213. Author(s): Monier B, Fauroux B, Chevalier JY, Leverger G, Nathanson M, Costil J, Tournier G. Source: Acta Paediatrica (Oslo, Norway : 1992). 1992 September; 81(9): 725-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1421920&dopt=Abstract
•
Molecular cloning and expression of an alpha-mannosidase gene in Mycobacterium tuberculosis. Author(s): Rivera-Marrero CA, Ritzenthaler JD, Roman J, Moremen KW. Source: Microbial Pathogenesis. 2001 January; 30(1): 9-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11162181&dopt=Abstract
•
Neural tuberculosis detected by F-18 FDG positron emission tomography. Author(s): Braga FJ, Maes A, Vanteenkiste P, Flamen P, Peetermans W, Mortelmans L. Source: Clinical Nuclear Medicine. 2001 August; 26(8): 706. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11452180&dopt=Abstract
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•
Ngaka ya setswana, ngaka ya sekgoa or both? Health seeking behaviour in Batswana with pulmonary tuberculosis. Author(s): Steen TW, Mazonde GN. Source: Social Science & Medicine (1982). 1999 January; 48(2): 163-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10048775&dopt=Abstract
•
Oxidative stress increases susceptibility of Mycobacterium tuberculosis to isoniazid. Author(s): Bulatovic VM, Wengenack NL, Uhl JR, Hall L, Roberts GD, Cockerill FR 3rd, Rusnak F. Source: Antimicrobial Agents and Chemotherapy. 2002 September; 46(9): 2765-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183226&dopt=Abstract
•
Patient compliance with tuberculosis treatment in Ghana: factors influencing adherence to therapy in a rural service programme. Author(s): van der Werf TS, Dade GK, van der Mark TW. Source: Tubercle. 1990 December; 71(4): 247-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2267678&dopt=Abstract
•
Patients' beliefs: do they affect tuberculosis control? A study in a rural district of South Africa. Author(s): Edginton ME, Sekatane CS, Goldstein SJ. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2002 December; 6(12): 1075-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546115&dopt=Abstract
•
Plants from Puerto Rico with anti-Mycobacterium tuberculosis properties. Author(s): Frame AD, Rios-Olivares E, De Jesus L, Ortiz D, Pagan J, Mendez S. Source: P R Health Sci J. 1998 September; 17(3): 243-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9883470&dopt=Abstract
•
Positron-emission tomography used to diagnose tuberculosis in a renal transplant patient. Author(s): Kukrej N, Cook GJ, Pattison JM. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2002 January; 2(1): 105-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12095049&dopt=Abstract
•
Preventive therapy for tuberculosis. Author(s): Strachan DP, Millard JF, Maxwell JD.
Alternative Medicine 339
Source: Lancet. 1995 June 3; 345(8962): 1439. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7760628&dopt=Abstract •
Prophylaxis for tuberculosis in Europe--ongoing research. Author(s): Carosi G, Matteelli A. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 1996 April; 22 Suppl 1: S55-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8785258&dopt=Abstract
•
Prostatic tuberculosis and AIDS. Author(s): Lanjewar DN, Maheshwari MB. Source: Natl Med J India. 1994 July-August; 7(4): 166-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7950947&dopt=Abstract
•
Protective effect of green tea extract against the erythrocytic oxidative stress injury during mycobacterium tuberculosis infection in mice. Author(s): Guleria RS, Jain A, Tiwari V, Misra MK. Source: Molecular and Cellular Biochemistry. 2002 July; 236(1-2): 173-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12190117&dopt=Abstract
•
Pulmonary tuberculosis in Kweneng District, Botswana: delays in diagnosis in 212 smear-positive patients. Author(s): Steen TW, Mazonde GN. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1998 August; 2(8): 627-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9712276&dopt=Abstract
•
Purification, characterization, and genetic analysis of Mycobacterium tuberculosis urease, a potentially critical determinant of host-pathogen interaction. Author(s): Clemens DL, Lee BY, Horwitz MA. Source: Journal of Bacteriology. 1995 October; 177(19): 5644-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7559354&dopt=Abstract
•
Recombinant expression and characterization of the major beta-lactamase of Mycobacterium tuberculosis. Author(s): Voladri RK, Lakey DL, Hennigan SH, Menzies BE, Edwards KM, Kernodle DS. Source: Antimicrobial Agents and Chemotherapy. 1998 June; 42(6): 1375-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9624479&dopt=Abstract
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•
Regulation of IL-10 secretion after phagocytosis of Mycobacterium tuberculosis by human monocytic cells. Author(s): Shaw TC, Thomas LH, Friedland JS. Source: Cytokine. 2000 May; 12(5): 483-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10857763&dopt=Abstract
•
Risk of tuberculosis in immigrant Asians: culturally acquired immunodeficiency? Author(s): Finch PJ, Millard FJ, Maxwell JD. Source: Thorax. 1991 January; 46(1): 1-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1871690&dopt=Abstract
•
Should we ban B6 supplementation of INH therapy in childhood tuberculosis? Author(s): Mathur GP, Mathur S, Rastogi S. Source: Indian J Pediatr. 1993 November-December; 60(6): 717-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8200694&dopt=Abstract
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Social and cultural factors in the successful control of tuberculosis. Author(s): Rubel AJ, Garro LC. Source: Public Health Reports (Washington, D.C. : 1974). 1992 November-December; 107(6): 626-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1454974&dopt=Abstract
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Sociocultural aspects of tuberculosis control in Ethiopia. Author(s): Vecchiato NL. Source: Med Anthropol Q. 1997 June; 11(2): 183-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9186960&dopt=Abstract
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Socio-economic, gender and health services factors affecting diagnostic delay for tuberculosis patients in urban Zambia. Author(s): Needham DM, Foster SD, Tomlinson G, Godfrey-Faussett P. Source: Tropical Medicine & International Health : Tm & Ih. 2001 April; 6(4): 256-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11348515&dopt=Abstract
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Stevens' cure for tuberculosis. Author(s): Moss ML. Source: Journal of the Royal Society of Medicine. 2002 November; 95(11): 575. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12411633&dopt=Abstract
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Stevens' cure for tuberculosis. Author(s): Ernst E.
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Source: Journal of the Royal Society of Medicine. 2002 November; 95(11): 575. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12411631&dopt=Abstract •
The antigens of Mycobacterium tuberculosis, H37Rv, studied by crossed immunoelectrophoresis. Comparison with a reference system for Mycobacterium bovis, BCG. Author(s): Wiker HG, Harboe M, Bennedsen J, Closs O. Source: Scandinavian Journal of Immunology. 1988 February; 27(2): 223-39. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3124264&dopt=Abstract
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The glutaraldehyde test as a rapid screening method for pulmonary tuberculosis: a preliminary report. Author(s): Larsson S, Shrestha MP, Pokhrel BM, Upadhyay MP, Shrestha KB. Source: Annals of Tropical Medicine and Parasitology. 1990 April; 84(2): 111-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2116775&dopt=Abstract
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The molecular epidemiology of tuberculosis in western Canada. Author(s): FitzGerald JM, Fanning A, Hoepnner V, Hershfield E, Kunimoto D; Canadian Molecular Epidemiology of TB Study Group. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 2003 February; 7(2): 132-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588013&dopt=Abstract
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The white plague in Utopia: tuberculosis in nineteenth-century Shaker communes. Author(s): Murray JE. Source: Bulletin of the History of Medicine. 1994 Summer; 68(2): 278-306. Erratum In: Bull Hist Med 1994 Fall; 68(3): 510. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8049601&dopt=Abstract
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Three models of social work intervention with tuberculosis patients. Author(s): Andrews AB, Williams H, Kinney J. Source: Health & Social Work. 1988 Fall; 13(4): 288-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3229681&dopt=Abstract
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Traditional healers and pulmonary tuberculosis in Malawi. Author(s): Brouwer JA, Boeree MJ, Kager P, Varkevisser CM, Harries AD. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1998 March; 2(3): 2314. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9526196&dopt=Abstract
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Traditional healers as tuberculosis treatment supervisors: precedent and potential. Author(s): Wilkinson D, Gcabashe L, Lurie M. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1999 September; 3(9): 838-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10488894&dopt=Abstract
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Triple trouble: the role of malnutrition in tuberculosis and human immunodeficiency virus co-infection. Author(s): van Lettow M, Fawzi WW, Semba RD. Source: Nutrition Reviews. 2003 March; 61(3): 81-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723640&dopt=Abstract
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Tuberculosis and immune thrombocytopenia. Author(s): Madkaikar M, Ghosh K, Jijina F, Gupta M, Rajpurkar M, Mohanty D. Source: Haematologica. 2002 August; 87(8): Elt38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161383&dopt=Abstract
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Tuberculosis and the assimilation of germ theory in China, 1895-1937. Author(s): Andrews BJ. Source: Journal of the History of Medicine and Allied Sciences. 1997 January; 52(1): 11457. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9071849&dopt=Abstract
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Tuberculosis and the haemopoietic system. Author(s): Knox-Macaulay HH. Source: Baillieres Clin Haematol. 1992 January; 5(1): 101-29. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1596588&dopt=Abstract
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Tuberculosis in aboriginal Canadians. Author(s): Hoeppner VH, Marciniuk DD. Source: Can Respir J. 2000 March-April; 7(2): 141-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10859400&dopt=Abstract
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Tuberculosis in Bombay: new insights from poor urban patients. Author(s): Nair DM, George A, Chacko KT. Source: Health Policy and Planning. 1997 March; 12(1): 77-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10166105&dopt=Abstract
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Tuberculosis in free-ranging, semi free-ranging and captive cervids. Author(s): Hunter DL.
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Source: Rev Sci Tech. 1996 March; 15(1): 171-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8924703&dopt=Abstract •
Tuberculosis in the 1990s. Issues for primary care physicians. Author(s): Fitzgerald JM. Source: Can Fam Physician. 1995 June; 41: 1030-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7780315&dopt=Abstract
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Tuberculosis of the ankle in childhood: clinical, roentgenographic and computed tomography findings. Author(s): Ruggieri M, Pavone V, Polizzi A, Smilari P, Di Fede GF, Sorge G, Musumeci S. Source: Clinical Pediatrics. 1997 September; 36(9): 529-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9307087&dopt=Abstract
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Tuberculosis patients and practitioners in private clinics in India. Author(s): Uplekar M, Juvekar S, Morankar S, Rangan S, Nunn P. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1998 April; 2(4): 3249. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9559404&dopt=Abstract
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Tuberculosis screening and prevention for foreign-born students: eight years experience at Ohio University. Author(s): Nelson ME, Fingar AR. Source: American Journal of Preventive Medicine. 1995 May-June; 11(3 Suppl): 48-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7669364&dopt=Abstract
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Tuberculosis status and social adaptation of Indochinese refugees. Author(s): Peters D, Hershfield ES, Fish DG, Manfreda J. Source: Int Migr Rev. 1987 Fall; 21(3): 845-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12314908&dopt=Abstract
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Tuberculosis, malnutrition and wasting. Author(s): Schwenk A, Macallan DC. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 2000 July; 3(4): 28591. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10929675&dopt=Abstract
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Tuberculosis, poverty, and “compliance”: lessons from rural Haiti. Author(s): Farmer P, Robin S, Ramilus SL, Kim JY.
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Source: Seminars in Respiratory Infections. 1991 December; 6(4): 254-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1810004&dopt=Abstract •
Tuberculosis: a search for novel therapy starting with natural products. Author(s): Mitscher LA, Baker W. Source: Medicinal Research Reviews. 1998 November; 18(6): 363-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9828037&dopt=Abstract
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Vegetarian diet and cobalamin deficiency: their association with tuberculosis. Author(s): Chanarin I, Stephenson E. Source: Journal of Clinical Pathology. 1988 July; 41(7): 759-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3410971&dopt=Abstract
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Vegetarian diet and tuberculosis in immigrant Asians. Author(s): Davis L. Source: Thorax. 1995 August; 50(8): 915-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7570453&dopt=Abstract
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Vegetarian diet and tuberculosis in immigrant Asians. Author(s): Hayward A, Kumar D, Bruce J, Sufi F. Source: Thorax. 1995 August; 50(8): 915. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7570452&dopt=Abstract
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Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians. Author(s): Strachan DP, Powell KJ, Thaker A, Millard FJ, Maxwell JD. Source: Thorax. 1995 February; 50(2): 175-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7701458&dopt=Abstract
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Weight as a surrogate marker of treatment response in tuberculosis. Author(s): Gillespie SH, Kennedy N. Source: The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1998 June; 2(6): 522-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9626614&dopt=Abstract
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When tuberculosis treatment fails. A social behavioral account of patient adherence. Author(s): Sumartojo E. Source: Am Rev Respir Dis. 1993 May; 147(5): 1311-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8484650&dopt=Abstract
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to tuberculosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview AIDS and HIV Source: Integrative Medicine Communications; www.drkoop.com Alcoholism Source: Integrative Medicine Communications; www.drkoop.com Amenorrhea Source: Integrative Medicine Communications; www.drkoop.com Amyloidosis Source: Integrative Medicine Communications; www.drkoop.com Brain Inflammation, Meningitis Source: Integrative Medicine Communications; www.drkoop.com Colds and Flus Source: Prima Communications, Inc.www.personalhealthzone.com
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Erythema Source: Integrative Medicine Communications; www.drkoop.com Histoplasmosis Source: Integrative Medicine Communications; www.drkoop.com HIV and AIDS Source: Integrative Medicine Communications; www.drkoop.com Lung Cancer Source: Healthnotes, Inc. www.healthnotes.com Meningitis Source: Integrative Medicine Communications; www.drkoop.com Prostatitis Source: Healthnotes, Inc. www.healthnotes.com Sarcoidosis Source: Integrative Medicine Communications; www.drkoop.com Tuberculosis Source: Integrative Medicine Communications; www.drkoop.com Urinary Tract Infection Source: Healthnotes, Inc. www.healthnotes.com Uveitis Source: Integrative Medicine Communications; www.drkoop.com •
Alternative Therapy Apitherapy Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,669,00.html Chinese System of Food Cures Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/c.html Color therapy Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,683,00.html Grape Cure Alternative names: grape diet Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/g.html
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Chinese Medicine Baiji Alternative names: Common Bletilla Tuber; Rhizoma Bletillae Source: Chinese Materia Medica Loulu Alternative names: Globethistle Root; Yuzhou loulu; Radix Echinopsis Source: Chinese Materia Medica Maozhaocao Alternative names: Catclaw Buttercup Root; Radix Ranunculi Ternati Source: Chinese Materia Medica Shancigu Alternative names: Appendiculate Cremastra Pseudobulb or Common Pleione Pseudobulb; Pseudobulbus Cremastrae seu Pleiones Source: Chinese Materia Medica Tubeimu Alternative names: Paniculate Bolbostemma; Rhizoma Bolbostemmae Source: Chinese Materia Medica Yuzhou loulu Alternative names: Globethistle Root; Radix Echinopsis Source: Chinese Materia Medica
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Herbs and Supplements Anti-Infective Agents Source: Healthnotes, Inc. www.healthnotes.com Antitubercular Agents Source: Healthnotes, Inc. www.healthnotes.com Antituberculosis Agents Source: Integrative Medicine Communications; www.drkoop.com Arnica Alternative names: Arnica montana L. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Astragalus sp Alternative names: Vetch, Rattlepod, Locoweed; Astragalus sp. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Berberis Alternative names: Barberry; Berberis sp. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org
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Calciferol Source: Integrative Medicine Communications; www.drkoop.com Calciferol Alternative names: Vitamin D Source: Integrative Medicine Communications; www.drkoop.com Calcitrol Alternative names: Vitamin D Source: Integrative Medicine Communications; www.drkoop.com Cat’s Claw Alternative names: Uncaria tomentosa Source: Healthnotes, Inc. www.healthnotes.com Cat's Claw Alternative names: Uncaria tomentosa Source: Integrative Medicine Communications; www.drkoop.com Centella Alternative names: Gotu Kola; Centella asiatica (Linn.) Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Cholecalciferol Alternative names: Vitamin D Source: Integrative Medicine Communications; www.drkoop.com Cholecalciferol Source: Integrative Medicine Communications; www.drkoop.com Cycloserine Source: Healthnotes, Inc. www.healthnotes.com Echinacea Alternative names: Echinacea purpurea, Echinacea angustifolia, Echinacea pallida Source: Healthnotes, Inc. www.healthnotes.com Echinacea Alternative names: Echinacea angustifolia, Echinacea pallida, Echinacea purpurea, Purple Coneflower Source: Integrative Medicine Communications; www.drkoop.com Echinacea Source: Prima Communications, Inc.www.personalhealthzone.com Echinacea Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,775,00.html Echinacea angustifolia Source: Integrative Medicine Communications; www.drkoop.com
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Echinacea pallida Source: Integrative Medicine Communications; www.drkoop.com Echinacea purpurea Source: Integrative Medicine Communications; www.drkoop.com Elecampane Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Erocalciferol Alternative names: Vitamin D Source: Integrative Medicine Communications; www.drkoop.com Hops Source: Prima Communications, Inc.www.personalhealthzone.com Horsetail Alternative names: Equisetum arvense Source: Healthnotes, Inc. www.healthnotes.com Horsetail Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10105,00.html Hydrastis Alternative names: Goldenseal; Hydrastis canadensis L. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Isoniazid Source: Healthnotes, Inc. www.healthnotes.com Isoniazid Alternative names: Laniazid, Nydrazid Source: Prima Communications, Inc.www.personalhealthzone.com Lepidium meyenii1 Alternative names: Maca; Lepidium meyenii Walp. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Licorice Alternative names: Glycyrrhiza glabra, Glycyrrhiza uralensis Source: Healthnotes, Inc. www.healthnotes.com Matricaria Alternative names: Chamomile; Matricaria chamomilla Source: Alternative Medicine Foundation, Inc. www.amfoundation.org
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Momordica Alternative names: Bitter Gourd, Karela; Momordica charantia Linn. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Mullein flower Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,865,00.html Nettle Alternative names: Urtica dioica Source: Healthnotes, Inc. www.healthnotes.com Piper nigrum Alternative names: Black Pepper Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Purple Coneflower Source: Integrative Medicine Communications; www.drkoop.com Swertia Alternative names: Swertia sp Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Syzygium Clove Alternative names: Clove, Jamun; Syzygium sp. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Tanacetum Alternative names: Feverfew; Tanacetum parthenium (L.) Schultz-Bip. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Thymus Alternative names: Thyme; Thymus vulgaris Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Uncaria tomentosa Source: Integrative Medicine Communications; www.drkoop.com Yellow Dock Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Yerba Santa Source: Prima Communications, Inc.www.personalhealthzone.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the
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MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON TUBERCULOSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to tuberculosis. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “tuberculosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on tuberculosis, we have not necessarily excluded nonmedical dissertations in this bibliography.
Dissertations on Tuberculosis ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to tuberculosis. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
A Computer Simulation of the Spread of Tuberculosis in Prehistoric Populations of the Lower Illinois River Valley by Mcgrath, Janet Winifred, Phd from Northwestern University, 1986, 302 pages http://wwwlib.umi.com/dissertations/fullcit/8621833
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A Consumptives' Refuge: Colorado and Tuberculosis by Stout, Cynthia Kay, Phd from The George Washington University, 1997, 257 pages http://wwwlib.umi.com/dissertations/fullcit/9726673
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A Descriptive and Epizootiologic Study of Brucellosis and Tuberculosis in Bison in Northern Canada by Tessaro, Stacy Victor; Phd from The University of Saskatchewan (canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL40826
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'An Antitoxin of Self Respect': North American Debates over Vaccination against Tuberculosis, 1890-1960 (koch, United States, Canada) by Feldberg, Georgiana Danielle, Phd from Harvard University, 1989, 476 pages http://wwwlib.umi.com/dissertations/fullcit/9013207
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'And I? I Am in a Consumption:' the Tuberculosis Patient, 1780-1930 (medicine, United States, Europe) by Mcmurry, Nan Marie, Phd from Duke University, 1985, 330 pages http://wwwlib.umi.com/dissertations/fullcit/8614438
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Array-based Parallel Gene Expression Studies in Mycobacterium Tuberculosis and Mycobacterium Smegmatis by Fisher, Mark Aaron; Phd from Emory University, 2002, 184 pages http://wwwlib.umi.com/dissertations/fullcit/3050097
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Aspects of the Ecology and Physiology of the Eurasian Badger (meles Meles L.), Cattle Management and the Epidemiology of Bovine Tuberculosis (mycobacterium Bovis) by Mccann, Paul James Joseph; Phd from Queen's University of Belfast (northern Ireland), 2002, 357 pages http://wwwlib.umi.com/dissertations/fullcit/f315217
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Attitudinal Components of Selected Occupational Groups in Tuberculosis Hospitals by Guerrin, Robert Francis, Phd from New York University, 1970, 128 pages http://wwwlib.umi.com/dissertations/fullcit/7019002
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Benefit-cost Analysis and Public Health : a Case Study of the Tuberculosis Control Program in Ontario, 1948-1966 by Sharma, Ram Karan; Phd from The University of Western Ontario (canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK14973
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Benefit-cost Analysis and Public Health: a Case Study of the Tuberculosis Control Program in Ontario, 1948-1966 by Sharma, Ram Karan, Phd from The University of Western Ontario (canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/f407559
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Biodegradable Poly(l-lactide) Microparticles for Pulmonary Drug Delivery with Targeting to Alveolar Macrophages: Applications in Treating Tuberculosis by Biggs, Danielle Lee; Phd from University of Colorado at Boulder, 2003, 168 pages http://wwwlib.umi.com/dissertations/fullcit/3087520
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Capillary and Microdevice Electrophoretic Tools for Genetic Analyses: Heteroduplex Analysis for Tuberculosis Drug Susceptibility and Ligase Detection Reaction for Colorectal Cancer Detection by Thomas, Gloria Ann; Phd from Louisiana State University and Agricultural & Mechanical College, 2002, 158 pages http://wwwlib.umi.com/dissertations/fullcit/3049237
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Characterisation of Naturally Occurring Variants of the Enzyme, Udp-nacetylglucosamine Enolpyruvyltransferase and Analysis of Conformational Changes (mycobacterium Tuberculosis) by Thomas, Alison Margaret; Drscnat from Eidgenoessische Technische Hochschule Zuerich (switzerland), 2002, 111 pages http://wwwlib.umi.com/dissertations/fullcit/f349761
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Consumed in the City: Observing Tuberculosis in the 1990s by Draus, Paul Joseph; Phd from Loyola University of Chicago, 2001, 328 pages http://wwwlib.umi.com/dissertations/fullcit/3001601
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'curing the Indian': Therapeutic Care and Acculturation at the Sac and Fox Tuberculosis Sanatorium, 1912--1942 (iowa) by Lykins, Lisa Dianne; Phd from University of Kentucky, 2002, 270 pages http://wwwlib.umi.com/dissertations/fullcit/3070664
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'dancing in the Wards, Powwows on the Reservation': a Social History of the Antituberculosis Drug Isoniazid and the Emergence of Rational Drug Development (tuberculosis, Navajo) by Rothschild, A. Frank, Jr., Phd from University of California, Berkeley with San Francisco State Univ., 1994, 607 pages http://wwwlib.umi.com/dissertations/fullcit/9529714
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Delayed Diagnosis of Tuberculosis in the State of Maryland and Its Impact on Transmission by Golub, Jonathan Eric; Phd from The Johns Hopkins University, 2003, 168 pages http://wwwlib.umi.com/dissertations/fullcit/3080667
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Development of T Cell Immunity to Listeria Monocytogenes and Mycobacterium Tuberculosis-dendritic Cells As an 'achilles' Heel' and Immune Deficiency in Dopamine Beta-hydroxylase Knock-out Mice by Alaniz, Robert Christopher; Phd from University of Washington, 2002, 109 pages http://wwwlib.umi.com/dissertations/fullcit/3062908
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Disease, Medicine, and the State: a Social History of Tuberculosis in Japan, 1850-1950 by Johnston, William Donald, Phd from Harvard University, 1987, 468 pages http://wwwlib.umi.com/dissertations/fullcit/8806048
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Diseases on the Margin: Morphologies of Tuberculosis and Smallpox in San Francisco, 1860-1940 (california) by Craddock, Susan Leigh, Phd from University of California, Berkeley, 1994, 249 pages http://wwwlib.umi.com/dissertations/fullcit/9529272
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Economic Issues Relating to the Control of Bovine Tuberculosis in New Zealand: a Bioeconomic Model of Livestock Disease Control by Bicknell, Kathryn Blackman, Phd from University of California, Davis, 1995, 134 pages http://wwwlib.umi.com/dissertations/fullcit/9608838
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Evasion of the Macrophage Apoptotic Response by Virulent Strains of Mycobacterium Tuberculosis by Riendeau-arnold, Carrie Judith; Phd from Boston University, 2003, 116 pages http://wwwlib.umi.com/dissertations/fullcit/3084506
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Functions of Transforming Growth Factor-beta1 in Immune Responses against Mycobacterium Tuberculosis by Allen, Shannon Sedberry; Phd from Texas A&m University, 2002, 120 pages http://wwwlib.umi.com/dissertations/fullcit/3072406
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Health Beliefs and Health Locus-of-control As Predictors of Adherence to Preventive Treatment for Tuberculosis (treatment Adherence) by Davis, Toni Kenneth, Phd from New York University, 1992, 168 pages http://wwwlib.umi.com/dissertations/fullcit/9237746
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Health Seeking and Patient Adherence: Tuberculosis Screening and Latino Immigrants by Hass, Michael Ray, Phd from University of California, Irvine, 1993, 151 pages http://wwwlib.umi.com/dissertations/fullcit/9320077
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Immune Mechanisms of Protection in Tuberculosis by Perdow Hickman, Somia; Phd from Temple University, 2002, 140 pages http://wwwlib.umi.com/dissertations/fullcit/3040354
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Immunological Properties of Mycolic Acids, the Major Lipid Cell Wall Component of Mycobacterium Tuberculosis by Stoltz, Anton Carel; Phd from University of Pretoria (south Africa), 2002 http://wwwlib.umi.com/dissertations/fullcit/f276097
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Implementation Problems of the Tuberculosis Control Program in Korea by Kim, Kyuil, Phd from The University of Texas at Austin, 1981, 278 pages http://wwwlib.umi.com/dissertations/fullcit/8128646
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Infectious Fear: Tuberculosis, Public Health, and the Logic of Race and Illness in Baltimore, Maryland, 1880--1930 by Roberts, Samuel Kelton; Phd from Princeton University, 2002, 499 pages http://wwwlib.umi.com/dissertations/fullcit/3062512
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Interagency Relations in the Provision of Health Services: Tuberculosis Control in a Metropolitan Region by Wysong, Jere Allen, Phd from Purdue University, 1968, 232 pages http://wwwlib.umi.com/dissertations/fullcit/6907413
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Introducing a Tuberculosis Control Program in Sidama: a Case Study in Crosscultural Communication by Aadland, Oyvind, Phd from Northwestern University, 1996, 385 pages http://wwwlib.umi.com/dissertations/fullcit/9828245
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Inventing the Cure: Tuberculosis in Twentieth Century Nova Scotia by Penney, Sheila M., Phd from Dalhousie University (canada), 1990, 418 pages http://wwwlib.umi.com/dissertations/fullcit/NN71556
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Knowledge and Beliefs of Patients Who Are Suspects or Smear- and Culture-positive for Tuberculosis in Manhattan's Central Harlem District in New York City by Ilongo, Ikoli, Edd from Columbia University Teachers College, 1994, 203 pages http://wwwlib.umi.com/dissertations/fullcit/9432532
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Malade Et Maladie: Degradation Physique Et Ecriture Fin-de-siecle (french Text, Aids, Immune Deficiency, Tuberculosis, Syphilis, Herve Guibert, Guy De Maupassant, Gilles Barbedette, Marie Bashkirtseff, Pascal De Duve, Catherine Pozzi) by Spoiden, Stephane Joseph, Phd from The Ohio State University, 1996, 272 pages http://wwwlib.umi.com/dissertations/fullcit/9630981
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Mechanisms of Phagosomal Development and the Maturation Arrest of Mycobacterium Tuberculosis Phagosomes by Fratti, Rutilio A. Phd from University of Michigan, 2002, 322 pages http://wwwlib.umi.com/dissertations/fullcit/3057949
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Models for the Design and Evaluation of Tuberculosis Control Programs by Chorba, Ronald William, Phd from The University of Arizona, 1971, 278 pages http://wwwlib.umi.com/dissertations/fullcit/7124912
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Mycobacterial Mycolic Acids As Immunoregulatory Lipid Antigens in the Resistance to Tuberculosis by Siko, Dismore Gilbert Ramathudi; Phd from University of Pretoria (south Africa), 2003 http://wwwlib.umi.com/dissertations/fullcit/f38289
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Mycobacterium Tuberculosis: Resistance to Reactive Nitrogen and Oxygen Intermediates by Firmani, Marcia Ann; Phd from University of California, Berkeley, 2002, 171 pages http://wwwlib.umi.com/dissertations/fullcit/3063360
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'on What Authority Is This Being Done?' Tuberculosis Control, Poverty and Coercion in Seattle, 1909-1973 by Lerner, Barron H., Phd from University of Washington, 1996, 725 pages http://wwwlib.umi.com/dissertations/fullcit/9716870
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Outcomes of Community-based, Individualized Therapy for Multidrug-resistant Tuberculosis in Urban Peru by Mitnick, Carole Diane; Sd from Harvard University, 2002 http://wwwlib.umi.com/dissertations/fullcit/f693281
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Perceptions and Experiences of Tuberculosis in Rural Eastern Nepal: a Biobehavioral Perspective by Zvosec, Deborah L., Phd from University of Hawaii, 1996, 507 pages http://wwwlib.umi.com/dissertations/fullcit/9700561
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Problems of Regimen Compliance in Tuberculosis Treatment by Klink, Walter Bernard, Phd from Columbia University, 1969, 275 pages http://wwwlib.umi.com/dissertations/fullcit/7219072
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Pulmonary Tuberculosis: a Comparative Immunopathological Investigation by Turner, Oliver Christian; Phd from Colorado State University, 2002, 237 pages http://wwwlib.umi.com/dissertations/fullcit/3053455
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Reform and Resistance in Post-soviet Tuberculosis Control by Bukhman, Gene; Phd from The University of Arizona, 2001, 385 pages http://wwwlib.umi.com/dissertations/fullcit/3040139
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Rejecting the Patient's Role in Tuberculosis Treatment by Boros, Alexander, Phd from Case Western Reserve University, 1969, 172 pages http://wwwlib.umi.com/dissertations/fullcit/7025940
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Role of Fbpa and Fbpb in the Pathogenesis and Mycolyltransferase Activity of Mycobacterium Tuberculosis by Armitige, Lisa Yvonne; Phd from The Univ. of Texas H.s.c. at Houston Grad. Sch. of Biomed. Sci., 2002, 142 pages http://wwwlib.umi.com/dissertations/fullcit/3061113
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Sige-regulated Genes of Mycobacterium Tuberculosis by Alligood, Molly Mclendon; Phd from Emory University, 2002, 179 pages http://wwwlib.umi.com/dissertations/fullcit/3058992
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Studies on Bovine Tuberculosis in Cattle and Badgers in Ireland (ireland) by Oleapopelka, Francisco Javier; Msc from University of Guelph (canada), 2003, 110 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76102
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The American Tuberculosis Crusade, 1889-1917: the Rise of a Modern Health Campaign by Teller, Michael E., Phd from The University of Chicago, 1985 http://wwwlib.umi.com/dissertations/fullcit/T-29462
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The Anti-tuberculosis Crusade and the Texas African-american Community, 19001950 by Hardman, Peggy Jane, Phd from Texas Tech University, 1997, 274 pages http://wwwlib.umi.com/dissertations/fullcit/9725893
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The Carbohydrate Surface of Mycobacterium Tuberculosis: Antigenicity and Antibody Immunity by Schwebach, J. Reid; Phd from Yeshiva University, 2002, 250 pages http://wwwlib.umi.com/dissertations/fullcit/3041168
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The Cost-benefit Analysis of Disease Control Programs in Developing Countries with Applications to the Indian National Tuberculosis Programme. by Chasse, John Dennis, Phd from Syracuse University, 1974, 341 pages http://wwwlib.umi.com/dissertations/fullcit/7513966
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The Distribution of Tuberculosis in Foreign-born Population Compared with the Distribution of Tb in United States-born in the City of Hartford, Connecticut by Poyser, Desmond Livingstone Anthony; Mph from Southern Connecticut State University, 2002, 45 pages http://wwwlib.umi.com/dissertations/fullcit/1408474
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The Economic Benefits from a Tuberculosis Control Program in Indonesia: Effects of Chemotherapy by Prijono, Phd from University of Hawaii, 1981 http://wwwlib.umi.com/dissertations/fullcit/f408710
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The Effect of Tuberculosis on Viral Load and Immune Function in Hiv-infected Gambians (immune Deficiency) by Jobe, Ousman Baboucarr; Phd from Open University (united Kingdom), 2002 http://wwwlib.umi.com/dissertations/fullcit/f680177
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The Effects of Short-term Localized Changes on the Decline of Tuberculosis Mortality in Gibraltar, 1860--1967 by Choong, Henry H. C. Phd from University of Toronto (canada), 1999, 177 pages http://wwwlib.umi.com/dissertations/fullcit/NQ41124
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The Effects of Tuberculosis on Hiv-1 Heterogeneity, Quasispecies Distribution, and Implications on Viral Fitness by Collins, Kalonji Rashaud; Phd from Case Western Reserve University (health Sciences), 2003, 193 pages http://wwwlib.umi.com/dissertations/fullcit/3088687
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The Intellectual Origins and Cultural Form of Tuberculosis in the United States, 18701925. (volumes I and Ii) by Ott, Katherine, Phd from Temple University, 1991, 531 pages http://wwwlib.umi.com/dissertations/fullcit/9120810
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The Interaction of Mycobacterium Tuberculosis with Murine Dendritic Cells by Bodnar, Kendra Anne; Phd from University of Pittsburgh, 2002, 159 pages http://wwwlib.umi.com/dissertations/fullcit/3068705
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The Making of a Social Disease: Tuberculosis in Nineteenth-century France (nineteenth Century) by Barnes, David Stepanek, Phd from University of California, Berkeley, 1992, 355 pages http://wwwlib.umi.com/dissertations/fullcit/9304856
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The Road to Health: the Experience of Tuberculosis in Southern Chile by Paluzzi, Joan Elizabeth; Phd from University of Pittsburgh, 2002, 372 pages http://wwwlib.umi.com/dissertations/fullcit/3054319
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The Role of Interleukin-8 and Monocyte Chemoattractant Protein-1 in Bcg Vaccine Induced Resistance to Mycobacterium Tuberculosis by Lyons, Mark Joseph; Phd from Texas A&m University, 2002, 77 pages http://wwwlib.umi.com/dissertations/fullcit/3072495
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The Role of Tumor Necrosis Factor-alpha (tnf-alpha) in Host Resistance to Experimental Pulmonary Tuberculosis by Lasco, Todd Michael; Phd from Texas A&m University, 2002, 130 pages http://wwwlib.umi.com/dissertations/fullcit/3072478
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The Years of Tuberculosis: Buenos Aires, 1870-1950 by Armus, Diego Claudio, Phd from University of California, Berkeley, 1996, 558 pages http://wwwlib.umi.com/dissertations/fullcit/9722857
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Toward a New Vaccine for Tuberculosis: Immunogenicity of Mycobacterium Tuberculosis Culture Filtrate Proteins in Nonhuman Primates by Pehler Harrington, Karen Marie; Phd from Georgia State University, 2002, 113 pages http://wwwlib.umi.com/dissertations/fullcit/3057025
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Transmission and Control of Mycobacterium Tuberculosis by Rhee, Jeanne Tigerlily; Phd from Stanford University, 2002, 105 pages http://wwwlib.umi.com/dissertations/fullcit/3038140
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Tuberculosis and the Growth of Denver's Eastern European Jewish Community: the Accommodation of an Immigrant Group to a Medium-sized Western City, 1900-1920. by Giese, James Richard, Phd from University of Colorado at Boulder, 1979, 456 pages http://wwwlib.umi.com/dissertations/fullcit/7923240
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Tuberculosis As Chronic Illness in the United States: Understanding, Treating, and Living with the Disease, 1884-1954 by Mcquien, Carolyn June, Phd from The University of Texas at Austin, 1993, 332 pages http://wwwlib.umi.com/dissertations/fullcit/9413555
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Tuberculosis in West Texas, 1870-1940 by Price, Johanna E., Phd from The University of Texas Graduate Sch. of Biomedical Sci. at Galveston, 1982, 428 pages http://wwwlib.umi.com/dissertations/fullcit/8217366
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Tuberculosis Mortality in the Jewish Community of Gibraltar a Historical Study in Family Perspective by Herring, Ann; Phd from University of Toronto (canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL43430
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Tuberculosis Prevention by Barnwell, Mary D., Phd from The Union Institute, 1990, 158 pages http://wwwlib.umi.com/dissertations/fullcit/9033314
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Tuberculosis Transmission in a Community of Rio De Janeiro, Brazil by Lauria, Lilian De Mello; Phd from University of California, Berkeley, 2002, 83 pages http://wwwlib.umi.com/dissertations/fullcit/3082271
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Tuberculosis, the Navajos, and Western Healthcare Providers, 1920--1960 (arizona, New Mexico) by Macmahon, Sandra Varney; Phd from The University of New Mexico, 2003, 357 pages http://wwwlib.umi.com/dissertations/fullcit/3085718
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Ugandan Women's Health Beliefs, Social Networks and Tuberculosis Treatmentseeking by Chard, Sarah Ellen; Phd from Case Western Reserve University, 2001, 287 pages http://wwwlib.umi.com/dissertations/fullcit/3036337
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White Plague in Black Los Angeles: Tuberculosis among African Americans in Los Angeles, 1930--1950 (california) by Moorhead, Laura Kaye; Phd from The University of North Carolina at Chapel Hill, 2000, 151 pages http://wwwlib.umi.com/dissertations/fullcit/9968644
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Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. CLINICAL TRIALS AND TUBERCULOSIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning tuberculosis.
Recent Trials on Tuberculosis The following is a list of recent trials dedicated to tuberculosis.8 Further information on a trial is available at the Web site indicated. •
A Study of the Effectiveness and Tolerability of Weekly Rifapentine/Isoniazid for Three Months Versus Daily Isoniazid for Nine Months for the Treatment of Latent Tuberculosis Infection Condition(s): Tuberculosis Study Status: This study is currently recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: The primary objective of this open-label Phase III clinical trial is to compare the effectiveness of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose) regimen of daily isoniazid (9INH). This trial will be conducted among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent infection (TLI) to prevent tuberculosis (TB). The 3RPT/INH regimen will be given under direct observation and the 9INH regimen will be self-administered. Secondary Objective: Compare the rates of drug discontinuation due to adverse drug reactions associated with 3RPT/INH and 9INH. Compare the rates of drug discontinuation for any reason associated with 3RPT/INH and 9INH. Compare the rates of any grade 3, 4, or 5 drug toxicity associated with 3RPT/INH and 9INH. Compare treatment completion rates of 3RPT/INH and 9INH. Compare the efficacy (i.e., among persons who complete study-phase therapy) of 3RPT/INH and 9INH. Compare the effectiveness and tolerability of 3RPT/INH and 9INH in HIV-infected persons. Compare the effectiveness and tolerability of 3RPT/INH and 9INH in children < 18 years old. Compare the rates of
8
These are listed at www.ClinicalTrials.gov.
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methadone withdrawal associated with 3RPT/INH and 9INH among persons concomitantly receiving methadone. Describe patterns of antibiotic resistance among M. tuberculosis isolates in patients who develop TB despite treatment of latent infection. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023452 •
Diagnosing Tuberculosis in HIV Infected Children in Peru Condition(s): Tuberculosis; Tuberculosis, Pulmonary; HIV Infections Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: Tuberculosis is a major cause of mortality among AIDS patients in the developing world. The diagnosis of tuberculosis in HIV infected children is complicated by inefficient and expensive tuberculosis tests and vague diagnostic criteria. This study will evaluate the accuracy and efficiency of several different tuberculosis tests that could be used in developing countries. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00054769
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Disseminated Tuberculosis in HIV Infection Condition(s): Tuberculosis; HIV Infections Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: A significant number of HIV infected patients in Africa also have disseminated tuberculosis (infection throughout multiple organs). This type of tuberculosis is a significant cause of mortality in these patients. The purpose of this study is to evaluate the safety and effectiveness of a vaccine designed to prevent disseminated tuberculosis. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00052195
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Intensive Pharmacokinetics of the Nelfinavir-Rifabutin Interaction in Patients with HIV-Related Tuberculosis Treated with a Rifabutin-Based Regimen Condition(s): Tuberculosis; HIV Infections Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Centers for Disease Control and Prevention Purpose - Excerpt: The primary objective of this multi-center sub-study of USPHS Study 23: "Intensive Pharmacokinetic Study of Intermittent Rifabutin and Isoniazid with Daily
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Efavirenz in Combination with Two Nucleoside Analogs for Treatment of HIV and Tuberculosis Co-infections," is to compare the pharmacokinetics of rifabutin at 600 mg twice a week in combination with efavirenz 600 mg daily to the pharmacokinetics of rifabutin 300 mg twice a week without efavirenz. Secondary objectives are: (1) To describe pharmacokinetics of both rifabutin and efavirenz in combination regimen, (2) To evaluate the safety of concomitant efavirenz and rifabutin, (3) To assess the effect on absolute neutrophil count by changing rifabutin dose and adding efavirenz to the regimen, (4) To develop models of optimal sampling times for rifabutin dosed twice a week, (5) To describe the pharmacokinetics of isoniazid in combination with efavirenz daily with two NRTIs, (6) To compare the pharmacokinetics of isoniazid with and without efavirenz. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018083 •
Tuberculosis Prevention for HIV Infected Adults Condition(s): HIV Infections; Tuberculosis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study compares three different tuberculosis (TB) prevention regimens against the standard regimen of 6 months of isoniazid. It is being conducted in Soweto, South Africa. People who are HIV positive and have a positive tuberculin skin test without signs of active tuberculosis may join. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00057122
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Vitamin A Therapy for Tuberculosis Condition(s): Pulmonary Tuberculosis; HIV Infections Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The study will determine whether a daily vitamin and mineral supplement (a multivitamin including Vitamin A) will improve health when added to standard chemotherapy for tuberculosis. This study will compare the effectiveness of the multivitamin in HIV infected and HIV uninfected patients. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00057434
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A Non-Comparative Study of the Efficacy of a Largely-Intermittent, Six-Month Tuberculosis Treatment Regimen Among Patients Who Will Not Receive Isoniazid Due to Initial Isoniazid Resistance or Intolerance Condition(s): Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: Primary Objective: To evaluate the efficacy of a directly-observed, largely-intermittent, six-month regimen of rifampin, pyrazinamide, ethambutol among patients with culture confirmed isoniazid-resistant M. tuberculosis. Secondary Objectives: To describe the rate, severity and timing of toxicities and drug intolerances associated with this treatment regimen. To describe the utility of this regimen among patients who are unable to continue the standard 4-drug regimen due to the development of intolerance to isoniazid Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023374
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A Registry of Tuberculosis Cases in the CPCRA Condition(s): HIV Infections; Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: PRIMARY: To estimate the proportion of tuberculosis patients in the CPCRA who have drug-resistant tuberculosis (TB) and to describe the patterns of drug resistance. SECONDARY: To compare drug resistance data on the Mycobacterium tuberculosis isolates of HIV-positive patients to those of HIV-negative patients who are being followed in the CPCRA. To assess the relationship of resistance data with geographic, demographic, and HIV and TB risk factor information. Geographic areas and demographic subgroups affected by the TB epidemic appear to be congruent and associated with the concurrent HIV epidemic. The total number of CPCRA patients who will develop, or who have experienced, confirmed TB is unknown. It is critical to determine the depth and breadth of the current problem of drug-resistant TB. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000785
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Efficacy of Once-Weekly Rifapentine and Isoniazid in Treatment of Tuberculosis Condition(s): Pulmonary Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: Primary Objective: To compare, at the completion of the follow-up phase, the clinical and bacteriologic relapse rates associated with the two study regimens. Secondary Objectives: To compare the clinical and bacteriologic failure rates of the two study regimens at the completion of the study phase therapy. To compare the clinical and bacteriologic response rates for the two study regimens among patients who began study phase therapy with signs and symptoms of tuberculosis or cultures positive
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for M. tuberculosis. To compare the toxicity associated with the two study regimens by comparing discontinuation rates due to adverse events and occurrence rates of signs and symptoms associated with adverse events during study phase therapy. To compare mortality rates of the two study regimens. To compare the rates of completion of therapy within 22 weeks for the two study regimens. To compare the rate of development of drug-resistant tuberculosis in the two study regimens among study patients classified as treatment failures or relapses. To compare all of the above performance characteristics for the two study regimens in a small subset of HIV seropositive patients. To compare attitudes and beliefs about participation in this study between patients who complete study therapy and those who fail to complete study therapy. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023335 •
Intensive Pharmacokinetic Study of Three Doses of Rifapentine and 25-desacetyl Rifapentine Condition(s): Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: Primary objective: To compare the pharmacokinetics of rifapentine and 25-desacetyl rifapentine at three different doses: 600 mg, 900 mg, and 1200 mg. Secondary objective: To describe any correlation between pharmacokinetic parameters of three different doses of rifapentine plus a standard dose of isoniazid and the occurrence of toxicity attributed to anti-tuberculosis treatment. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023387
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Intensive Pharmacokinetics of the Nelfinavir Rifabutin Interaction in Patients with HIV-Related Tuberculosis Treated with a Rifabutin-Based Regimen Condition(s): HIV Infections; Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: Primary Objective: To define the impact of nelfinavir (given at 1250mg bid as part of a combination antiretroviral regimen) on peak levels and area under the curve for rifabutin and the rifabutin metabolite, 25-O-desacetyl rifabutin when rifabutin is given at 300 mg bi-weekly as part of tuberculosis chemotherapy. Secondary Objectives: To compare the pharmacokinetics of nelfinavir given twice daily at 1250 mg bid with twice-weekly isoniazid and rifabutin to the pharmacokinetics of nelfinavir 1250 mg twice-daily in historical HIV-infected patients not receiving isoniazid and rifabutin. To evaluate the correlation between pharmacokinetic parameters of rifabutin and 25-O-desacetyl rifabutin and the occurrence of toxicity attributed to rifabutin in patients with HIV-related tuberculosis. To define detailed pharmacokinetics of isoniazid given at 15mg/kg or 900 mg in patients with HIV-related tuberculosis. To
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attempt to derive optimal sampling times for nelfinavir and rifabutin pharmacokinetic studies. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023400 •
Pharmacokinetics of Intermittent Isoniazid Condition(s): HIV Infections; Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: Primary Objectives: 1) To determine the proportion of patients with HIV-related tuberculosis who have abnormal pharmacokinetic parameters for isoniazid and rifabutin. Secondary Objectives: 1) To determine risk factors for abnormal pharmacokinetic parameters for isoniazid and rifabutin. 2) To evaluate the correlation between pharmacokinetic parameters of isoniazid and rifabutin and the occurrence of toxicity attributed to antituberculous therapy. 3) To evaluate the correlation between pharmacokinetic parameters of isoniazid and rifabutin and the efficacy of TB therapy. 4) To define and correlate phenotypic INH acetylator status with the results of genotypic acetylator data obtained in the parent trial. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023348
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Pharmacokinetics of Intermittent Rifabutin and Isoniazid with Daily Efavirenz Condition(s): HIV Infections; Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: The aim of this trial is to study the efavirenz-rifabutin interaction. Thus, this trial will enroll patients with HIV and tuberculosis co-infections who are receiving a rifabutin-based regimen and who plan to begin an antiretroviral regimen containing efavirenz dosed at 600 mg daily. Enrollment in TB Trials Consortium Study 23 is not a requirement for participation in this study. Primary Objective: To compare the pharmacokinetics of rifabutin at 600 mg twice a week in combination with efavirenz 600 mg daily to the pharmacokinetics of rifabutin 300 mg twice a week without efavirenz. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023413
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Pilot Study to Evaluate Nucleic Acid Amplification Methods in the Diagnosis and Management of Active TB Condition(s): Tuberculosis
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Study Status: This study is no longer recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: This is a pilot study to evaluate the performance of several nucleic acid amplification methodologies in the diagnosis and management of active tuberculosis Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023439 •
Prophylaxis Against Tuberculosis (TB) in Patients With Human Immunodeficiency Virus (HIV) Infection and Confirmed Latent Tuberculous Infection Condition(s): HIV Infections; Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To evaluate and compare the effectiveness of a 2-month regimen of rifampin and pyrazinamide versus a 1-year course of isoniazid (INH) to prevent the development of tuberculosis in patients who are coinfected with HIV and latent Mycobacterium tuberculosis (MTb). Current guidelines recommend 6 to 12 months of treatment with INH for purified protein derivative (PPD)-positive individuals. Problems with this treatment include compliance, adverse reaction, and the possibility of not preventing disease due to INH-resistant organisms. Studies suggest that two or three months of rifampin and pyrazinamide may be more effective than longer courses of INH. A two-month prevention course should help to increase compliance. In addition, the use of two drugs (rifampin and pyrazinamide) may help overcome problems with drug resistance. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000636
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Prophylaxis Against Tuberculosis (TB) in Patients With Human Immunodeficiency Virus (HIV) Infection and Suspected Latent Tuberculous Infection Condition(s): HIV Infections; Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To evaluate the safety and effectiveness of a 6-month course of isoniazid ( INH ) in the prevention of clinical tuberculosis in anergic (having diminished or absent reactions to specific antigens) HIV-infected persons who are at high risk for tuberculous infection. A substantial number of HIV-infected persons are anergic, and thus do not respond to the only currently available diagnostic tool for tuberculosis infection (that is, the PPD (purified protein derivative) skin test). Many of these anergic persons are, however, infected with Mycobacterium tuberculosis and eventually develop reactivation tuberculosis, causing both individual illness and spread of infection to others in the community. This study examines the possibility of using INH prophylaxis (that is, for prevention) in anergic HIV-infected patients at high risk for tuberculosis as a means of decreasing the sharp rise in the incidence of tuberculosis due
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to HIV infection. INH is inexpensive and relatively safe, and thus may demonstrate an acceptable risk/benefit ratio as a medication that can be given over a limited period of time to a population suspected of having, but not proved to have, M. tuberculosis infection. If this study shows INH to be safe and effective in this setting, it could have a major effect on public health in this country. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000959 •
Randomized Study of Interventions to Enhance Adherence to Isoniazid Prevention Therapy for Tuberculosis in Injection Drug Users Condition(s): Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute on Drug Abuse (NIDA); Johns Hopkins University Purpose - Excerpt: Objectives: I. Recruit 300 injection drug users with positive tuberculin skin tests who are candidates for isoniazid chemoprophylaxis into a trial of several interventions to enhance adherence to preventive therapy. II. Compare the effectiveness of self-administered isoniazid chemoprophylaxis supplemented with peer education and support groups versus directly observed preventive therapy delivered by a licensed nurse versus self-administered therapy with standard clinic follow-up and education. Outcome measures are adherence to prescribed doses of medication and the proportion of patients who complete therapy. III. Compare the impact of monetary incentives on therapy adherence by random assignment to immediate vs. deferred financial incentive. IV. Assess attitudes, knowledge, and beliefs about tuberculosis and preventive therapy in these patients and determine the association of these factors with demographic, social, and clinical characteristics. V. Assess attitudes and beliefs about tuberculosis susceptibility, seriousness, benefits of preventive therapy, barriers to therapy, and selfefficacy as predictors of health-related behaviors as measured by adherence with therapy, and determine the impact of the assigned interventions on these attitudes and beliefs. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004740
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Study of the Tolerability of Higher Doses of Rifapentine in the Treatment of Tuberculosis Condition(s): Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: This is a randomized, double-blind study of the tolerability of three different doses of rifapentine Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023426
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Two-Stage Tuberculin (PPD) Skin Testing Immunodeficiency Virus (HIV) Infection
in
Individuals
With
Human
Condition(s): HIV Infections; Tuberculosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Warner Lambert - Parke Davis Purpose - Excerpt: To quantitate in an HIV-infected population the percentage of patients demonstrating the "booster" phenomenon (attainment of a positive response to a second tuberculin purified protein derivative skin test when the first skin test was negative); to determine the relationship between the booster phenomenon and CD4positive lymphocyte cell counts; to detect any relationship between the booster phenomenon and HIV exposure category. The accuracy of skin testing to detect Mycobacterium tuberculosis (MTb) infection is dependent upon the host's ability to mount a delayed-type hypersensitivity (DTH) reaction; however, the DTH response may be impaired or absent in patients with impaired cell-mediated immunity, a classic characteristic of HIV infection. Patients in whom immunity is diminished, but not absent, may test negative the first time a purified protein derivative skin test for MTb is administered, but if the same skin test is repeated, a positive DTH response may then be elicited. This occurrence is known as the "booster" phenomenon. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000955 •
A Pilot Study of Methodology to Rapidly Evaluate Drugs for Bactericidal Activity, Tolerance, and Pharmacokinetics in the Treatment of Pulmonary Tuberculosis Using Isoniazid and Levofloxacin Condition(s): HIV Infections; Tuberculosis Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To evaluate the methodology for rapidly determining the early bactericidal activity (EBA), tolerance, and pharmacokinetics of isoniazid and levofloxacin in the treatment of pulmonary tuberculosis (TB). Traditionally, in trials for treatment of TB, a new drug is administered in combination with two or more other antituberculous agents of known effectiveness over a long period of time. In this setting, it is difficult to determine the effect of any single drug or dose level. Development of new agents for the treatment of TB may be accelerated by a methodology in which a new agent could be evaluated for activity by administering it as a single agent over a short time period. This study utilizes a method to measure the amount of bacteria present each day in the lungs. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000778
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•
A Prospective Study of Multidrug Resistance and a Pilot Study of the Safety of and Clinical and Microbiologic Response to Levofloxacin in Combination With Other Antimycobacterial Drugs for Treatment of Multidrug-Resistant Pulmonary Tuberculosis (MDRTB) in Condition(s): HIV Infections; Tuberculosis Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To determine the demographic, behavioral, clinical, and geographic risk factors associated with the occurrence of multidrug-resistant pulmonary tuberculosis (MDRTB). To evaluate the clinical and microbiological responses and overall survival of MDRTB patients who are treated with levofloxacin-containing multiple-drug regimens chosen from a hierarchical list. Per 9/28/94 amendment, to assess whether persistent or recurrent positive sputum cultures of patients who show failure or relapse are due to the same strain or reinfection with a new strain. Among TB patients, there has been an increase in progressive disease due to the emergence of antimycobacterial drug-resistant strains of Mycobacterium tuberculosis. Failure to identify patients at high risk for MDRTB increases the hazard for both treatment failure and development of resistance to additional therapeutic agents. Efforts to improve survival in patients with MDRTB will depend on improved methods of assessing the risk of acquisition of MDRTB and identifying drug susceptibility patterns in a timely fashion. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000796
•
A Study to Evaluate the Safety and Efficacy of Azithromycin in Individual Patients With Serious Nontuberculous Mycobacterial Disease Who Are Failing or Intolerant of Other Available Therapy Condition(s): Mycobacterium avium-intracellulare Tuberculosis, Mycobacterium Infection
Infection;
HIV
Infections;
Study Status: This study is completed. Sponsor(s): Pfizer Purpose - Excerpt: To evaluate the efficacy and safety of azithromycin given chronically for the treatment of serious nontuberculous mycobacterial infection in patients failing or intolerant of other available therapy. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002085 •
Behavioral Interventions for Control of TB Condition(s): Lung Diseases; Tuberculosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To compare alternative methods to ensure completion of treatment and preventive therapy for TB in inner cities, and to identify the most cost-effective
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methods to accomplish that. The basis for comparison included adherence rates and cost savings as primary outcomes, and other parameters such as patient satisfaction, development of social networks, and participation in support programs as secondary outcomes. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005739 •
Behavioral Interventions for Control of Tuberculosis Condition(s): Lung Diseases; Tuberculosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To develop and test various educational strategies targeting primarily minority TB-infected adolescents at two health centers in Los Angeles in an experimental design to assess the relative effectiveness on medication adherence, appointment keeping, and completion of therapy. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005742
•
Effectiveness of Anti-HIV Therapy (HAART) in HIV-Infected Patients with Tuberculosis Condition(s): HIV Infections; Tuberculosis Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to see if a type of anti-HIV therapy called HAART is effective in lowering levels of HIV and boosting the immune system in HIVinfected patients with tuberculosis (TB). HIV-infected patients with TB have higher levels of HIV and lower CD4 cell counts (cells in the body that fight infection) than HIVinfected patients without TB. HAART has been effective in reducing HIV levels and increasing CD4 cells in patients without TB. However, its effects in HIV-infected patients with TB are unknown. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004736
•
Indigenous Outreach Among Injection Drug Users to Treat and Control TB Condition(s): Lung Diseases; Tuberculosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: The Community Outreach Intervention Project (COIP) implemented and evaluated a TB intervention with injection drug users (IDUs) in two Chicago
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Neighborhoods, guided by the indigenous outreach leadership model that had been used for AIDS prevention among drug users. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005741 •
Interferon Gamma for Drug Resistant Tuberculosis Condition(s): Pneumonia; Pulmonary Tuberculosis Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will determine what dose of recombinant interferongamma is safe and effective for treating multiple drug-resistant tuberculosis. Recombinant interferon-gamma is a genetically engineered form of a substance normally produced by the body and is used to boost immune function. Patients 5 years of age and older with multiply drug-resistant tuberculosis may be eligible for this study. Participants will be admitted to either the NIH Clinical Center in Bethesda, Maryland, the Texas Center for Infectious Diseases in San Antonio or the South Texas Hospital or Valley Baptist Hospital, both in Harlingen, Texas. On admission, patients will have a medical history, physical examination, blood and urine tests, sputum culture, X-rays, pulmonary function tests and a computed tomography (CT) scan. CT produces 3dimensional images of body tissues and organs in small sections. For the procedure, the patient lies still on a table surrounded by the scanner. All patients will continue treatment with anti-tuberculosis antibiotics during and after the study period and may elect whether or not to take gamma interferon in addition to the antibiotic. Five patients will receive only antibiotic treatment, and 5 each will receive one of 3 doses (0.025, 0.05 or 0.1 milligrams per square meter of body surface area) of interferon-gamma injected under the skin 3 times a week. The patient or caregiver will be taught to give the injections, which are similar to insulin injections for diabetes. Patients will be in isolation in the hospital from the start of therapy until sputum samples show no evidence of tuberculosis for 3 consecutive weeks. Following that, they will repeat the tests done on admission (except CT) during follow-up visits (1- to 2-day hospitalizations) at 3, 6, 9, 12, 15, 18 and 24 months after the start of therapy. Patients taking interferon gamma will have blood drawn more frequently (monthly) for the first 6 months, and patients with lung infection will have sputum samples collected more frequently-weekly for the first 3 months or until three consecutive negative samples are obtained and then monthly throughout the course of therapy. Patients with lung infection will also have repeat CT scans at 6 and 12 months while on interferon gamma. In one or two patients on the drug, blood will be drawn frequently following one injection of gamma interferon (just before the injection and again at 0.25, 0.5, 1, 6, 12, 18, 24 and 48 hours after it) to see if a difference in blood levels of the drug can be detected. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001407
•
Metabolism of Antituberculosis Drugs in HIV-Infected Persons With Tuberculosis Condition(s): HIV Infections; Tuberculosis
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Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to determine if a relationship exists between the level of antituberculosis drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) in the blood and the outcome of HIV-positive patients with tuberculosis. This study also evaluates how these drugs are absorbed and metabolized in the body. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000950 •
Phase II Placebo Controlled Study of Thalidomide in Patients With Mycobacterial and HIV Infections Condition(s): HIV Infections; Mycobacterium Infections; Tuberculosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); National Institute of Allergy and Infectious Diseases (NIAID); Rockefeller University Purpose - Excerpt: Objectives: I. Evaluate whether thalidomide modulates toxic host inflammatory responses in patients receiving antitubercular therapy. II. Evaluate whether thalidomide modifies tumor necrosis factor-mediated toxic symptoms of HIV and mycobacterial infections, and limits progression of HIV immunodeficiency. III. Evaluate whether thalidomide stimulates immunity in patients with HIV and/or mycobacterial infections. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004276
•
Pilot Randomized Study of Paromomycin (Aminosidine) vs Streptomycin for Uncomplicated Pulmonary Tuberculosis Condition(s): Tuberculosis, Pulmonary Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; University of Illinois Purpose - Excerpt: Objectives: I. Compare the pharmacokinetics and early bactericidal activity of paromomycin (aminosidine) vs streptomycin for the treatment of uncomplicated pulmonary tuberculosis. II. Compare the tolerability of these two drugs in these patients. III. Establish the relationships between achieved serum concentration, minimal inhibitory concentration, and early bactericidal activity of paromomycin and streptomycin. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004444
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•
Placebo-Controlled Trial of Safety and Efficacy of Thalidomide in Patients With Infections Due to Mycobacterium and/or HIV Condition(s): Mycobacterium avium-intracellulare Tuberculosis, Mycobacterium Infection
Infection;
HIV
Infections;
Study Status: This study is completed. Sponsor(s): Aaron Diamond AIDS Research Center Purpose - Excerpt: To demonstrate, in patients with tubercular or nontubercular mycobacterium infections with or without HIV infection, the safety of thalidomide use as judged by symptoms, physical exam, and studies of microbiologic, immunologic, hematologic, renal, and hepatic status. To demonstrate efficacy of the drug as judged by status of fever, nutrition, tuberculosis lesions, and immune responses. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002104 •
Preventive Treatment Against Tuberculosis (TB) in Patients With Human Immunodeficiency Virus (HIV) Infection and Confirmed Latent Tuberculous Infection Condition(s): HIV Infections; Tuberculosis Study Status: This study is completed. Sponsor(s): Hoechst Marion Roussel; Lederle Laboratories; National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To evaluate and compare the safety and effectiveness of a one-year course of isoniazid (INH) versus a two-month course of rifampin plus pyrazinamide for the prevention of reactivation tuberculosis in individuals infected with both HIV and latent (inactive) Mycobacterium tuberculosis. Current guidelines from the American Thoracic Society and the Centers for Disease Control recommend 6 to 12 months of INH for PPD (purified protein derivative)-positive individuals. Although the effectiveness of this treatment is not known for HIV-infected individuals, several studies using INH to prevent tuberculosis in presumably normal hosts have shown 60 to 80 percent effectiveness. Problems with this treatment include compliance, adverse reaction, and the possibility of not preventing disease due to tuberculosis organisms being resistant to INH. A two-month preventive treatment plan should help in increasing compliance. In addition, the use of two drugs (rifampin / pyrazinamide) may help overcome problems with drug resistance. If this study shows equal or greater effectiveness of the two-month rifampin / pyrazinamide treatment, it could alter the approach to tuberculosis prevention for both HIV-positive and HIV-negative individuals. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000638
•
Promoting Adherence to TB Regimens in Latino Adolescents Condition(s): Lung Diseases; Tuberculosis Study Status: This study is completed.
Clinical Trials 375
Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To test a public health model of screening, preventive isoniazid treatment, and adherence counseling plus medical education of primary care clinicians to enhance their skills and attention to TB control. Also, to test a behavioral adherence intervention for Latino adolescents with latent disease and a medical education program designed to enhance primary care (community clinic) practitioners' treatment of active and latent TB infection. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005738 •
TB Contact Investigation: Behavioral Intervention Condition(s): Lung Diseases; Tuberculosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To develop a behavioral intervention aimed at public health workers who perform tuberculosis contact investigation and designed to enhance the contact investigation process. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005740
•
The Treatment of Tuberculosis in HIV-Infected Patients Condition(s): HIV Infections; Tuberculosis Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: PER 5/30/95 AMENDMENT: To compare the combined rate of failure during therapy and relapse after therapy between two durations of intermittent therapy (6 versus 9 months) for the treatment of pulmonary tuberculosis (TB) in HIVinfected patients. To compare toxicity, survival, and development of resistance in these two regimens. ORIGINAL: To compare the efficacy and safety of induction and continuation therapies for the treatment of pulmonary TB in HIV-infected patients who are either from areas with known high rates of resistance to one or more anti-TB drugs or from areas where TB is expected to be susceptible to commonly used anti-TB drugs. PER 5/30/95 AMENDMENT: In HIV-negative patients, intermittent anti-TB therapy has been shown to be as effective as daily therapy, but the optimal duration of therapy in HIV-infected patients has not been established. ORIGINAL: In some areas of the country, resistance to one or more of the drugs commonly used to treat TB has emerged. Thus, the need to test regimens containing a new drug exists. Furthermore, the optimal duration of anti-TB therapy for HIV-infected patients with TB needs to be determined. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001033
376 Tuberculosis
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Treatment of HIV-Related Tuberculosis Using a Rifabutin-Based Regimen Condition(s): HIV Infections; Tuberculosis Study Status: This study is suspended. Sponsor(s): Centers for Disease Control and Prevention; Department of Veterans Affairs Purpose - Excerpt: Primary objective: To determine the rate of confirmed treatment failure and relapse with an intermittent rifabutin-based regimen for the treatment of isoniazid and rifamycin-susceptible HIV-related tuberculosis. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023361
•
Tuberculosis in a Multiethnic Inner City Population Condition(s): Acquired Immunodeficiency Syndrome; HIV Infections; Lung Diseases; Tuberculosis; Mycobacterium tuberculosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the incidence of tuberculosis in an inner city population, identify risk factors for TB, describe the natural history in adults and children, evaluate the effect of Mycobacterium tuberculosis (Mtb) co-infection on the progression of human immunodeficiency virus disease, and determine factors that contribute to compliance and non-compliance with prophylaxis and treatment. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005379
•
Tuberculosis in HIV Infected Patients in Uganda Condition(s): Tuberculosis; HIV Infections Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This was a clinical trial in HIV infected patients with tuberculosis. The study assessed whether the addition of prednisolone, a type of steroid medication, to the standard treatment for tuberculosis improved immune and viral outcomes in the patients. The study demonstrated that prednisolone increased the CD4 cell count as was hoped, but the beneficial effect was short-lived and was gone within 4 months of stopping therapy. Therefore, the use of prednisolone for tuberculosis in HIV infected patients is not recommended at this time. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00057421
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Tuberculosis Prophylaxis in the Homeless--A Controlled Trial Condition(s): Lung Diseases; Tuberculosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a three-arm, randomized controlled trial of methods to improve adherence to biweekly directly observed prophylaxis (DOPT) for tuberculosis in homeless adults in San Francisco. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005737
Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “tuberculosis” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •
For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/
•
For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html
•
For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/
•
For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm
•
For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm
•
For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm
•
For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp
•
For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm
378 Tuberculosis
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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/
•
For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm
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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm
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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm
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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm
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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm
•
For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials
379
CHAPTER 6. PATENTS ON TUBERCULOSIS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “tuberculosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on tuberculosis, we have not necessarily excluded nonmedical patents in this bibliography.
Patents on Tuberculosis By performing a patent search focusing on tuberculosis, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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example of the type of information that you can expect to obtain from a patent search on tuberculosis: •
12-kDa protein derived from M. Tuberculosis useful for treatment of autoimmune diseases Inventor(s): Ben-Nun; Avraham (Yavne, IL) Assignee(s): Yeda Research and Development Co., Ltd. (Rehovot, IL) Patent Number: 5,976,543 Date filed: August 1, 1997 Abstract: Disclosed is a 12-kDa PPD protein isolated and purified from the purified protein derivative, the major fraction of Mycobacterium tuberculosis that protects mice against the induction of experimental autoimmune encephalomyelitis (EAE), and salts, functional derivatives, analogs and active fractions thereof, and pharmaceutical compositions comprising them for the treatment of autoimmune diseases. Excerpt(s): The present invention relates to agents that may be used for the treatment of autoimmune diseases, and more particularly to a protein having a molecular weight of about 12-kDa isolated and purified from the purified protein derivative (PPD), the major fraction of Mycobacterium tuberculosis (Mt) that protects mice against the induction of experimental autoimmune encephalomyelitis (EAE), and to salts, functional derivatives, analogs and active fractions thereof. In the specification, the following abbreviations will be used: Ag, antigen; EAE, experimental autoimmune encephalomyelitis; PPD, purified protein derivative; MBP, myelin basic protein; Mt, Mycobacterium tuberculosis; PLP, proteolipid protein; RPLC, reverse phase high-pressure liquid chromatography; CFA, complete Freund's adjuvant; IFA, incomplete Freund's adjuvant; SDS-PAGE, sodium dodecyl sulphate polyacrylamide gel electrophoresis; hsp, heat shock protein. Increasing evidence suggests that infectious agents can affect the development of autoimmune diseases. Viruses have been most often implicated in the etiology of autoimmune diseases, although bacteria may also be involved: streptococcal infection may lead to rheumatic fever and myocarditis, Mycoplasma arthriditis or its toxins can cause arthritis in mice or rats, and arthritis has also been associated with reactivity to mycobacterial antigens, both in humans and rats. However, several reports indicate that viruses and bacteria may also enhance the natural propensity of mice to become resistant to an autoimmune disease. Thus, non-obese diabetic mice infected with lymphocytic choriomeningitis virus become resistant to the development of insulin-dependent diabetes mellitus, and mice infected with lactic dehydrogenase virus are refractory to the development of experimental autoimmune encephalomyelitis (EAE). Similarly, bacteria may also be involved in conferring resistance to autoimmune diseases, as demonstrated in a previous study by the present inventor (Lehman and Ben-Nun, 1992). Web site: http://www.delphion.com/details?pn=US05976543__
•
Agar medium for the growth of Mycobacterium tuberculosis Inventor(s): Sanchez; Tracy (Lafayette, CO), Heifets; Leonid (Denver, CO) Assignee(s): National Jewish Medical and Research Center (Denver, CO) Patent Number: 6,579,694 Date filed: March 20, 2001
Patents 381
Abstract: A novel agar medium for the isolation, sub-cultivation, and indirect or direct drug-susceptibility testing of Mycobacterium tuberculosis is disclosed. Also disclosed are methods of isolating and growing Mycobacterium tuberculosis and methods of drug-resistance screening using the agar medium of the invention. Excerpt(s): This invention relates to a novel agar medium for the isolation, subcultivation, and indirect or direct drug-susceptibility testing of Mycobacterium tuberculosis. The invention also relates to methods of isolating and growing Mycobacterium tuberculosis and to methods of drug-resistance screening using the agar medium of the invention. At first glance, it seems that nothing is new in the cultivation of Mycobacterium tuberculosis. The first attempts of M. tuberculosis cultivation on agar medium go back to the report by Fannie and Walter Hesse in 1881. In 1882, Robert Koch used blood serum coagulated on glass slides for M. tuberculosis cultivation. Apparently, he was not too much concerned about the biosafety of such a procedure. He later improved this method, which was called the "plate technique", by adding peptone, some salts and glycerol. Also, in 1882, Richard Petri invented the petri dish to be used instead of a glass slide. These attempts at cultivation on a transparent type of media were interrupted in 1903 with introduction of the first egg-based media by Dorset (Dorset, Science. 17:374, 1903), followed by a variety of egg-based media recipes (American Trudeau Society, Handbook of Tuberculosis Laboratory Methods, Washington, D.C., 1962; IUAT, Bull Int Union Tuberc Lung Dis. 24:78, 1954; Jensen, Abteilung Originale. 125:222-239, 1932; Ogawa et al., Kekkaku. 24:13-29, 1949; Petragnani, Bollettino dell'Istituto sieroterapico Milanese. 5:173-185,1926; Petroff, J. Exp. Med. 21:38-42, 1915; Stonebrink, Acta Tuberc. Scand. 35:67-80, 1958). Based on systemic studies of the tubercle bacilli requirements, Dubos and Middlebrook in 1947 introduced the first effective agar medium under the name "Dubos Oleic Acid Albumin Agar" (Dubos, Amer. Rev. Tuberc. Pulm. Dis., 56:334-345, 1947). It followed by an invention by Middlebrook and Cohn of the 7H10 agar in 1958 (Middlebrook et al., Amer. J. Publ. Health, 48:844-853, 1958) and 7H11 agar in 1968 (Cohn et al., Am. Rev. Respir. Dis. 98:295-296, 1968). Subsequently, two recipes of a selective agar medium containing four antimicrobials to prevent the growth of contaminants (PolymyxinB, AmphotericinB, Carbenicillin, Trimethoprim) were introduced in 1972 (Mitchison et al., J. Med. Microbiol. 5:165-175, 1972) and in 1976 (McClatchy et al., Am. J. Clin. Pathol. 65:412-415, 1976). A powder base for all these media, 7H10 agar, contains agar, combination of seven salts, L-glutamic acid, pyridoxine, biotin, malachite green. It is available commercially from a number of manufacturers. Preparation of an agar medium requires addition of the OADC growth supplement, which contains sodium oleate, albumin (bovine, fr. V) dextrose, catalase. Web site: http://www.delphion.com/details?pn=US06579694__ •
Antibodies Which Bind Mycobacterial Tuberculosis Proteins Inventor(s): Pescher; Pascale (Paris, FR), Laqueyrerie; Anne (Paris, FR), Marchal; Gilles (Ivry Sur Seine, FR), Romain; Felix (Fontenay les Briis, FR) Assignee(s): Institut Pastuer (Paris, FR) Patent Number: 6,221,353 Date filed: August 11, 1998 Abstract: Antibodies that bind Mycobacterium tuberculosis 28 kDa proteins and immune complexes between the antibodies and proteins.
382 Tuberculosis
Excerpt(s): The object of the present invention is mycobacterial proteins and microorganisms producing them. It also relates to the use of these proteins in vaccines or for the detection of tuberculosis. At present, a definite diagnosis made by the demonstration of cultivatable bacilli in a sample taken from the patient is only obtained in less than half the cases of tuberculosis. Even for pulmonary tuberculosis, which represents 80 to 90% of the tuberculosis cases, and which is the form of the disease for which the detection of the bacilli is the easiest, the examination of expectorations is only positive for less than half the cases. Web site: http://www.delphion.com/details?pn=US06221353__ •
Anti-mycobacterial compositions and their use for the treatment of tuberculosis and related diseases Inventor(s): Barry, III; Clifton E. (Hamilton, MT), Yuan; Ying (Missoula, MT) Assignee(s): The United States of America as represented by the Department of Health (Washington, DC) Patent Number: 5,610,198 Date filed: March 18, 1994 Abstract: Compounds, pharmaceutical compositions, and methods for the treatment of mycobacterial diseases, such as tuberculosis and leprosy, are provided. Use of the compounds for promoting an antiseptic condition of a surface are also included. Some of the preferred compounds include thiatetracosanoic acids, esters, and fluorinated analogs. Excerpt(s): Mycobacterium is a genus of bacteria which are aerobic, mostly slow growing, slightly curved or straight rods, sometimes branching and filamentous, and distinguished by acid-fast staining. They are sometimes referred to as acid-fast bacilli (AFB) as application of alcohol (e.g., acid-alcohol or 95% ethanol with 3% hydrochloric acid) will not decolorize bacilli stained with basic dye. Typically, the mycobacteria are obligate aerobes, and they can be characterized as gram-positive. However, some have stated that gram-staining is unhelpful or unclassifiable. The genus mycobacterium includes the highly pathogenic organisms that cause tuberculosis (M. tuberculosis and sometimes M. bovis) and leprosy (M. leprae). There are many other species of mycobacterium, some of which are important in veterinary medicine. The following species of the genus mycobacterium are known pathogens for humans, and some are pathogenic for certain animals as well: M. tuberculosis, M. leprae, M. aviumintracellulare, M. bovis, M. chelonei (also known as borstelense and abscessus), M. africanum, M. marinium (also known as balnei and platypoecilus, the causative agent of "swimming pool granuloma"), M. buruli (also known as ulcerans), M. fortuitum (also known as giae, minetti, and ranae), M. haemophilum, M. intracellulare, M. kansasii (also known as luciflavum), M. littorale (also known as xenopi), M. malmoense, M. marianum (also known as scrofulaceum and paraffinicum), M. simiae, M. szulgai, and M. ulcerans (which is the agent responsible for Buruli ulcer). Mycobacterium which are pathogenic for animals but not believed to be pathogenic for humans include the following: M. avium (also known as brunense), M. flavascens, M. lepraemurium, M. microti, and M. paratuberculosis (which is the causative agent for Johne's Disease). The following species of the genus mycobacterium are believed to be non-pathogenic: M. gordonae (also known as aquae), M. gastri, M. phlei (also known as moelleri and as timothy bacillus), M. nonchromogenicum, M. smegmatis, M. terrae, M. triviale, and M. vaccae.
Patents 383
Web site: http://www.delphion.com/details?pn=US05610198__ •
Carbohydrate complex extracted from Mycobacterium tuberculosis and process for the preparation thereof Inventor(s): Chung; Tai-Ho (Cheongun Apt. 7-309, #111-1, Daebong-dong, Jung-gu, Daegu, KR), Chung; Chong-Chan (Garden Heights 1st. 101-601, #300, Bumeo 4-dong, Suaeong-gu, Daegu, KR) Assignee(s): none reported Patent Number: 6,274,356 Date filed: December 9, 1999 Abstract: A carbohydrate complex, which is a mixture of low molecular-weight polysaccharides of an arabinomannan structure extracted from Mycobacterium tuberculosis, is highly effective in treating various cancer patients without incurring any adverse side effects. Excerpt(s): The present invention relates to a carbohydrate complex extracted from Mycobacterium tuberculosis, which has an anticancer activity, and to a process for the preparation thereof. It is generally known that the anticancer activity of Mycobacterium tuberculosis is attributable to active agents in the cytoplasmic membrane thereof, particularly the polysaccharide and lipid derivatives. For instance, Azuma et al. succeeded in isolating N-acetylmuramyl-L-alanyl-D-isoglutamin(MDP) which is an active component of M. tuberculosis [Azuma, L. et al., J. Bact., 96, 1885-1887(1968)]. Web site: http://www.delphion.com/details?pn=US06274356__
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Compositions and methods for the prevention and treatment of M. tuberculosis infection Inventor(s): Reed; Steven G. (Bellevue, WA), Dillon; Davin C. (Redmond, WA), Skeiky; Yasir A. W. (Seattle, WA) Assignee(s): Corixa Corporation (Seattle, WA) Patent Number: 6,350,456 Date filed: April 7, 1998 Abstract: Compositions and methods for treatment and vaccination against tuberculosis are disclosed. In one aspect the compositions provided include at least two polypeptides that contain an immunogenic portion of a M. tuberculosis antigen or at least two DNA molecules encoding such polypeptides. In a second aspect, the compositions provided include a fusion protein comprising at least two polypeptides that contain an immunogenic portion of a M. tuberculosis antigen. Such compositions may be formulated into vaccines and/or pharmaceutical compositions for immunization against M. tuberculosis infection, or may be used for the diagnosis of tuberculosis. Excerpt(s): The present invention relates generally to compositions for the prevention and treatment of tuberculosis. The invention is more particularly related to compositions comprising at least two Mycobacterium tuberculosis antigens, and the use of such compositions for treating and vaccinating against Mycobacterium tuberculosis infection. Tuberculosis is a chronic, infectious disease, that is generally caused by infection with Mycobacterium tuberculosis. It is a major disease in developing countries,
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as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result. Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance. Web site: http://www.delphion.com/details?pn=US06350456__ •
Compositions and methods of their use in the treatment, prevention and diagnosis of tuberculosis Inventor(s): Skeiky; Yasir (Seattle, WA) Assignee(s): Corixa Corporation (Seattle, WA) Patent Number: 6,465,633 Date filed: December 23, 1999 Abstract: The present invention relates to Mycobacterium antigens, optionally from a species such as M. tuberculosis, M. bovis, M. smegmatis, BCG, M. leprae, M. scrofulaceum, M avium-intracellulare, M. marinum, M. ulcerans, M. kansasii, M. xenopi, M. szulgai, M. fortuium, or M. chelonei. In particular, the invention relates to M. tuberculosis secretory polypeptides, polynucleotides that encode the polypeptides, and methods of using such compositions in the treatment, prevention and diagnosis of M. tuberculosis infection. Excerpt(s): Not applicable. The present invention relates to Mycobacterium tuberculosis antigens. In particular, the invention relates to M. tuberculosis secretory polypeptides, polynucleotides that encode the polypeptides, and methods-of using such compositions in the treatment, prevention and diagnosis of M. tuberculosis infection. Tuberculosis is a chronic infectious disease caused by infection with M. tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If untreated, serious complications and death typically result. Web site: http://www.delphion.com/details?pn=US06465633__
Patents 385
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Compounds and methods for immunotherapy and diagnosis of tuberculosis Inventor(s): Vedvick; Thomas S. (Federal Way, WA), Houghton; Raymond (Bothell, WA), Campos-Neto; Antonio (Bainbridge Island, WA), Dillon; Davin C. (Redmond, WA), Skeiky; Yasir A. W. (Seattle, WA), Reed; Steven G. (Bellevue, WA), Twardzik; Daniel R. (Bainbridge Island, WA), Lodes; Michael J. (Seattle, WA), Hendrickson; Ronald C. (Seattle, WA) Assignee(s): Corixa Corporation (Seattle, WA) Patent Number: 6,592,877 Date filed: May 5, 1998 Abstract: Compounds and methods for inducing protective immunity against tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one immunogenic portion of one or more M. tuberculosis proteins and DNA molecules encoding such polypeptides. Such compounds may be formulated into vaccines and/or pharmaceutical compositions for immunization against M. tuberculosis infection, or may be used for the diagnosis of tuberculosis. Excerpt(s): The present invention relates generally to detecting, treating and preventing Mycobacterium tuberculosis infection. The invention is more particularly related to polypeptides comprising a Mycobacterium tuberculosis antigen, or a portion or other variant thereof, and the use of such polypeptides for diagnosing and vaccinating against Mycobacterium tuberculosis infection. Tuberculosis is a chronic, infectious disease, that is generally caused by infection with Mycobacterium tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result. Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance. Web site: http://www.delphion.com/details?pn=US06592877__
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Compounds for diagnosis of tuberculosis and methods for their use Inventor(s): Campos-Neto; Antonio (Bainbridge Island, WA), Alderson; Mark Raymond (Bainbridge Island, WA), Skeiky; Yasir A. W. (Seattle, WA), Dillon; Davin C. (Redmond, WA) Assignee(s): Corixa Corporation (Seattle, WA) Patent Number: 6,555,653 Date filed: May 5, 1998 Abstract: Compounds and methods for diagnosing tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one antigenic portion of one or more M. tuberculosis proteins, and DNA sequences encoding such polypeptides. Diagnostic kits containing such polypeptides or DNA sequences and a suitable detection
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reagent may be used for the detection of M. tuberculosis infection in patients and biological samples. Antibodies directed against such polypeptides are also provided. Excerpt(s): The present invention relates generally to the detection of Mycobacterium tuberculosis infection. The invention is more particularly related to polypeptides comprising a Mycobacterium tuberculosis antigen, or a portion or other variant thereof, and the use of such polypeptides for the serodiagnosis of Mycobacterium tuberculosis infection. Tuberculosis is a chronic, infectious disease, that is generally caused by infection with Mycobacterium tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result. Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance. Web site: http://www.delphion.com/details?pn=US06555653__ •
Desaturase antigen of Mycobacterium tuberculosis Inventor(s): Gicquel; Brigitte (Paris, FR), Jackson; Mary (Paris, FR) Assignee(s): Institut Pasteur (FR) Patent Number: 6,204,038 Date filed: October 22, 1999 Abstract: The present invention relates to the isolation of a new gene, des, which encodes a M. tuberculosis protein named DES. The des gene appears to be conserved among different Mycobacteria species. The amino acid sequence of the DES protein contains two sets of motifs that are characteristic of the active sites of enzymes from the class II diiron-oxo protein family. Among this family of proteins, DES shares significant homology with soluble stearoyl-ACP desaturases. DES is a highly antigenic protein, which is recognized by human sera from patients infected with M. tuberculosis and M. leprae but not by sera from tuberculous cattle. Thus, the DES protein provides a useful tool for the serodiagnostic analysis of tuberculosis. Excerpt(s): Tuberculosis and leprosy, caused by the bacilli from the Mycobacterium tuberculosis complex and M. leprae respectively are the two major mycobacterial diseases. Pathogenic mycobacteria have the ability to survive within host phagocytic cells. From the interactions between the host and the bacteria results the pathology of the tuberculosis infection through the damages the host immune response causes on tissues (Andersen & Brennan, 1994). Alternatively, the protection of the host is also dependent on its interactions with mycobacteria. Identification of the bacterial antigens involved in these interactions with the immune system is essential for the understanding of the pathogenic mechanisms of mycobacteria and the host immunological response in relation to the evolution of the disease. It is also of great importance for the improvement of the strategies for mycobacterial disease control through vaccination and immunodiagnosis. Through the years, various strategies have
Patents 387
been followed for identifying mycobacterial antigens. Biochemical tools for fractionating and analysing bacterial proteins permitted the isolation of antigenic proteins selected on their capacity to elicit B or T cell responses (Romain et al., 1993; Sorensen et al., 1995). The recent development of molecular genetic methods for mycobacteria (Jacobs et al., 1991; Snapper et al., 1990; Hatful, 1993; Young et al., 1985) allowed the construction of DNA expression libraries of both M. tuberculosis and M. leprae in the.lambda.gtl1 vector and their expression in E. coli. The screening of these recombinant libraries using murine polyclonal or monoclonal antibodies and patient sera led to the identification of numerous antigens (Braibant et al., 1994; Hermans et al., 1995; Thole & van der Zee, 1990). However, most of them turned out to belong to the group of highly conserved heat shock proteins (Thole & van der Zee, 1990; Young et al., 1990). Web site: http://www.delphion.com/details?pn=US06204038__ •
Detection and differentiation of mycobacterium tuberculosis complex bacteria by direct variant repeat oligotyping Inventor(s): Schouls; Leendert Marinus (Wijk Bij Duurstede, NL), Van Embden; Johannes Dirk Anthonie (Utrecht, NL), Kamerbeek; Judith (Utrecht, NL) Assignee(s): De Staat der Nederlanden, Vertegenwoordigd door de Minister van Welzijn, (Rijswijk, NL) Patent Number: 6,074,820 Date filed: January 22, 1997 Abstract: A method and primary pair and kit for the in vitro amplification of nucleic acid using amplification primers in amplification reactions. There is used a pair of primers comprising oligonucleotide sequences complementary to a part of a Direct Repeat sequence of a microorganism belonging to the M tuberculosis complex of microorganisms, whereby hybridization to a Direct Repeat occurs and subsequently elongation of the hybridized primer takes place. The primers are such that elongation in the amplification reaction occurs for one primer in a 5' direction and for the other primer in a 3' direction. Excerpt(s): Tuberculosis is an infectious disease that yearly kills more people than any other single infectious disease. The WHO estimates that yearly about 10 million people contract tuberculosis and that 3 million people die from this disease (37). After a long period of slow decrease in incidence, tuberculosis is on the increase again in most Western countries. Furthermore, the emergence of multidrug-resistant M. tuberculosis strains and the association of tuberculosis and Human Immunodeficiency Virus infected individuals are worsening the situation dramatically (1, 2, 4, 6, 7, 10, 37). One of the key factors in the control of tuberculosis is the rapid diagnosis of the disease and the identification of the sources of infection. M. tuberculosis strain typing has already proved to be extremely useful in outbreak investigations (6, 14, 33) and is being applied to a variety of epidemiologic questions in numerous laboratories. Traditionally, laboratory diagnosis is done by microscopy, culturing of the micro-organism, skin testing and X-ray imaging. Unfortunately, these methods are often not sensitive, not specific and are very time-consuming, due to the slow growth rate of M. tuberculosis. Therefore, new techniques like in vitro amplification of M. tuberculosis DNA have been developed to rapidly detect the micro-organism in clinical specimens (14). The ability to differentiate isolates of M. tuberculosis by DNA techniques has revolutionarized the potential to identify the sources of infection and to establish main routes of transmission and risk factors for acquiring tuberculosis by infection (1, 3-10, 14, 16, 19-22, 25, 26, 29-
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36). The use of an effective universal typing system will allow strains from different geographic areas to be compared and the movement of individual strains to be tracked. Such data may provide important insights and identify strains with particular problems such as high infectivity, high virulency and/or multidrug resistance. Analysis of large numbers of isolates may provide answers to long-standing questions regarding the efficacy of BCG vaccination and the frequency of reactivation versus reinfection. Because M. tuberculosis complex bacteria constitute a genetically remarkably homogenous group of bacteria, repetitive DNA elements and transposable elements, that are associated with genetic rearrangements of chromosomal DNA, have been exploited for strain differentiation of M. tuberculosis. Two of these are insertion sequences and the remainder are short repetitive DNA sequences with no known function or phenotype. Web site: http://www.delphion.com/details?pn=US06074820__ •
Detection of isoniazid resistant strains of M. tuberculosis Inventor(s): Kline; Bruce C. (Rochester, MN), Cockerill, III; Franklin R. (Rochester, MN), Uhl; James R. (Rochester, MN) Assignee(s): Mayo Foundation For Medical Education And Research (Rochester, MN) Patent Number: 5,658,733 Date filed: April 7, 1995 Abstract: A method for determining the susceptibility of a strain of M. tuberculosis to isoniazid is provided comprising employing the techniques of restriction fragment length polymorphism analysis to determine whether or not the DNA of said strain has an MspI restriction site at the codon corresponding to codons 315 or 463 of an M. tuberculosis katG gene consensus sequence. Excerpt(s): Despite more than a century of research since the discovery of Mycobacterium tuberculosis, the aetiological agent of tuberculosis, this disease remains one of the major causes of human morbidity and mortality. There are an estimated 3 million deaths annually attributable to tuberculosis (see, D. Snider, Rev. Inf. Dis., S335 (1989)), and although the majority of these are in developing countries, the disease is assuming renewed importance in the West due to the increasing number of homeless people and the impact the AIDS epidemic (see, R. E. Chaisson et at., Am. Res. Resp. Dis., 23, 56 (1987); D. E. Snider, Jr. et al., New Engl. J. Med., 326, 703 (1992); M. A. Fischl et al., Ann. Int. Med., 117, 177 (1992) and ibid. at 184. Isonicotinic acid hydrazide or isoniazid (INH) has been used in the treatment of tuberculosis for the last forty years due to its exquisite potency against the members of the "tuberculosis" groups--Mycobacterium tuberculosis, M. bovis and M. africanum (G. Middlebrook, Am. Rev. Tuberc., 69, 471(1952) and J. Youatt, Am. Rev. Resp. Dis., 99, 729 (1969)). Neither the precise target of the drug, nor its made of action are known, but INH treatment results in the perturbation of several metabolic pathways of the bacterium. However, shortly after its introduction, INH-resistant isolates of Mycobacterium tuberculosis emerged. See M. L. Pearson et al., Ann. Int. Med., 117, 191 (1992) and S. W. Dooley et al., Ann. Int. Med., 117, 257 (1992). Several investigators have associated the toxicity of INH for mycobacteria with endogenous catalase activity. See, for example, "Isonicotinic acid hydrazide," in F. E. Hahn, Mechanism of Action of Antibacterial Agents, SpringerVerlag (1979) at pages 98-119. This relationship was strengthened by a recent report by Ying Zhang and colleagues in Nature, 358, 591 (1992) which described the restoration of INH susceptibility in an INH resistant Mycobacterium smegmatis strain after
Patents 389
transformation using the catalase-peroxide (katG) gene from an INH sensitive M. tuberculosis strain. In a follow-up study, Zhang and colleagues in Molec. Microbiol., 8, 521 (1993) demonstrated the restoration of INH susceptibility in INH resistant M. tuberculosis strains after transformation by the functional katG gene. As reported by B. Heym et al., J. Bacteriol., 175, 4255 (1993), the katG gene encodes for a 80,000-dalton protein. Web site: http://www.delphion.com/details?pn=US05658733__ •
Detection of M. tuberculosis complex via reverse transcriptase SDA Inventor(s): Cave; Mac Donald (Little Rock, AR), DesJardin; Lucy Ellen (Little Rock, AR), Eisenach; Kathleen Davis (Little Rock, AR) Assignee(s): The Board of Trustees of the University of Arkansas (Little Rock, AR) Patent Number: 6,204,026 Date filed: November 5, 1997 Abstract: The present invention provides primers which can be used for M. tuberculosis complex-specific detection of.alpha.-antigen DNA in a diagnostic assay performed on clinical specimens or in a culture-confirmation assay following growth of the organism in vitro. These primers and probes can also be employed in a reverse transcriptasemediated amplification system for M. tuberculosis complex.alpha.-antigen mRNA. Such an assay provides a means by which to determine the viability of M. tuberculosis complex organisms either in clinical specimens or when grown in culture. Also described are methods for the detection of the products of amplification with a radiolabeled probe by chemiluminescent assay or fluorescence polarization analysis. Excerpt(s): This invention was produced in part using funds obtained through a grant from the National Institutes of Health. Consequently, the federal government has certain rights in this invention. The present invention relates generally to the field of clinical microbiology. Specifically, the present invention relates to the detection of viable organisms of the Mycobacterium tuberculosis complex using a reverse transcriptase polymerase chain reaction assay. The resurgence of tuberculosis in the United States over the past decade and its continued worldwide dominance as a cause of morbidity and mortality (Raviglione et al, 1995) have focused attention on the need for more rapid and reliable means of diagnosis. Traditionally, diagnosis is dependent upon acid-fast staining and culture of the causative agent, Mycobacterium tuberculosis (M. tuberculosis), in broth or on solid media. However, this process may require up to 6 weeks owing to the slow growth rate of the organism. In contrast, nucleic acid amplification assays have the potential to reduce the time for definitive diagnosis to as little as one day. Several assays have been described for the detection of nucleic acid sequences that are specific for the M. tuberculosis complex which comprises M. tuberculosis, M. bovis, M. bovis bacille Calmette-Guerin (BCG), M. africanum and M. microti (Eisenach et al, 1991; Iovannisci et al, 1993; Jonas et al, 1993; Shah et al, 1995; van der Vliet et al, 1993; Walker et al, 1992). Although beneficial to the initial diagnosis of infection, such assays have so far proven unsuitable for monitoring the response of patients to therapy. Web site: http://www.delphion.com/details?pn=US06204026__
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Diagnostic skin test for tuberculosis Inventor(s): Hasl.o slashed.v; Kaare (S.o slashed.borg, DK), Oettinger; Thomas (Hellerup, DK), Andersen;.ANG.se Bengaard (Br.o slashed.nsh.o slashed.j, DK) Assignee(s): Statens Seruminstitut (Copenhagen, DK) Patent Number: 6,120,776 Date filed: February 12, 1996 Abstract: Diagnostic methods capable of discriminating between cell mediated immunologic responses due to on the one hand active tuberculosis caused by bacteria belonging to the tuberculosis complex (Mycobacterium tuberculosis, Mycobacterium africanum and Mycobacterium bovis) and on the other hand vaccination with an immunogenic agent conferring immunity to tuberculosis. A diagnostic kit is also provided, comprising a polypeptide (e.g. MPT64) capable of eliciting a delayed type hypersensitivity reaction (Dth) in animals with active tuberculosis, but not in animals vaccinated against TB with an immunogenic agent (e.g. M. bovis BCG strain: Danish 1331). Also provided are polypeptide fragments comprising a T-cell epitope of MPT64 as well as nucleic acid fragments encoding these polypeptide fragments. Excerpt(s): The present invention relates to a kit comprising as one part of the kit a vaccine containing as the effective component an immunogenic agent (e.g. mycobacteria from the BCG strain: Danish 1331) capable of conferring substantially increased immunity to tuberculosis, and as the other part of the kit at least one diagnostic skin test comprising a pharmaceutical composition containing a polypeptide with which lymphoid cells previously primed with mycobacteria belonging to the tuberculosiscomplex are capable of reacting and with which lymphoid cells previously primed with the immunogenic agent are not capable of reacting, or a variant which is immunologically equivalent to the polypeptide, as well as a method of diagnosing tuberculosis caused by Mycobacterium tuberculosis, Mycobacterium africanum or Mycobacterium bovis in a person, comprising intradermally injecting, in the person, the skin test, a positive skin response at the location of injection being indicative of the person having or having had tuberculosis, and a negative skin response at the location of injection being indicative of the person not having or not having had tuberculosis, the polypeptide preferably being MPT64 or an immunologically equivalent variant, analogue or subsequence thereof. The invention further relates to a pharmaceutical composition comprising the polypeptide, a DNA fragment encoding a polypeptide which is an immunological equivalent to MPT64, the polypeptide which is an immunological equivalent to MPT64, as well as a method for vaccinating one or more persons in a population and subsequently subjecting the population to a diagnostic test for tuberculosis by the method described above. Tuberculosis remains a major world health problem. In fact, the incidence is increasing in both the so-called developing part of the world as well as in industrialized countries like the United States of America. Recently, tuberculosis was ranked by the World Health Organization as the most frequent cause of death ascribable to a single infectious agent (Memorandum from a WHO meeting: Tuberculosis control and research strategies for the 1990s. Bulletin of the World Health Organization 70:17-21, 1992). The means to effectively intervene transmission and thereby ultimately to get the disease under control are based on early diagnosis and treatment combined with vaccination of the populations at risk. The currently available anti-tuberculosis vaccine was developed in the beginning of this century by Calmette and Guerin and is often referred to as "the Bacille Calmette et Guerin (BCG)". The vaccine strain evolved after serial passages of a virulent isolate of M. bovis on a bile containing growth medium. The resultant strain appeared to be avirulent
Patents 391
for humans. The nature of the loss of virulence is still not clearly understood at the molecular level. However, the BCG vaccine is estimated to be the most widely used live vaccine in the world and the remarkable low number of serious complications observed as a consequence of the use of BCG clearly demonstrate that the strain is fully attenuated (Lotte et al., Adv. Tuberc. Res. 21, 107-193 (1984)). When the reports of the first successful vaccinations were published, several laboratories and vaccine producers around the world requested the strain from Calmette and Guerin and the strain was subcultured locally under conditions which varied from one laboratory to another. This is the historical background for the occurrence of several substrains of BCG. Modern BCG producers make use of freeze-lot systems which ensure that the genetic composition of the bacteria--the product--has been conserved. Despite the widely accepted use of the BCG vaccine in many countries some countries never introduced it for use in general population vaccination programmes. This is the case in e.g. USA and Belgium. One of the reasons for these countries to be reluctant is that vaccination with BCG interferes with the use of tuberculin skin testings for diagnosing tuberculosis and for use in population surveys. Web site: http://www.delphion.com/details?pn=US06120776__ •
DNA encoding stationary phase, stress response sigma factor from Mycobacterium tuberculosis Inventor(s): DeMaio; James (Tacoma, WA), Zhang; Ying (Baltimore, MD), Young; Douglas B. (London, GB), Bishai; William R. (Baltimore, MD) Assignee(s): The Johns Hopkins University (Baltimore, MD) Patent Number: 5,700,925 Date filed: March 27, 1996 Abstract: SigF is a gene that controls M. tuberculosis latency. A diagnostic test for latent tuberculosis involves detecting M. tuberculosis sigF in clinical specimens. A tuberculosis vaccine includes a M. tuberculosis strain with a mutation which disrupts the reading frame of its sigF gene. Excerpt(s): The present invention is directed to a gene involved in latency of infection and a diagnostic method for detecting latent M tuberculosis. The present invention is also directed to M. tuberculosis vaccines having mutant sigF genes. Tuberculosis is the leading cause of death due to infection, causing an estimated 2.5 million deaths and 7.5 million cases per year worldwide (1). In the United States, rates of tuberculosis began to increase in 1985 after 40 years of steady decline. In addition, a number of American cities are reporting high rates of infection by multiply drug resistant tuberculosis. Such mycobacteria cause a high mortality rate because available antibiotics are ineffective (2). About 90% of individuals who become infected with M. tuberculosis do not have immediate symptoms but develop a positive reaction to the tuberculin skin test and carry the bacteria in a dormant or latent state (3). Over a lifetime, these individuals have a 10% risk of developing reactivation tuberculosis in which, after years of quiescence, the tubercle bacilli resume growth and cause classic pulmonary tuberculosis as well as other forms of disease. One billion people, roughly one-third of the world's population, have latent tuberculosis (4). Individuals with latent tuberculosis currently require prolonged therapy because antimycobacterial drugs work poorly against dormant bacilli. Web site: http://www.delphion.com/details?pn=US05700925__
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DNA from mycobacterium tuberculosis which codes for a 45/47 kilodalton protein Inventor(s): Laqueyrerie; Anne (Paris, FR), Marchal; Gilles (Ivry Sur Seine, FR), Romain; Felix (Fontenay les Briis, FR), Pescher; Pascale (Paris, FR) Assignee(s): Institut Pasteur (Paris Cedex, FR) Patent Number: 5,714,593 Date filed: February 1, 1995 Abstract: Mycobacterium tuberculosis protein having a molecular weight of 28 779 Da, and hybrid proteins containing at least portions of its sequence. These proteins may in particular be used in vaccines or for the detection of specific tuberculosis antibodies. Excerpt(s): The object of the present invention is mycobacterial proteins and microorganisms producing them. It also relates to the use of these proteins in vaccines or for the detection of tuberculosis. At present, a definite diagnosis made by the demonstration of cultivatable bacilli in a sample taken from the patient is only obtained in less than half the cases of tuberculosis. Even for pulmonary tuberculosis, which represents 80 to 90% of the tuberculosis cases, and which is the form of the disease for which the detection of the bacilli is the easiest, the examination of expectorations is only positive for less than half the cases. Web site: http://www.delphion.com/details?pn=US05714593__
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DNA molecule conferring on Mycobacterium tuberculosis resistance against antimicrobial reactive oxygen and nitrogen intermediates Inventor(s): Ehrt; Sabine (Berkeley, CA), Riley; Lee W. (Berkeley, CA), Nathan; Carl F. (Larchmont, NY) Assignee(s): Cornell Research Foundation, Inc. (Ithaca, NY) Patent Number: 6,177,086 Date filed: April 28, 1998 Abstract: The present invention relates to a DNA molecule conferring on Mycobacterium tuberculosis resistance to antimicrobial reactive oxygen intermediates and reactive nitrogen intermediates. The protein encoded by this DNA molecule is useful in vaccines to prevent invention by Mycobacterium tuberculosis, while the antibodies raised against this protein can be employed in passively immunizing those already infected by the organism. Both these proteins and antibodies may be utilized in diagnostic assays to detect Mycobacterium tuberculosis in tissue or bodily fluids. The protein or polypeptide is also useful as a therapeutic in treating conditions mediated by the production of reactive oxygen intermediates and nitrogen intermediates. Excerpt(s): The present invention relates to a DNA molecule conferring on Mycobacterium tuberculosis resistance against antimicrobial reactive oxygen and nitrogen intermediates and its use in drugs, vaccines, and diagnostic tests. Tuberculosis is the leading cause of death in the world with an estimated 9 million new cases of tuberculosis and 2.9 million deaths occurring from the disease each year. In the United States, the steadily declining incidents of tuberculosis has been reversed since 1985. This problem is compounded by the increasing incidence of drug-resistant strains of Mycobacterium tuberculosis. Recent outbreaks of tuberculosis have involved settings in
Patents 393
which a large number of HIV-infected persons resided in close proximity (e.g., AIDS wards in hospitals, correctional facilities, and hospices). Transmission of tuberculosis to health care workers occurred in these outbreaks; 18 to 50% of such workers showed a conversion in their skin tests. See F. Laraque et. al., "Tuberculosis in HIV-Infected Patients," The AIDS Reader (September/October 1992), which is hereby incorporated by reference. Web site: http://www.delphion.com/details?pn=US06177086__ •
DNA molecule encoding for cellular uptake of Mycobacterium tuberculosis and uses thereof Inventor(s): Riley; Lee W. (Berkeley, CA) Assignee(s): Cornell Research Foundation, Inc. (Ithaca, NY) Patent Number: 6,072,048 Date filed: August 6, 1997 Abstract: The present invention relates to DNA molecules associated with conferring on Mycobacterium tuberculosis an ability to enter mammalian cells. The protein encoded by these DNA molecules are useful in vaccines to prevent infection by Mycobacterium tuberculosis, while the antibodies raised against this protein can be employed in passively immunizing those already infected by the organism. Both these proteins and antibodies may be utilized in diagnostic assays to detect Mycobacterium tuberculosis in tissue or bodily fluids. The protein of the present invention can be associated with various other therapeutic materials, for administration to mammals, particularly humans, to achieve uptake of those materials by such cells. Excerpt(s): The present invention relates to a DNA molecule encoding for uptake of Mycobacterium tuberculosis and its use in drugs, vaccines, and diagnostic tests. Tuberculosis is the leading cause of death in the world with an estimated 9 million new cases of tuberculosis and 2.9 million deaths occurring from the disease each year. In the United States, the steadily declining incidents of tuberculosis has been reversed since 1985. This problem is compounded by the increasing incidence of drug-resistant strains of Mycobacterium tuberculosis. Recent outbreaks of tuberculosis have involved settings in which a large number of HIV-infected persons resided in close proximity (e.g., AIDS wards in hospitals, correctional facilities, and hospices). Transmission of tuberculosis to health care workers occurred in these outbreaks; 18 to 50% of such workers showed a conversion in their skin tests. See F. Laraque et. al., "Tuberculosis in HIV-Infected Patients," The AIDS Reader (September/October 1992), which is hereby incorporated by reference. Web site: http://www.delphion.com/details?pn=US06072048__
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DNA sequences for strain analysis in Mycobacterium tuberculosis Inventor(s): Fraser; Claire Marie (Potomac, MD), Venter; John Craig (Potomac, MD), White; Owen Richardson (Rockville, MD), Fleischmann; Robert David (Gaithersburg, MD) Assignee(s): The Institute for Genomic Research (Rockville, MD) Patent Number: 6,294,328 Date filed: June 24, 1998 Abstract: The present invention is directed to novel methodology whereby different populations of the tuberculosis bacterial pathogen, Mycobacterium tuberculosis, or related Mycobacteria, can be genetically classified in relation to other isolates. Sites in the genome of Mycobacterium, which define previously unrecognized points of variability, are disclosed. The existence of this variability is of use to the clinician in order to consistently determine the identity of isolates of Mycobacterium responsible for individual cases of disease or disease outbreaks, thus suggesting appropriate choices for treatment protocols. Excerpt(s): The present invention is directed to novel methodology, and DNA sequence libraries that result therefrom, whereby different strains of the tuberculosis bacterial pathogen, Mycobacterium tuberculosis, can be definitively identified, based upon the identification of differences in their respective DNA sequences. The invention has valuable application in the fields of tuberculosis genetics, epidemiology, patient treatment, and epidemic monitoring. Although certain chemotherapy and vaccine protocols have become available for he treatment of tuberculosis, the disease continues to claim more lives per year than any other infectious disease (see S. Cole et al., Nature, 393, pp.537-544, 1998). In fact, despite the widespread availablity of health measures in the industrialized world, the incidence of tuberculosis has been spreading in both the industrialized and developing nations. This increased incidence is of particular concern in view of the emergence of novel drug-resistant strains, and the strong presence of the disease in HIV-afflicted patients. It has been the recognized understanding in the art (see S. Cole et al., and S. Sreevatsan et al., Proc. Natl. Acad. Sci, USA, 94, pp.9869-9874, 1997) that M. tuberculosis is a member of a complex of closely related species. The complex is understood to substantially lack interstrain genetic diversity, nucleotide changes being very rare. It has thus been the perception that both vaccine development and strain characterization would continue to be difficult, given that most proteins were expected to be identical between strains. Web site: http://www.delphion.com/details?pn=US06294328__
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Fusion proteins of Mycobacterium tuberculosis antigens and their uses Inventor(s): Skeiky; Yasir A. (Seattle, WA), Reed; Steven G. (Bellevue, WA), Dillon; Davin C. (Redmond, WA), Campos-Neto; Antonio (Bainbridge Island, WA), Alderson; Mark (Bainbridge Island, WA) Assignee(s): Corixa Corporation (Seattle, WA) Patent Number: 6,627,198 Date filed: April 7, 1999 Abstract: The present invention relates to fusion proteins containing at least two Mycobacterium tuberculosis antigens. In particular, it relates to bi-fusion proteins which
Patents 395
contain two individual M. tuberculosis antigens, tri-fusion proteins which contain three M. tuberculosis antigens, tetra-fusion proteins which contain four M. tuberculosis antigens, and penta-fusion proteins which contain five M. tuberculosis antigens, and methods for their use in the diagnosis, treatment and prevention of tuberculosis infection. Excerpt(s): The present invention relates to fusion proteins containing at least two Mycobacterium tuberculosis antigens. In particular, it relates to bi-fusion proteins which contain two individual M. tuberculosis antigens, tri-fusion proteins which contain three M. tuberculosis antigens, tetra-fusion proteins which contain four M. tuberculosis antigens, and penta-fusion proteins which contain five M. tuberculosis antigens, and methods for their use in the diagnosis, treatment and prevention of tuberculosis infection. Tuberculosis is a chronic infectious disease caused by infection with M. tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If untreated, serious complications and death typically result. Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance. Web site: http://www.delphion.com/details?pn=US06627198__ •
Glycolipids for serodiagnosis of tuberculosis and leprosy Inventor(s): Laszlo; Adalbert (Nepean, CA), Handzel; Vera (Nepean, CA), Vera-Cabrera; Lucio (Ottawa, CA) Assignee(s): Her Majesty the Queen in right of Canada, as represented by the Minister (Ottawa, CA) Patent Number: 5,597,735 Date filed: September 2, 1994 Abstract: A Dot-Blot assay ("spot test") with Bis-N,N,dioctadecylamide (BDA.TDA) as antigen was developed to detect anti-BDA.TDA antibodies in tuberculosis patients. To develop the antigen-antibody reaction, as a first step and in order to enhance the reaction, an anti-human rabbit serum was used followed by incubation with a protein A-colloidal gold conjugate. This assay showed almost equal sensitivity and specificity as the.beta.-galactosidase ELISA test which was conducted in parallel. This simple and fast assay could be used in places where ELISA equipment is not easily available. Excerpt(s): This invention relates to glycolipids useful for serodiagnosis of tuberculosis and leprosy and to serodiagnosis techniques using such glycolipids. More particularly, the invention relates to synthetic pseudo cord factor-like glycolipids useful for these purposes. Enzyme-linked immunosorbant assays (usually referred to as ELISA) and similar techniques (e.g. so-called "spot tests" which are a simplified form of ELISA test) for diagnosing diseases in human and animal patients have become very useful and popular in recent years because of their simplicity and their acceptable sensitivity and specificity. These techniques are based on the binding effects of antibodies and antigens.
396 Tuberculosis
In one form of the ELISA assay, for example, an antigen produced by a specific organism is used to test for the presence of antibodies for the antigen in the sera of patients, thus providing an indication that the patients have been exposed to these organisms. The antigen is immobilized on a solid support and incubated with the serum to be tested. If a target antibody is present in the serum, indicating exposure of the patient to the disease-causing organism, it binds to the layer of antigen. The number of antigen/antibody bound molecular pairs produced in this way depends on the concentration of the antibody in the serum until saturation of the antigens in the layer takes place. After washing the layer attached to the support, a solution of an enzymelinked antibody (e.g. goat-antihuman IgG) for the bound protein is contacted with the supported layer. After a second washing step, the layer is contacted with a solution of a substrate for the enzyme and the bound enzyme, if present, converts the substrate to a detectable product. In the so-called "spot tests", the microtiter plate usually used as a solid support for the antigen in the ELISA test is replaced by a strip of paper (cellulose nitrate, etc.). The strip is spotted with the antigen and for instance Protein A is used instead of the conjugate and a colloidal gold solution in place of the substrate. Web site: http://www.delphion.com/details?pn=US05597735__ •
Hybrid plasmid for 38 kDa antigen of M. tuberculosis Inventor(s): Singh; Mahavir (Braunschweig, DE), Timmis; Kenneth Nigel (Braunschweig, DE) Assignee(s): Gesellschaft fuer Biotechnologische Forschung mbH (GBF) (Braunschweig, DE) Patent Number: 6,110,469 Date filed: August 5, 1993 Abstract: The invention concerns a hybrid plasmid for the expression of unfused 38 kDa antigen of M. tuberculosis in E. coli, E. coli with the plasmid, an 38 kDa antigen and a protein of about 33 kDa useful for diagnoses. Excerpt(s): The invention relates to polypeptides and more particularly to the 38 kDa antigen of M. tuberculosis. Tuberculosis is a highly contagious human disease with over 3 million deaths and 8 million new cases occurring annually. The advent of AIDS is expected to worsen the situation because of reactivation of the dormant M. tuberculosis in immunocompromised individuals. The infectious dose in tuberculosis is exceedingly low, e. g. one to three tubercle bacilli are sufficient to initiate a primary lesion in the lung. The diagnosis of the infected individuals plays a vital role in the epidemiology and prevention and spread of the disease. Currently, diagnosis rests on the cultivation of M. tuberculosis from the sputum which takes about 6 weeks because of the slow growth rate of the organism. Another important part of the diagnosis is the `Tuberculin-test`. Tuberculin or the purified protein derivative (PPD) is a mixture of proteins from heat killed M. tuberculosis culture filtrate. This test suffers from high non-specificity due to cross-reactions in individuals infected with or vaccinated with other mycobacteria. Thus, there is an obvious need for developing defined and specific sero-diagnostic and skin-testing reagents for tuberculosis. Serological studies have shown that the 38 kDa antigen of M. tuberculosis contains immunodominant epitopes specific to the virulent strains of M. tuberculosis. This antigen is produced in minor quantities in the vaccine strain BCG which is an avirulent derivative of the bovine-tubercle bacillus M. bovis. Thus, on the basis of serology, this antigen can be used to distinguish between organisms of M. tuberculosis complex and other mycobacteria. Purification of the native
Patents 397
38 kDa antigen directly from M. tuberculosis is not practicable because of the low yields, slow growth rates and the virulent nature of the organism. Web site: http://www.delphion.com/details?pn=US06110469__ •
IS6110 based molecular detection of mycobacterium tuberculosis Inventor(s): Sandhu; Gurpreet S. (Rochester, MN), Kline; Bruce C. (Rochester, MN), Stockman; Leslie (Rochester, MN), Roberts; Glenn D. (Rochester, MN), Lewis; Marcia E. (Cohasset, MA) Assignee(s): Chiron Diagnostic Corporation (East Walpole, MA) Patent Number: 5,731,150 Date filed: November 1, 1995 Abstract: The detection of the IS6110 insertion element in a clinical specimen is a rapid way of diagnosing infection by Mycobacterium tuberculosis. A reliable diagnostic test for tuberculosis based on the IS6110 DNA is described in this disclosure. A "Universal" specimen preparation protocol that eliminates live organisms and purifies nucleic acids from all types of clinical specimens is described. Two nucleic acid primers designed to amplify IS6110 DNA with high specificity in a polymerase chain reaction are also described. The amplified IS6110 DNA is identified by a restriction endonuclease and electrophoresis based assay. The identification process also renders the DNA unamplifiable in a subsequent PCR, thereby reducing the possibility of contaminating other specimens. Time, labor and cost is minimized, while user safety and test reliability are maximized. The complete DNA extraction, amplification and analysis is accomplished with ease within an 8 hour period, with a sensitivity of 92% and a specificity approaching 100%. Testing of serially obtained samples from the same patient increases the overall rate of detection to 100%. Excerpt(s): The inventions described and claimed herein relate to the design and composition of an assay to determine infection due to Mycobacterium tuberculosis by detecting the M. tuberculosis insertion element IS6110 in any clinical specimen. The inventions described and claimed herein also relate to the design and composition of a "Universal" method of extracting nucleic acids from all types of clinical specimens. The inventions described and claimed herein also relate to the design and composition of two nucleic acid primers capable of specifically amplifying a portion of IS6110 in a polymerase chain reaction, and a restriction endonuclease and electrophoresis based test for identifying the amplified IS6110 DNA. Mycobacterium tuberculosis is expected to kill 3 million people in 1995 (Dolin et al.), making tuberculosis the world's number one cause of death due to an infectious agent. The number of new people getting infected each year is on the rise and is currently estimated at 8.8 million. An increase in HIV infection, and changing global migration and travel patterns have led to a resurgence of this disease in the industrialized nations. Tuberculosis is caused by infection due to M. tuberculosis, with a few cases being caused by M. bovis. Several dozen species of Mycobacteria are known, and most are non-pathogenic for humans. Early tuberculosis often goes unrecognized in an otherwise healthy individual. Classical initial methods of diagnosis include examination of a sputum smear under a microscope for acid-fast mycobacteria and an x-ray of the lungs. However, in a vast majority of cases the sputum smear examination is negative for Mycobacteria in the early stages of the disease, and lung changes may not be obvious on an x-ray until several months following infection. Another complicating factor is that acid-fast bacteria in a sputum smear may often be other species of mycobacteria.
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Web site: http://www.delphion.com/details?pn=US05731150__ •
M. tuberculosis RNA polymerase alpha subunit Inventor(s): Lam; Kelvin T. (Belmont, MA), Healy; Judith M. (Lexington, MA), Bodorova; Jana (Rockville, MA), Lesoon; Andrea J. (Cambridge, MA) Assignee(s): Anadys Pharmaceuticals, Inc. (Waltham, MA) Patent Number: 6,355,464 Date filed: January 26, 1999 Abstract: The present invention provides isolated nucleic acids encoding RNA polymerase alpha subunit from M. tuberculosis, vectors comprising the nucleic acids, cells comprising the vectors, and methods for producing M. tuberculosis alpha subunit. The invention also provides in vitro and in vivo methods for high-throughput screening to identify inhibitors of M. tuberculosis RNA polymerase. Excerpt(s): The present invention relates to novel nucleic acids encoding RNA polymerase alpha subunit from M. tuberculosis and methods for use thereof. The intracellular pathogen Mycobacterium tuberculosis is the causative agent of tuberculosis in humans and is responsible for millions of deaths worldwide each year (Bloom et al. Science 257:1055, 1992). The emergence of multidrug resistant forms of tuberculosis has mandated the development of new antibiotics effective against refractory M. tuberculosis strains. Novel drugs which, like rifampin (Vall-Spinosa et al., N. Eng. J. Med. 283: 616, 1970), may be capable of inhibiting the prokaryotic transciptional machinery, could contribute significantly to the development of therapies to combat M. tuberculosis. The RNA polymerase of eubacteria consists of four subunits (.alpha.,.beta.,.beta.', and.sigma.) and exists in two major forms: core enzyme (.alpha.sub.2,.beta.,.beta.') and holoenzyme (.alpha.sub.2,.beta.,.beta.' plus one of several.sigma. subunits) (Chamberlin, in RNA Polymerase, Losick et al., eds., Cold Spring Harbor, 1976, pp. 17-67). The.alpha. subunit contains determinants for proteinprotein interactions with transcription activators and protein-DNA interaction with upstream elements (Ishihama, Mol.Microbiol. 6:3283, 1992; Russo et al., J. Biol.Chem. 267:14515, 1992; Ebright et al., Curr.Opin.Genet.Dev. 5:197, 1995). The amino terminal domain of.alpha. is also required for assembly of the multisubunit core RNA polymerase (Ishihama, Adv. Biophys. 14:1, 1981). The.beta. subunit is essential for transcript initiation and elongation, which.beta.' apparently functions in binding of the core enzyme to template DNA (Yura et al., Ann.Rev.Genet. 13:59, 1979). Core RNA polymerase is capable of RNA synthesis; however,.sigma. is required for specific initiation of transcripts at promoter sequences (Gross et al., in Transcriptional Regulation, Cold Spring Harbor, 1992, pp. 129-176). Web site: http://www.delphion.com/details?pn=US06355464__
Patents 399
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Materials and methods for the detection of mycobacterium tuberculosis Inventor(s): Manlove; Matthew T. (Vernon Hills, IL), Solomon; Natalie A. (Buffalo Grove, IL), Semple-Facey; Ingrid E. (Beach Park, IL), Davis; Alan H. (Vernon Hills, IL), Leckie; Gregor W. (Highland Park, IL) Assignee(s): Abbott Laboratories (Abbott Park, IL) Patent Number: 5,786,149 Date filed: December 23, 1996 Abstract: The present invention is directed to oligonucleotides useful in detection, e.g., by ligase chain reaction (LCR) of target DNA from Mycobacterium tuberculosis. The present invention is also directed to methods of detecting target DNAs from Mycobacterium tuberculosis. Excerpt(s): The invention relates to oligonucleotides useful in detecting M. tuberculosis. This invention also relates to methods useful in amplifying and/or detecting M. tuberculosis. After decades of decline in the incidence of tuberculosis, an alarming increase in new cases is occurring. Infection with M. tuberculosis, the causative agent of tuberculosis, most commonly occurs by inhalation of droplets containing only a few live bacilli. The mycobacteria replicate in lung tissue to form a primary focus of infection and from there enter the local lymphatic system. The infection then disseminates widely through the body via the blood and lymphatic system. The initial lesions usually heal to form tiny granulomas that may harbor viable tubercle bacilli indefinitely. Post-primary tuberculosis is the most common form of clinical tuberculosis and is usually pulmonary. The disease can occur many years after initial infection and is thought to be due to a temporary loss or diminishing of cell-mediated immunity (due to, for example, increasing age, illness, malnutrition, or alcoholism) leading to reactivation of dormant tubercle bacilli in lesions. Acquired Immunodeficiency Syndrome (AIDS), increased poverty and its attendant malnutrition are now important factors leading to the increased incidence of the disease. A tentative diagnosis of tuberculosis or other mycobacterial diseases may be made on a basis of clinical grounds, radiology, and on the finding of acid-fast bacilli in smears of sputum, blood bronchial-lavage, gastricwashing, urine, or cerebral spinal fluid. Smears of these specimens typically are stained by the Ziehl-Neelsen technique or by fluorescent rhodamine-auramine dye and examined by microscopy. However, microscopically positive sputum samples are found in only about 30 to 50 percent of pulmonary tuberculosis patients and thus, cultures must always be performed. Culturing for the presence of M. tuberculosis and other mycobacterial species is a time-consuming and difficult process because some mycobacterial species are very slow-growing and have fastidious nutritional requirements. While some samples may be inoculated directly onto culture medium, most specimens require decontamination with, for example, strong alkali. Specimens are then typically inoculated onto egg-based media such as Lowenstein-Jensen medium and/or defined media such as Middlebrook 7H9 broth in the presence of antibiotics such as penicillin to inhibit growth of other bacteria. Cultures are then incubated at 35.degree. C. to 37.degree. C. for 1-7 weeks. However, even culture techniques are only about 70% effective. Web site: http://www.delphion.com/details?pn=US05786149__
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Method and a tobramycin aerosol formulation for treatment prevention and containment of tuberculosis Inventor(s): Montgomery; Alan Bruce (Bellevue, WA) Assignee(s): Pathogenesis, Corp. (Seattle, WA) Patent Number: 6,083,922 Date filed: April 2, 1997 Abstract: A method for treatment, prevention and containment of acute and chronic tuberculosis using a preservative-free concentrated tobramycin aerosol formulation delivering tobramycin to the lung endobronchial space including alveoli in an aerosol having mass medium average diameter predominantly between 1 to 5.mu. The method comprises administration of tobramycin in concentration one to ten thousand times higher than the minimal inhibitory concentration of Mycobacterium tuberculosis. A method for containment of and decreasing infectivity periods of tuberculosis patients to shorter periods of time. Excerpt(s): The current invention concerns a method for treatment, prevention and containment of tuberculosis using a tobramycin aerosol formulation. In particular, the invention concerns a preservative-free formulation containing concentrated tobramycin dissolved in full strength or diluted saline adjusted to pH between 5.5 and 7.0. The tobramycin aerosol formulation delivers tobramycin to the lung endobronchial space of airways including alveoli in an aerosol having mass medium average diameter predominantly between 1 to 5.mu. The method for treatment and prophylaxis of acute and chronic tuberculosis caused by the Mycobacterium tuberculosis comprises administration of tobramycin in concentration one to ten thousand times higher than the minimal inhibitory concentration of Mycobacterium tuberculosis. The invention additionally provides a method for containment of infectivity of tuberculosis patients to shorter periods of time. Mycobacterium tuberculosis or Tuberculum bacilli (T. B.) grows in the endobronchial space and is found in the sputum of infected individuals. During exacerbations of infection, such growth also occurs in the alveoli. Tuberculosis is a highly infectious disease that is characterized by the inflammation and progressive destruction of lung tissue. The debilitation of the lungs in patients with tuberculosis is associated with accumulation of purulent sputum produced as a result of chronic endobronchial infections caused by Mycobacterium tuberculosis. Nearly all individuals suffering from tuberculosis eventually die of respiratory failure. Web site: http://www.delphion.com/details?pn=US06083922__
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Method for treating Mycobacterium tuberculosis Inventor(s): Grandoni; Jerry (Haddonfield, NJ) Assignee(s): University of Medicine & Dentistry of New Jersey (Newark, NJ) Patent Number: 5,998,420 Date filed: April 8, 1996 Abstract: The present invention is directed to a method for treating tuberculosis in a mammal which comprises administering to the mammal a therapeutically effective amount of an inhibitor compound that inhibits an enzyme in the branched chain amino acid biosynthetic pathway in Mycobacterium tuberculosis.
Patents 401
Excerpt(s): The present invention is directed to a method for treating tuberculosis in a mammal which comprises administering to the mammal a therapeutically effective amount of an inhibitor compound that inhibits an enzyme in the branched chain amino acid biosynthetic pathway in Mycobacterium tuberculosis. The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are referenced in the following text and respectively grouped in the appended bibliography. Tuberculosis (TB) kills 2.5 million people annually and the World Health Organization estimated that, at the current rate of increase, there will be 4 million tuberculosis deaths worldwide per year by the year 2005 (Bloom and Murray, 1992). In addition, the percentage of clinical tuberculosis isolates that are resistant to the first-line drugs isoniazid and rifampicin has increased substantially (Collins, 1993; Jacobs, 1994). Outbreaks of drug-resistance tuberculosis have occurred in correctional facilities, hospitals, and urban areas in the United States. Most of the drug-resistant tuberculosis has occurred in patients who are co-infected with HIV and the mortality rate associated with these infections is as high as 90% (Collins, 1993; Dunlap and Kimerling, 1994). The rise in tuberculosis cases in the United States is also attributed to an increase in immigration from areas of the world in which tuberculosis infection rates are high (Dunlap and Kimerling, 1994; Hutchins and Hershfield, 1993). A major part of the strategy to overcome the worldwide tuberculosis problem will be the development of new therapeutic agents to treat this disease (Collins, 1993). Web site: http://www.delphion.com/details?pn=US05998420__ •
Method of identification of animals resistant or susceptible to disease such as ruminant brucellosis, tuberculosis, paratuberculosis and salmonellosis Inventor(s): Adams; L. Garry (College Station, TX), Smith, III; Roger (College Station, TX), Feng; Jianwei (College Station, TX), Schurr; Erwin (Montreal, CA), Gros; Philippe (Montreal, CA), Davis; Donald S. (College Station, TX), Templeton; Joe W. (College Station, TX) Assignee(s): McGill University (Montreal, CA), Texas A&M University System (College Station, TX) Patent Number: 6,114,118 Date filed: July 30, 1997 Abstract: The present invention relates to materials and methods for identifying animals that are resistant or susceptible to diseases associated with intracellular parasites such as brucellosis, tuberculosis, paratuberculosis and salmonellosis. More particularly, the present invention relates to the identification of a gene, called NRAMP1, which is associated with the susceptibility or resistance of an animal, such as an artiodactyla to diseases such as brucellosis, tuberculosis, paratuberculosis and salmonellosis. Still more particularly, the present invention relates to the identification of specific sequences of bovine NRAMP1 which associate with resistance or susceptibility to ruminant brucellosis, tuberculosis, paratuberculosis and salmonellosis, and to the method of identifying said sequences to identify animals who are susceptible or resistant to disease. Excerpt(s): The present invention relates to a method for identifying animals that are resistant or susceptible to diseases associated with intracellular parasites. More particularly, the present invention relates to the identification of a gene, called NRAMP1, associated with the susceptibility or resistance of an animal, such as an
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artiodactyla, to diseases such as brucellosis, tuberculosis, paratuberculosis and salmonellosis. Still more particularly, the present invention relates to the identification of specific sequences of the 3' untranslated region (3' UTR) of bovine NRAMP1 which associate with resistance or susceptibility to bovine brucellosis, tuberculosis, paratuberculosis and salmonellosis, and to the use of the general sequence patterns to identify artiodactyl animals containing those sequences in situ, allowing therefore the identification of animals predicted to be either resistant or susceptible to diseases associated with intracellular parasites. Intracellular zoonotic bacterial diseases like brucellosis and tuberculosis cause significant losses in livestock industries despite widespread application of antimicrobials, vaccination, isolation and quarantine, test and slaughter, or a combination of these. The lack of success in eradicating infectious diseases of animals using these approaches indicates a need for a different strategy, such as the development of a means to identify genetic sequences associated with resistance and/or susceptibility, where such means could allow the identification of animals that are resistant or susceptible to disease. This could then allow the treatment, prophylactic or therapeutic, or elimination of susceptible animals, and the use of and/or selective breeding of resistant animals (see, for example, Templeton et al. 1988). Diseases such as ruminant brucellosis, tuberculosis, paratuberculosis and salmonellosis cause an estimated $250,000,000 loss annually to the U.S.A. beef and dairy industry. Further, tuberculosis especially is a health threat to all ungulates including rare and endangered mammals. These are diseases for which the usual eradication programs have been longterm, expensive, and somewhat unsuccessful. For example, bovine tuberculosis was thought to be a disease of antiquity in 1970 but has re-emerged as an endemic disease in the El Paso, Tex. dairy herds. Outbreaks of bovine tuberculosis have been reported in the past 5 years in California, Idaho, Indiana, Louisiana, Missouri, Montana, Nebraska, New Mexico, New York, North Carolina, Pennsylvania, South Carolina, Texas, Wisconsin, and Virginia (Essey and Koller 1994; and Essey M. A. 1991). Web site: http://www.delphion.com/details?pn=US06114118__ •
Method of identifying compounds that regulate the binding of M. tuberculosis sigF to M. tuberculosis orfX Inventor(s): DeMaio; James (Tacoma, WA), Zhang; Ying (Baltimore, MD), Young; Douglas B. (London, GB), Bishai; William R. (Baltimore, MD) Assignee(s): Johns Hopkins University (Baltimore, MD) Patent Number: 6,004,764 Date filed: April 9, 1997 Abstract: sigF is a gene that controls M. tuberculosis latency. A diagnostic test for latent tuberculosis involves detecting M. tuberculosis sigF in clinical specimens. Two genes orfX and orfY regulate sigF expression and sigF activity. M. tuberculosis sigF, orfX, and orfY are used in screening methods for potential therapeutic agents which regulate the growth of M. tuberculosis. Excerpt(s): The present invention is directed to a gene involved in latency of infection, a diagnostic method for detecting latent M. tuberculosis, and methods for developing therapeutics for treating active and latent M. tuberculosis. The present invention is also directed to screening methods to identify agents that affect expression of a M. tuberculosis sigF gene or activity of a M. tuberculosis sigF protein. Tuberculosis is the leading cause of death due to infection, causing an estimated 2.5 million deaths and 7.5 million cases per year worldwide (1). In the United States, rates of tuberculosis began to
Patents 403
increase in 1985 after 40 years of steady decline. In addition, a number of American cities are reporting high rates of infection by multiply drug resistant tuberculosis. Such mycobacteria cause a high mortality rate because available antibiotics are ineffective (2). About 90% of individuals who become infected with M. tuberculosis do not have immediate symptoms but develop a positive reaction to the tuberculin skin test and carry the bacteria in a dormant or latent state (3). Over a lifetime, these individuals have a 10% risk of developing reactivation tuberculosis in which, after years of quiescence, the tubercle bacilli resume growth and cause classic pulmonary tuberculosis as well as other forms of disease. One billion people, roughly one-third of the world's population, have latent tuberculosis (4). Individuals with latent tuberculosis currently require prolonged therapy because antimycobacterial drugs work poorly against dormant bacilli. Web site: http://www.delphion.com/details?pn=US06004764__ •
Method of treatment of tuberculosis Inventor(s): Lim; Helong (662 Union St., Vancouver, British Columbia, CA) Assignee(s): none reported Patent Number: 4,259,322 Date filed: March 20, 1978 Abstract: A tuberculosis medication using approximately 10 grams of calcium gluconate combined with approximately 4 grams of sodium iodine in a vehicle of water to a volume of 100 ccs can be used for intramuscular or intravenous injections at a rate of 5 or 10 ccs per injection to relieve and treat tuberculosis. Excerpt(s): I have invented a new and novel tuberculosis medication. My improved medication can treat tuberculosis of the pulmonary system glandular system bones and the intestines. Further, this improved medication is of particular value in its ability to kill the tubercle baccillus directly and to dissolve caseation of the focus, thereby producing a radical treatment with no side effects in the patients. The medication has been used at various treatment rates and at various times during research done over several years and has established a successful cure record. Prior art references known at the time of preparation of this application include the following U.S. Pat. Nos. 1,903,614, 1,889,195, 1,435,335, 87,603, 308,596, and 112,329. My improved tuberculosis medication utilizes a portion of calcium gluconate combined with a portion of sodium iodine by mixing to which distilled water is added to form a product a portion of which is used for the individual treatments by injection either intravenously or intramuscularly. Web site: http://www.delphion.com/details?pn=US04259322__
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Molecular differences between species of the M. tuberculosis complex Inventor(s): Wilson; Michael A. (Stanford, CA), Small; Peter (Stanford, CA), Behr; Marcel (Montreal, CA), Schoolnik; Gary (Stanford, CA) Assignee(s): The Board of Trustees of the Leland Stanford Junior University (Palo Alto, CA) Patent Number: 6,291,190 Date filed: May 25, 1999
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Abstract: Specific genetic deletions are identified in mycobacteria isolates, including variations in the M. tuberculosis genome sequence between isolates, and numerous deletion present in BCG as compared to M. tb. These deletions are used as markers to distinguish between pathogenic and avirulent strains, and as a marker for particular M. tb isolates. Deletions specific to vaccine strains of BCG are useful in determining whether a positive tuberculin skin test is indicative of actual tuberculosis infection. The deleted sequences may be re-introduced into BCG to improve the efficacy of vaccination. Alternatively, the genetic sequence that corresponds to the deletion(s) are deleted from M. bovis or M. tuberculosis to attenuate the pathogenic bacteria. Excerpt(s): Tuberculosis is an ancient human scourge that continues to be an important public health problem worldwide. It is an ongoing epidemic of staggering proportions. Approximately one in every three people in the world is infected with Mycobacterium tuberculosis, and has a 10% lifetime risk of progressing from infection to clinical disease. Although tuberculosis can be treated, an estimated 2.9 million people died from the disease last year. There are significant problems with a reliance on drug treatment to control active M. tuberculosis infections. Most of the regions having high infection rates are less developed countries, which suffer from a lack of easily accessible health services, diagnostic facilities and suitable antibiotics against M. tuberculosis. Even where these are available, patient compliance is often poor because of the lengthy regimen required for complete treatment, and multidrug-resistant strains are increasingly common. Prevention of infection would circumvent the problems of treatment, and so vaccination against tuberculosis is widely performed in endemic regions. Around 100 million people a year are vaccinated with live bacillus CalmetteGuerin (BCG) vaccine. BCG has the great advantage of being inexpensive and easily administered under less than optimal circumstances, with few adverse reactions. Unfortunately, the vaccine is widely variable in its efficacy, providing anywhere from 0 to 80% protection against infection with M. tuberculosis. Web site: http://www.delphion.com/details?pn=US06291190__ •
Monoclonal antibodies to mycobacterium tuberculosis and a modified ELISA assay Inventor(s): Casadevall; Arturo (Pelham, NY), Glatman-Freedman; Aharona (Irvington, NY) Assignee(s): Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) Patent Number: 6,545,130 Date filed: June 4, 1997 Abstract: The present invention provides for monoclonal antibodies, the hybridoma cell lines which produce these antibodies, and the use of such monoclonal antibodies in the detection of M. tuberculosis. More specifically, the present invention provides for monoclonal antibodies that react with surface epitopes of M. tuberculosis and the use of these monoclonal antibodies for detecting and diagnosing M. tuberculosis. Also provided by the present invention is a modified ELISA assay for detection of microorganisms, and a modified ELISA assay employing the monoclonal antibodies of the present invention for detecting M. tuberculosis. Excerpt(s): Tuberculosis continues to be a major worldwide health problem and is responsible for most incidences of death by an infectious agent. The worldwide incidence of tuberculosis was estimated by the World Health Organization to be 8.8 million in 1995, with a mortality estimate of 3.0 million persons, and is expected to rise
Patents 405
to 10.2 million by the year 2000 (Dolin, et al., Bull. WHO. 72: 213-220 (1994)). The tuberculosis problem has been compounded by the development of the AIDS epidemic and the growing number of HIV-related cases of tuberculosis (Dolin, et al., Bull. WHO. 72: 213-220 (1994)). As the incidence of tuberculosis increases, major problems also develop concerning this disease. For example, the lack of a sensitive and rapid laboratory method of diagnosing tuberculosis makes it difficult to differentiate between M. tuberculosis and M. avium-intracellulare, both of which are frequently present in HIV infected patients. Multiple methods of detection of M. tuberculosis employing polyclonal and monoclonal antibodies have been described (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Friedman, et al., Am. Rev. Respir. Dis. 140: 668-671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901904(1986); Mason, et al., Tubercle Lung Dis. 74:195-199(1993); Papa, et al., Res. Microbiol. 143: 327-331 (1992); Sada, et al., Lancet 2 651-652 (1983); Schoningh, et al., J. Clin. Microbiol. 28: 708-713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991) Watt, et al., J Infect Dis. 158:681-686 (1988); Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., Clin. Microbiol. 23: 822-825 (1986)), but none have acquired a widespread role in the diagnosis of tuberculosis as these antibodies crossreact with other mycobacterial strains (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Friedman, et al., Am. Rev. Respir. Dis. 140: 668-671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901-904 (1986); Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., J. Clin. Microbiol. 23: 822-825 (1986)). In addition, in order to obtain significant results, a large amount of mycobacteria or mycobacterial antigen is required (Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Mason, et al., Tubercle Lung Dis. 74:195-199 (1993); Papa, et al., Res. Microbiol. 143: 327-331 (1992); Schoningh, et al., J. Clin. Microbiol. 28: 708-713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991)). Improvements in antibody-based diagnostic tests for the detection of M. tuberculosis would require specific antibody reagents with high affinity for mycobacterial antigens. Several monoclonal antibodies have been generated against surface components of M. tuberculosis (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Mauch, et al., J. Clin. Microbiol. 26:1691-1694 (1988)) but they are often cross reactive with other strains or cytoplasmic fractions (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Mauch, et al., J. Clin. Microbiol. 26:1691-1694 (1988)). There is thus a need for a monoclonal antibody that selectively binds to M. tuberculosis and does not cross react with other strains of mycobacteria. An additional problem concerns the protocol used for detecting M. tuberculosis. The protocols described thus far for detecting mycobacteria, such as direct ELISA (Mason, et al., Tubercle Lung Dis. 74:195-199 (1993); Schoningh, et al., J. Clin. Microbiol. 28: 708-713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991)), capture ELISA (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Friedman, et al., Am. Rev. Respir. Dis. 140: 668-671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901-904 (1986); Rattan, et al., Tubercle Lung Dis. 74: 200-203 (1993); Sada, et al., Lancet 2 651-652 (1983); Watt, et al., J Infect Dis. 158:681-686 (1988); Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., J. Clin. Microbiol. 23: 822825 (1986)) and DOT ELISA (Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Papa, et al., Res. Microbiol. 143: 327-331 (1992)), are deficient in many areas. For example, none of the methods listed above allow for visualization of single captured microorganisms. Furthermore, many of these methods require the use of polyclonal immunoglobulins which have the potential disadvantages of lot to lot variation, reliance on animal sources and unwanted cross-reactivities. Accordingly, there is an outstanding need for a method of detecting M. tuberculosis which eliminates the problems existing in current methods of detection.
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Web site: http://www.delphion.com/details?pn=US06545130__ •
Mutations in the katG gene useful for detection of M. tuberculosis Inventor(s): Uhl; James R. (Rochester, MN), Cockerill, III; Franklin R. (Rochester, MN), Kline; Bruce C. (Rochester, MN) Assignee(s): Mayo Foundation for Medical Education & Research (Rochester, MN) Patent Number: 5,922,575 Date filed: May 7, 1997 Abstract: A method for selectively detecting M. tuberculosis is provided employing restriction fragment length polymorphism analysis of an enzymatic digest of the M. tuberculosis katG gene. Excerpt(s): Despite more than a century of research since the discovery of Mycobacterium tuberculosis, the aetiological agent of tuberculosis, this disease remains one of the major causes of human morbidity and mortality. There are an estimated 3 million deaths annually attributable to tuberculosis (sec, D. Snider, Rev. Inf. Dis., S335 (1989)), and although the majority of these are in developing countries, the disease is assuming renewed importance in the W. due to the increasing number of homeless people and the impact the AIDS epidemic (see, R. E. Chaisson et al., Am. Res. Resp. Dis., 23, 56 (1987); D. E. Snider, Jr. et al., New Engl. J. Med, 326, 703 (1992); M. A. Fischl et al., Ann. Int. Med., 117, 177 (1992) and ibid. at 184. Isonicotinic acid hydrazide or isoniazid (INH) has been used in the treatment of tuberculosis for the last forty years due to its exquisite potency against the members of the "tuberculosis" groups--Mycobacterium tuberculosis, M. bovis and M. africanum (G. Middlebrook, Am. Rev. Tuberc., 69, 471(1952) and J. Youatt, Am. Rev. Resp. Dis., 99, 729 (1969)). Neither the precise target of the drug, nor its made of action are known, but INH treatment results in the perturbation of several metabolic pathways of the bacterium. However, shortly after its introduction, INH-resistant isolates of Mycobacterium tuberculosis emerged. See M. L. Pearson et al., Ann. Int. Med., 117, 191(1992) and S. W. Dooley et al., Ann. Int. Med., 117, 257 (1992). Several investigators have associated the toxicity of INH for mycobacteria with endogenous catalase activity. See, for example, "Isonicotinic acid hydrazide," in F. E. Hahn, Mechanism of Action of Antibacterial Agents, Springer-Verlag (1979) at pages 98-119. This relationship was strengthened by a recent report by Ying Zhang and colleagues in Nature, 358, 591 (1992) which described the restoration of INH susceptibility in an INH resistant Mycobacterium smegmatis strain after transformation using the catalase-peroxide (katG) gene from an INH sensitive M. tuberculosis strain. In a follow-up study, Zhang and colleagues in Molec. Microbiol., 8, 521 (1993) demonstrated the restoration of INH susceptibility in INH resistant M. tuberculosis strains after transformation by the functional katG gene. As reported by B. Heym et al., J. Bacieriol., 175, 4255 (1993), the katG gene encodes for a 80,000-dalton protein. Web site: http://www.delphion.com/details?pn=US05922575__
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Mycobacterial proteins, microorganisms producing them and their use for vaccines and for the detection of tuberculosis Inventor(s): Pescher; Pascale (Paris, FR), Laqueyrerie; Anne (Paris, FR), Romain; Felix (Fontenay les Briis, FR), Marchal; Gilles (Ivry sur Seine, FR) Assignee(s): Institut Pasteur (Paris, FR) Patent Number: 6,335,181 Date filed: June 21, 2000 Abstract: Mycobacterium tuberculosis protein having a molecular weight of 28.779 Da, and hybrid proteins containing at least portions of its sequence.These proteins may in particular be used in vaccines or for the detection of specific tuberculosis antibodies. Excerpt(s): The object of the present invention is mycobacterial proteins and microorganisms producing them. It also relates to the use of these proteins in vaccines or for the detection of tuberculosis. At present, a definite diagnosis made by the demonstration of cultivatable bacilli in a sample taken from the patient is only obtained in less than half the cases of tuberculosis. Even for pulmonary tuberculosis, which represents 80 to 90% of the tuberculosis cases, and which is the form of the disease for which the detection of the bacilli is the easiest, the examination of expectorations is only positive for less than half the cases. Web site: http://www.delphion.com/details?pn=US06335181__
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Mycobacterium tuberculosis DNA sequences encoding immunostimulatory peptides Inventor(s): Nano; Francis E. (Victoria, CA) Assignee(s): University of Victoria Innovation and Development Corp. (Victoria, CA) Patent Number: 6,228,371 Date filed: December 15, 1997 Abstract: Nucleotide sequences isolated from Mycobacterium tuberculosis are disclosed. These sequences are shown to encode immunostimulatory peptides. The invention encompasses, among other things, vaccine preparations formulated using these peptides. Excerpt(s): Over the past few years the editors of the Morbidity and Mortality Weekly Report have chronicled the unexpected rise in tuberculosis cases. It has been estimated that worldwide there are one billion people infected with M. tuberculosis, with 7.5 million active cases of tuberculosis. Even in the United States, tuberculosis continues to be a major problem especially among the homeless, Native Americans, AfricanAmericans, immigrants, and the elderly. HIV-infected individuals represent the newest group to be affected by tuberculosis. Of the 88 million new cases of tuberculosis expected in this decade approximately 10% will be attributable to HIV infection. The emergence of multi-dug resistant strains of M. tuberculosis has complicated matters further and even raises the possibility of a new tuberculosis epidemic. In the U.S. about 14% of M. tuberculosis isolates are resistant to at least one drug, and approximately 3% are resistant to at least two drugs. M. tuberculosis strains have even been isolated that are resistant to all seven drugs in the repertoire of drugs commonly used to combat tuberculosis. Resistant strains make treatment of tuberculosis extremely difficult: for example, infection with M. tuberculosis strains resistant to isoniazid and rifampin leads to mortality rates of approximately 90% among HIV-infected individuals. The mean
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time to death after diagnosis in this population is 4-16 weeks. One study reported that of nine immunocompetent health care workers and prison guards infected with drug resistant M. tuberculosis, five died. The expected mortality rate for infection with drug sensitive M. tuberculosis is 0%. The unrelenting persistence of mycobacterial disease worldwide, the emergence of a new, highly susceptible population, and the recent appearance of drug resistant strains point to the need for new and better prophylactic and therapeutic treatments of mycobacterial diseases. Web site: http://www.delphion.com/details?pn=US06228371__ •
Mycobacterium tuberculosis specific DNA fragment Inventor(s): Srivastava; Brahm Shanker (Lucknow-1, IN), Kumar; Deepak (Lucknow-1, IN), Srivastava; Ranjana (Lucknow-1, IN) Assignee(s): Council of Scientific and Industrial Research (New Delhi, IN) Patent Number: 6,242,585 Date filed: September 18, 1998 Abstract: This invention relates to a Mycobacterium tuberculosis specific DNA fragment containing IS like and repetitive sequences, a method of production of such DNA fragment and the use of such DNA fragment, for example, to rapidly diagnose Mycobacterium tuberculosis infection in clinical samples, and to identify clinical isolates of Mycobacterium tuberculosis. The DNA fragment may be used to determine information about the epidemiology of Mycobacterium tuberculosis infection. Excerpt(s): This invention relates to a Mycobacterium tuberculosis specific DNA fragment containing IS like and repetitive sequences, a method of production of such DNA fragment and the use of such DNA fragment, for example, to rapidly diagnose Mycobacterium tuberculosis infection in clinical samples, and to identify clinical isolates of Mycobacterium tuberculosis. The DNA fragment may be used to determine information about the epidemiology of Mycobacterium tuberculosis infection. Specifically this invention relates to the use of sequence specific DNA fragments to diagnose Mycobacterium tuberculosis and strains of Mycobacterium tuberculosis. A purpose of the study of the epidemiology of tuberculosis is to distinguish the genetic diversity of the causative agent Mycobacterium tuberculosis and to obtain information about strain to strain variability. This can be achieved by molecular epidemiological methods including DNA fingerprinting and restriction fragment length polymorphism (RFLP) analysis. Such approaches, can aid the investigation of point source outbreaks, transmission, pathogenesis and may be employed as a marker of strain typing. Tuberculosis (TB) is a major cause of infectious mortality. According to a recent WHO report, the number of deaths attributed to TB was larger number in 1995 than in any other year in history (Moran, N. 1996. WHO Issues Another Gloomy Report. Nature Medicine 4:377). Tuberculosis remains widespread worldwide and constitutes a major health problem particularly in developing countries. One third of the total world's population (nearly two billion people) is infected with Mycobacterium tuberculosis out of which 5 to 10% develop the disease. TB causes more than 3 million deaths per year and recently WHO has predicted that 30 million people will die of TB in the next ten years (Joint International Union Against Tuberculosis and World Health Organization Study Group. Tubercl 63:157-169, 1982). Tuberculosis is caused by a gram positive acid fact bacterium Mycobacterium tuberculosis or M. bovis, which are the tubercle bacilli of the family of Mycobacteriaceae. M. bovis is a species which causes tuberculosis in cattle and can be transmitted to humans and other animals in which it causes tuberculosis. At
Patents 409
present nearly all tuberculosis in humans is caused by Mycobacterium tuberculosis. Infections occasionally result from other species of mycobacteria that are common environmental saprophytes. These species have been collectively termed as MOTT (Mycobacteria other than typical tubercle), environmental or tuberculoid bacilli. The difference between the two infections is that infection with Mycobacterium tuberculosis is always transmitted from host to host. In contrast, human beings infected with other mycobacteria rarely transmit the disease. Hence the essential component of any tuberculosis control program is containment of the disease. Identification of infected individuals, especially those most likely to transmit viable bacilli, comes as a first priority in strategies for tuberculosis control. Early and timely diagnosis of tuberculosis is essential for identifying individuals carrying the bacilli. Therefore a need has arisen for a method of diagnosis of tuberculosis which is rapid, sensitive and specific. Routine diagnostic methods used for identification of Mycobacterium tuberculosis includes acid fast smear test in clinical samples like sputum, tests based on growth of bacilli of specific media and differential biochemical tests. The culture of mycobacteria from clinical samples is the most reliable and provides for definite diagnosis of tuberculosis. Although 100% specific, it takes six to eight weeks due to slow growth of organisms and further biochemical testing before identification can be made (Heifests, L B. and Good, R. C. 1994. Current Laboratory Methods for the Diagnosis of Tuberculosis. Tuberculosis Pathogenesis, Protection and Control (ed. B. R. Bloom) ASM Washington D.C., pp. 85110). Web site: http://www.delphion.com/details?pn=US06242585__ •
Mycobacterium tuberculosis specific proteins and genes, mixtures of anitgens and uses thereof Inventor(s): Gennaro; Maria L. (New York, NY), Manca; Claudia M.A. (New York, NY), Lyashchenko; Konstantin P. (Newark, NJ) Assignee(s): The Public Health Research Institute of the City of New York, Inc. (New York, NY) Patent Number: 6,087,163 Date filed: February 6, 1997 Abstract: Two genes for proteins of M. tuberculosis have been sequenced. The DNAs and their encoded polypeptides can be used for immunoassays and vaccines. Cocktails of at least three purified recombinant antigens, and cocktails of at least three DNAs encoding them can be used for improved assays and vaccines for bacterial pathogens and parasites. Excerpt(s): One of the important goals of research on Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is the identification of mycobacterial antigens that induce protective T-cell responses and/or stimulate humoral immunity during tubercular infection. Antigens in the former class constitute potential candidates for the development of effective vaccines, while those in the latter group can be tested as new, improved tools for diagnosis of TB. Similarly, numerous other bacterial pathogens have pathogenicity that, as with TB, is not caused by a single protein, as is the case also with parasites generally. Antigens produced by these pathogens are also potential candidates for the development of effective vaccines. Proteins that are actively secreted by M. tuberculosis have attracted considerable attention as potent immunogens. The observation that only live, dividing mycobacteria efficiently induce protective immunity (7, 22) led to the hypothesis that proteins that are actively secreted by M. tuberculosis
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during growth are key in generating protective T-cell responses (4, 23). Indeed, experimental vaccines based on culture filtrate proteins have been shown to induce some levels of protective immunity in animal models of TB (5, 14, 15, 26). Secreted proteins of M. tuberculosis are also potent inducers of antibody production (13). Web site: http://www.delphion.com/details?pn=US06087163__ •
Mycobacterium tuberculosis superoxide dismutase Inventor(s): Lee; Fang-Jen S. (Taipei, TW), Wu; Chung-Hsiun H. (Taipei, TW) Assignee(s): Yung Shin Pharmaceutical Ind. Co., Ltd. (Taipei, TW) Patent Number: 6,517,845 Date filed: November 12, 1999 Abstract: The invention relates to Mycobacterium tuberculosis superoxide dismutase antibodies, methods of using them for detection of M. tuberculosis, methods of testing for an inhibitor of an M. tuberculosis superoxide dismutase, and methods of detecting tuberculosis infection. Excerpt(s): Superoxide dismutase catalyzes the conversion of superoxide radicals (O.sub.2.sup.-) into molecular oxygen (O.sub.2) and hydrogen peroxide (H.sub.2 O.sub.2). The conversion of superoxide radicals is generally beneficial to a cell, since such molecules can react with the cell's genomic DNA to induce mutations. Superoxide dismutases (SOD) have been classified based on the inorganic atoms they require for activity. Three SOD families have been identified: those requiring manganese (MnSOD), those requiring iron (FeSOD), and those requiring copper and zinc (Cu, ZnSOD). MnSODs have been found in mitochondria and prokaryotes, whereas FeSODs have been found in prokaryotes, primitive eukaryotes, and some plants. Cu, ZnSODs were originally found in eukaryotes and later found in several bacterial. Web site: http://www.delphion.com/details?pn=US06517845__
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Mycrobacterial proteins, microorganisms producing same and uses of said proteins in vaccines and for detecting tuberculosis Inventor(s): Laqueyrerie; Anne (Paris, FR), Pescher; Pascale (Paris, FR), Romain; Felix (Fontenay les Briis, FR), Marchal; Gilles (Ivry sur Seine, FR) Assignee(s): Institut Pasteur (Paris, FR) Patent Number: 6,379,902 Date filed: August 1, 1997 Abstract: Mycobacterium tuberculosis protein having a molecular weight of 28 779 Da, and hybrid proteins containing at least portions of its sequence.These proteins may in particular be used in vaccines or for the detection of specific tuberculosis antibodies. Excerpt(s): The object of the present invention is mycobacterial proteins and microorganisms producing them. It also relates to the use of these proteins in vaccines or for the detection of tuberculosis. At present, a definite diagnosis made by the demonstration of cultivatable bacilli in a sample taken from the patient is only obtained in less than half the cases of tuberculosis. Even for pulmonary tuberculosis, which represents 80 to 90% of the tuberculosis cases, and which is the form of the disease for
Patents 411
which the detection of the bacilli is the easiest, the examination of expectorations is only positive for less than half the cases. Web site: http://www.delphion.com/details?pn=US06379902__ •
Nucleic acid and amino acid sequences relating to mycobacterium tuberculosis and leprae for diagnostics and therapeutics Inventor(s): Smith; Douglas R. (Gloucester, MA), Mao; Jen-i (Lexington, MA) Assignee(s): Genome Therapeutics Corporation (Waltham, MA) Patent Number: 6,583,266 Date filed: September 16, 1994 Abstract: Embodiments of the present invention feature nucleic acid and proteins derived from Mycobacterium tuberculosis and leprae. The proteins and nucleic acid of the present invention have applications in diagnostics and therapeutics. Excerpt(s): The present invention relates to non-naturally occurring nucleic acid and peptides corresponding to nucleic acid and peptides of Mycobacterium tuberculosis and Mycobacterium leprae. The nucleic acid and peptides of the present invention have utility for diagnostics and therapeutics. Mycobacterium tuberculosis is the causative agent of tuberculosis. Tuberculosis is a chronic bacterial infection characterized by the formation of granulomas in infected tissues and by cell mediated hypersensitivity. The usual site of the disease is the lungs but other organs may be involved. In countries where human immuno-deficiency virus (HIV) infection is endemic, tuberculosis is a frequent cause of morbidity in AIDS patients. Tuberculosis has shown a resurgence in recent years worldwide. Mycobacteria contain an array of protein and polysaccharide antigens giving rise to a cell mediated hypersensitivity. The hypersensitivity is often used to diagnose tuberculosis and to monitor the disease pathogenesis. See: Harrison's Principles of Internal Medicine, Twelfth Edition, McGraw-Hill, Inc., (1991), pp. 637-645. Mycobacterium leprae is the causative agent of Hanson's disease or leprosy. Leprosy is a chronic infection of superficial tissues, especially the skin and peripheral nerves. Mycobacterium leprae multiplies slowly, and has not been grown in tissue culture or artificial media. Mycobacterium leprae does not elicit strong immunological responses in infected individuals. However, a serodiagnostic test for the detection of antibody to Mycobacterium leprae antigen is used to aid in the diagnosis. See Harrison, supra, pp. 645-648. Web site: http://www.delphion.com/details?pn=US06583266__
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Nucleic acid encoding M. tuberculosis algu protein Inventor(s): Lam; Kelvin T. (Belmont, MA) Assignee(s): Anadys Pharmaceuticals, Inc. (Waltham, MA) Patent Number: 6,355,469 Date filed: January 16, 1998 Abstract: The invention relates to Mycobacterium tuberculosis RNA polymerase algU sigma subunit protein, DNA encoding, and methods of detecting inhibitors of the RNA polymerase.
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Excerpt(s): Mycobacteria are gram-positive bacilli, nonmotile rod-shaped organisms that do not form spores. The composition of the cell wall includes a very high concentration of lipids complexed to a variety of peptides and polysaccharides. The unusual structure of the cell wall distinguishes mycobacteria from most other bacteria and is detectable by its resistance to acid-alcohol staining. The disease caused by M. tuberculosis is a progressive, deadly illness that tends to develop slowly and follows a chronic course (Plorde, 1994). It is presently estimated that one-third of the world's population is infected with M. tuberculosis, 30 million of whom have active disease (Plorde, 1994). An additional 8 million people develop the disease annually (Plorde, 1994). Most infections are caused by inhalation of droplet nuclei carrying the mycobacterium. A single cough can generate 3000 infected droplet nuclei and even 10 bacilli may be sufficient to cause a pulmonary infection. In addition to the primary infection, reactivation of the disease can occur in older people and in immunocompromised patients. When intracellular pathogens, such as Mycobacterium tuberculosis, are ingested by macrophages the bacteria are under environmental stress. The genes required for survival following uptake by macrophages can provide insight into mycobacterial pathogenesis, and provide novel targets for developing antibacterial agents. The ability to adapt to the intracellular stress requires regulation of complex gene expression and this regulation may be mediated in part by one or more alternative sigma factors. Therefore stress response alternative sigma factors (sigE family) from M. tuberculosis are potential novel targets for antibacterial therapeutics. Web site: http://www.delphion.com/details?pn=US06355469__ •
Nucleic acid probes to mycobacterium tuberculosis Inventor(s): Hammond; Philip W. (San Diego, CA) Assignee(s): Gen-Probe Incorporated (San Diego, CA) Patent Number: 5,906,917 Date filed: April 7, 1995 Abstract: Hybridization assay probes specific for members of the Mycobacterium tuberculosis Complex and no other Mycobacterium species. Excerpt(s): The inventions described and claimed herein relate to the design and construction of nucleic acid probes for Mycobacterium tuberculosis Complex (TB Complex) which are capable of detecting the organisms in test samples for, e.g., sputum, urine, blood and tissue sections, food, soil and water. Two single strands of deoxyribo("DNA") or ribo-("RNA") nucleic acid, formed from nucleotides (including the bases adenine (A), cytosine (C), thymidine (T), guanine (G), uracil (U), or inosine (I)), may associate ("hybridize") to form a double stranded structure in which the two strands are held together by hydrogen ponds between pairs of complementary bases. Generally, A is hydrogen bonded to T or U, while G is hydrogen bonded to C. At any point along the chain, therefore, one may find the classical base pairs AT or AU, TA or UA, GC, or CG. One may also find AG, GU and other "wobble" or mismatched base pairs. When a first single strand of nucleic acid contains sufficient contiguous complementary bases to a second, and those two strands are brought together under conditions which will promote their hybridization, double stranded nucleic acid will result. Under appropriate conditions, DNA/DNA, RNA/DNA, or RNA/RNA hybrids may be formed. Web site: http://www.delphion.com/details?pn=US05906917__
Patents 413
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Nucleic acid probes, sequences and methods for detecting mycobacterium tuberculosis resistant to isoniazid Inventor(s): Young; Douglas B. (Middlesex, GB), Zhang; Ying (Baltimore, MD), Cole; Stewart T. (Clamart, FR), Heym; Beate (Ville d'Avray, FR) Assignee(s): Institut Pasteur (Paris Cedex, FR) Patent Number: 5,871,912 Date filed: June 2, 1995 Abstract: Multi-drug resistant strains of Mycobacterium tuberculosis represent a considerable threat to public health worldwide. Resistance to isoniazid (INH), a key component of anti-tuberculosis regimens, is often associated with loss of catalase activity and virulence. The katG gene, encoding HPI catalase-peroxidase, mediates INHsensitivity and that the high level resistance encountered clinically may be due to deletions, insertions or point mutations which reduce or eliminate the expression of the catalase gene in the chromosomal region encompassing katG. INH-resistant strains of Mycobacterium tuberculosis are detected by nucleic acid hybridization with a unique nucleic acid sequence or by amplification techniques. Excerpt(s): This invention relates to the rapid detection of strains of Mycobacterium tuberculosis that are resistant to the antibiotic isoniazid. More particularly, this invention relates to a method of detecting isoniazid resistance in Mycobacterium tuberculosis by nucleic acid hybridization. This invention also relates to a nucleic acid probe and a kit for carrying out the nucleic acid hybridization. Despite more than a century of research since the discovery of Mycobacterium tuberculosis, the aetiological agent of tuberculosis, by Robert Koch, this disease remains one of the major causes of human morbidity and mortality. There are an estimated 3 million deaths annually attributable to tuberculosis (Snider, 1989), and although the majority of these are in developing countries, the disease is assuming renewed importance in the West due to the increasing number of homeless people and the impact of the AIDS epidemic (Chaisson et al., 1987; Snider and Roper, 1992). Isonicotinic acid hydrazide or isoniazid (INH) has been used in the treatment of tuberculosis for the last forty years due to its exquisite potency against the members of the "tuberculosis" groups--Mycobacterium tuberculosis, M. bovis and M. africanum (Middlebrook, 1952; Youatt, 1969). Neither the precise target of the drug, nor its mode of action, are known, and INH treatment results in the perturbation of several metabolic pathways. There is substantial evidence indicating that INH may act as an anti-metabolite of NAD and pyridoxal phosphate (Bekierkunst and Bricker, 1967; Sriprakash and Ramakrishnan, 1970; Winder and Collins, 1968, 1969, 1970), and other data indicating that the drug blocks the synthesis of the mycolic acids, which are responsible for the acid-fast character of mycobacterial cell walls (Winder and Collins 1970; Quemard et al., 1991). Shortly after its introduction, INH-resistant isolates of Mycobacterium tuberculosis emerged and, on characterization, were often found to have lost catalase-peroxidase activity and to show reduced virulence in guinea pigs (Middlebrook et al., 1954; Kubica et al., 1968; Sriprakash and Ramakrishnan, 1970). Web site: http://www.delphion.com/details?pn=US05871912__
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Nucleotide and amino acid sequences of protein MTP40 of M. tuberculosis and synthetic peptides derived therefrom Inventor(s): Patarroyo; Manuel E. (Calle 135 No.15-40, Bogota, CO) Assignee(s): none reported Patent Number: 5,254,459 Date filed: September 4, 1992 Abstract: The present invention relates to novel chemically synthesized nucleotides and novel chemically synthesized peptides which have been found to be effective in assaying for the presence of M. tuberculosis. Excerpt(s): This invention relates generally to the chemical synthesis of certain novel nucleotide sequences and novel synthetic peptides and, more particularly, to their use in diagnostic tests for M. tuberculosis and their immunoprophylactic value. Tuberculosis is a serious infectious disease which affects 30 million people worldwide, especially in the developing countries (World Health Organization, Bull. WHO, 61, 779, 1983). The diagnosis of tuberculosis relies on the observation of acid-fast bacilli in clinical specimens and on PPD (Purified Protein Derivative), a delayed type cutaneous hypersensitivity test (DCH). However, very often the number of bacterial cells in the sample is insufficient to make a successful diagnosis of the disease. On the other hand, the utility of PPD is limited both by its lack of specificity and by its inability to distinguish between an active disease state, previous sensitization by contact with M. tuberculosis, or cross-sensitization to other mycobacteria. The use of peptides as tools in the diagnosis of mycobacterial diseases was discussed recently in the First Vaccilep Workshop on the Immunology of Leprosy. (Immunology today. 10: 218-221, 1989.) The application of this strategy to tuberculosis would enable the production of highly specific and very stable reagents, at low cost, which could be used in immunoassays of excellent reproducibility. This type of easy-to-perform test would be useful in both seroepidemiological and clinical studies, looking to tuberculosis control and prevention. Besides, much attention has been focused on the use of nucleic acid probes to specifically detect a mycobacterial infection. Web site: http://www.delphion.com/details?pn=US05254459__
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Nucleotide sequences of protein MTP40 of M. tuberculosis Inventor(s): Patarroyo; Manuel E. (Calle 135 No. 15-40, Bogota, CO) Assignee(s): none reported Patent Number: 5,169,940 Date filed: February 11, 1992 Abstract: The present invention relates to novel chemically synthesized nucleotides which have been found to be effective in assaying for the presence of M. tuberculosis. Excerpt(s): This invention relates generally to the chemical synthesis of certain novel nucleotide sequences and novel synthetic peptides and, more particularly, to their use in diagnostic tests for M. tuberculosis and their immunoprophylactic value. Tuberculosis is a serious infectious disease which affects 30 million people worldwide, especially in the developing countries (World Health Organization, Bull. WHO, 61, 779, 1983). The diagnosis of tuberculosis relies on the observation of acid-fast bacilli in clinical specimens and on PPD (Purified Protein Derivative), a delayed type cutaneous
Patents 415
hypersensitivity test (DCH). However, very often the number of bacterial cells in the sample is insufficient to make a successful diagnosis of the disease. On the other hand, the utility of PPD is limited both by its lack of specificity and by its inability to distinguish between an active disease state, previous sensitization by contact with M. tuberculosis, or cross-sensitization to other mycobacteria. The use of peptides as tools in the diagnosis of mycobacterial diseases was discussed recently in the First Vaccilep Workshop on the Immunology of Leprosy. (Immunology today. 10: 218-221, 1989.) The application of this strategy to tuberculosis would enable the production of highly specific and very stable reagents, at low cost, which could be used in immunoassays of excellent reproducibility. This type of easy-to-perform test would be useful in both seroepidemiological and clinical studies, looking to tuberculosis control and prevention. Besides, much attention has been focused on the use of nucleic acid probes to specifically detect a mycobacterial infection. Web site: http://www.delphion.com/details?pn=US05169940__ •
Peptide sequence capable of inducing a delayed-type hypersensitivity reaction in the presence of living bacteria of the Mycobacterium tuberculosis complex and its applications Inventor(s): Marchal; Gilles (Ivry S/Seine, FR), Romain; Felix (Fontenay Les Briis, FR) Assignee(s): Institut Pasteur (Paris Cedex, FR) Patent Number: 5,599,541 Date filed: October 17, 1994 Abstract: Peptide sequence capable of initiating delayed hypersensitivity reactions of different intensity in the presence of living bacteria as opposed to dead bacteria of the Mycobacterium tuberculosis complex. The sequence is characterized in that it comprises no more than 0.5% by weight of tyrosine, phenylalanine, methionine, histidine, arginine and cysteine amino acids. The invention also concerns the diagnostic and therapeutic applications of a peptide or protein comprising said sequence. Excerpt(s): The present invention relates to a new antigenic protein capable of causing delayed hypersensitivity reactions of different intensity in the presence of living or dead bacteria of the Mycobacterium tuberculosis complex, its diagnostic and therapeutic applications especially as vaccine. This Mycobacterium tuberculosis complex comprises four species: Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti (le Minor et Veron; bacteriologie Madicale 1990, 2nd ed. p. 1966). The delayed-type hypersensitivity reaction to tuberculin is used commonly as means of diagnosing tuberculosis. This tuberculin challenge is particularly used as diagnostic means in the United States and in the Netherlands, countries where BCG vaccination does not or no longer exists. A recent development (1990) by the American Thoracic Society recommends in particular the use of this diagnostic test and specifies its limits for the national campaign for the total eradication of tuberculosis which is being put in place in the United States. For France, the medical practice is a little different because of the wide use of BCG and the still relatively high frequency of tuberculosis. The reaction to tuberculin is used to monitor secondary sensitization to the vaccination and also to provide arguments in favor of the existence of a tubercular infection. This diagnostic indication is based on the clear increase in the intensity of the reaction in a given subject or on the very high intensity of the reaction. But this quantitative notion is difficult to assess accurately when the tuberculin reactions are performed and/or read by different people.
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Web site: http://www.delphion.com/details?pn=US05599541__ •
Polynucleotide functionally coding for the LHP protein from Mycobacterium tuberculosis, its biologically active derivative fragments, as well as methods using the same Inventor(s): Andersen; Peter (Bronshoj, DK), Berthet; Francois-Xavier (Paris, FR), Gicquel; Brigitte (Paris, FR), Rasmussen; Peter Birk (Kobehavn, DK) Assignee(s): Institut Pasteur (Paris, FR) Patent Number: 6,436,409 Date filed: July 16, 1998 Abstract: The present invention is directed to a polynucleotide carrying an open reading frame coding for an antigenic polypeptide from Mycobacterium tuberculosis, named lhp, which is placed under the control of its own regulation signals which are functional in mycobacteria, specially in mycobacteria belonging to the Mycobacterium tuberculosis complex and also in fast growing mycobacteria such as Mycobacterium smegmatis. The invention is also directed to the polypeptide LHP encoded by lhp and most preferably to suitable antigenic portions of LHP as well as to oligomeric polypeptides containing more than one unit of LHP or an antigenic portion of LHP. The invention concerns also immunogenic and vaccine compositions containing a polypeptide or an oligomeric polypeptide such as defined above, as well as antibodies directed specifically against such polypeptides that are useful as diagnostic reagents. In another embodiment, the present invention is directed to a polynucleotide carrying the natural regulation signals of lhp which is useful in order to express heterologous proteins in mycobacteria. Finally, the present invention is directed to oligonucleotides comprising at least 12 consecutive nucleotides from the regulation sequence of lhp which are useful as reagents for detecting the presence of Mycobacterium tuberculosis in a biological sample. Excerpt(s): The present invention is directed to a polynucleotide comprising an open reading frame coding for a polypeptide from Mycobacterium tuberculosis, named LHP capable of inducing an immune response in a host. lhp is placed under the control of its own regulation signals which are functional in mycobacteria, especially in mycobacteria belonging to the Mycobacterium tuberculosis complex and also in fast growing mycobacteria such as Mycobacterium smegmatis and also in E. coli. The Mycobacterium tuberculosis complex has its usual meaning, i.e. the complex of mycobacteria causing tuberculosis which are Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti and the vaccine strain M. bovis BCG. The invention is also directed to the polypeptide LHP encoded by lhp and most preferably to suitable antigenic portions of LHP as well as to oligomeric polypeptides containing more than one unit of LHP or an antigenic portion of LHP. The invention concerns also immunogenic and vaccine compositions containing a polypeptide or an oligomeric polypeptide such as defined above or live recombinant attenuated mycobacteria transformed with a polynucleotide according to the present invention. The invention also concerns antibodies directed specifically against such polypeptides that are useful as diagnostic reagents. In another embodiment, the present invention is directed to a polynucleotide carrying the natural regulation signals of lhp which is useful in order to express heterologous proteins in mycobacteria as well as functionally active regulatory polynucleotides derived from said regulatory region. Finally, the present invention is directed to oligonucleotides comprising at least 12 consecutive nucleotides which are useful as reagents for detecting the presence of Mycobacterium
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tuberculosis in a biological sample. Mycobacterium tuberculosis and M. bovis cause tuberculosis, a disease which currently kills three million people each year. The virulence of pathogenic mycobacteria is associated with their ability to parasitize and survive within phagocytic cells. Little is known about mechanisms governing gene expression during the intracellular growth stage. This issue is of prime importance as the intracellular stage of pathogenic mycobacteria can be viewed as an adaptative process, involving transcriptional regulatory mechanisms. Mycobacterial genes affecting intracellular growth and virulence are being actively sought (Collins, 1996; Collins, 1995, Quinn, 1996). Using subtractive genomic hybridization between virulent M. bovis and the attenuated vaccine strain M. bovis BCG, Maheiras et al. (Maheiras et al., 1996) identified three regions of difference (RD1 to RD3). RD1 was detected in all strains of M. tuberculosis and M. bovis tested but is absent in all BCG substrains, suggesting that it may be an important determinant of virulence. Web site: http://www.delphion.com/details?pn=US06436409__ •
Polynucleotide tuberculosis vaccine Inventor(s): Ulmer; Jeffrey (Chalfont, PA), Content; Jean (Rhode-Saint-Genese, BE), Liu; Margaret A. (Rosemont, PA), Montgomery; Donna (Chalfont, PA), Huygen; Kris (Brussels, BE) Assignee(s): Merck & Co., Inc. (Rahway, NJ) Patent Number: 6,384,018 Date filed: January 22, 1998 Abstract: Genes encoding Mycobacterium tuberculosis (M.tb) proteins were cloned into eukaryotic expression vectors to express the encoded proteins in mammalian muscle cells in vivo. Animals were immunized by injection of these DNA constructs, termed polynucleotide vaccines or PNV, into their muscles. Immune antisera was produced against M.tb antigens. Specific T-cell responses were detected in spleen cells of vaccinated mice and the profile of cytokine secretion in response to antigen 85 was indicative of a T.sub.h 1 type of helper T-cell response (i.e., high IL-2 and IFN-.gamma.). Protective efficacy of an M.tb DNA vaccine was demonstrated in mice after challenge with M.bovis BCG, as measured by a reduction in mycobacterial multiplication in the spleens and lungs of M.tb DNA-vaccinated mice compared to control DNA-vaccinated mice or primary infection in naive mice. Excerpt(s): A major obstacle to the development of vaccines against viruses and bacteria, particularly those with multiple serotypes or a high rate of mutation, against which elicitation of neutralizing antibodies and/or protective cell-mediated immune responses is desirable, is the diversity of the external proteins among different isolates or strains. Since cytotoxic T-lymphocytes (CTLs) in both mice and humans are capable of recognizing epitopes derived from conserved internal viral proteins [J. W. Yewdell et al., Proc. Natl. Acad. Sci. (USA) 82, 1785 (1985); A. R. M. Townsend, et al., Cell 44, 959 (1986); A. J. McMichael et al., J. Gen. Virol. 67, 719 (1986); J. Bastin et al., J. Exp. Med. 165, 1508 (1987); A. R. M. Townsend and H. Bodmer, Annu. Rev. Immunol. 7, 601 (1989)], and are thought to be important in the immune response against viruses [Y.-L. Lin and B.A. Askonas, J. Exp. Med. 154, 225 (1981); I. Gardner et al., Eur. J. Immunol. 4, 68 (1974); K. L. Yap and G. L. Ada, Nature 273, 238 (1978); A. J. McMichael et al., New Engl. J. Med. 309, 13 (1983); P. M. Taylor and B. A. Askonas, Immunol. 58, 417 (1986)], efforts have been directed towards the development of CTL vaccines capable of providing heterologous protection against different viral strains. It is known that CTLs kill virally-
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or bacterially-infected cells when their T cell receptors recognize foreign peptides associated with MHC class I and/or class II molecules. These peptides can be derived from endogenously synthesized foreign proteins, regardless of the protein's location or function within the pathogen. By recognition of epitopes from conserved proteins, CTLs may provide heterologous protection. In the case of intracellular bacteria, proteins secreted by or released from the bacteria are processed and presented by MHC class I and II molecules, thereby generating T-cell responses that may play a role in reducing or eliminating infection. Most efforts to generate CTL responses have either used replicating vectors to produce the protein antigen within the cell [J. R. Bennink et al., ibid. 311, 578 (1984); J. R. Bennink and J. W. Yewdell, Top. Microbiol. Immunol. 163, 153 (1990); C. K. Stover et al., Nature 351, 456 (1991); A. Aldovini and R. A. Young, Nature 351, 479 (1991); R. Schafer et al., J. Immunol. 149, 53 (1992); C. S. Hahn et al., Proc. Natl. Acad. Sci. (USA) 89, 2679 (1992)], or they have focused upon the introduction of peptides into the cytosol [F. R. Carbone and M. J. Bevan, J. Exp. Med. 169, 603 (1989); K. Deres et al., Nature 342, 561 (1989); H. Takahashi et al., ibid. 344, 873 (1990); D. S. Collins et al., J. Immunol. 148, 3336 (1992); M. J. Newman et al., ibid. 148, 2357 (1992)]. Both of these approaches have limitations that may reduce their utility as vaccines. Retroviral vectors have restrictions on the size and structure of polypeptides that can be expressed as fusion proteins while maintaining the ability of the recombinant virus to replicate [A. D. Miller, Top. Microbiol. Immunol. 158, 1 (1992)], and the effectiveness of vectors such as vaccinia for subsequent immunizations may be compromised by immune responses against vaccinia [E. L. Cooney et al., Lancet 337, 567 (1991)]. Also, viral vectors and modified pathogens have inherent risks that may hinder their use in humans [R. R. Redfield et al., New Engl. J. Med. 316, 673 (1987); L. Mascola et al., Arch. Intern. Med. 149, 1569 (1989)]. Furthermore, the selection of peptide epitopes to be presented is dependent upon the structure of an individual's MHC antigens and, therefore, peptide vaccines may have limited effectiveness due to the diversity of MHC haplotypes in outbred populations. Web site: http://www.delphion.com/details?pn=US06384018__ •
Preparation of a tuberculosis test medium by reconstituting a storage stabilized dry powdered Lowenstein-Jensen medium Inventor(s): Williams; Wilmore (Chicago, IL) Assignee(s): Beatrice Foods Co. (Chicago, IL) Patent Number: 4,072,570 Date filed: February 20, 1976 Abstract: A storage stable Lowenstein-Jensen medium is prepared by spray drying the liquid medium at an outlet temperature of up to 212.degree. F. to provide a powder having a moisture content of less than 9% by weight. The spray-dried powder is stable at ambient temperature for at least six months and may be easily reconstituted to the fluid Lowenstein-Jensen medium and used in testing for tuberculosis by simple mixing at ambient conditions. Excerpt(s): The present invention relates to a stabilized growth medium for tuberculosis organisms, and more particularly to a stabilized medium which may be stored under ambient conditions for extended periods of time without degradation or other deterioration of the growth medium. The detection of the disease tuberculosis has long been performed by culturing a specimen from a suspected host in a medium referred to in the art as the Lowenstein-Jensen medium, or modifications thereof. By allowing the
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sample to incubate for a set period of time in the Lowenstein-Jensen medium, the M. tuberculosis organisms will develop to the substantial exclusion of other organisms and a positive test for tuberculosis is therefore performed. While this test is quite accurate and is widely practiced, the test has a decided disadvantage in that the LowensteinJensen medium is not storage stable at ambient temperatures and even when refrigerated must be used within 30 days of preparation. In view thereof, it has been the practice in the art to use the Lowenstein-Jensen medium within a relatively short period after preparation. Thus, it is necessary to frequently perform the time-consuming preparation of fresh medium. The time-consuming preparation has generally restricted the use of the Lowenstein-Jensen medium to organizations which would conduct numerous tuberculosis tests. The occasional tester or the smaller institution cannot economically test for tuberculosis, due to the difficulty and expense of frequently preparing fresh medium. The basic ingredient in the Lowenstein-Jensen medium is fresh whole eggs, e.g., eggs no older than three days. The medium must be prepared in a specific manner with specific nutrient salts added to the fresh eggs, as is well known in the art. Once the medium has been prepared, it must be refrigerated and should be used within a relatively short time of preparation, as discussed above, or the results obtained therewith are questionable. Attempts in the art at extending the useful life of a prepared Lowenstein-Jensen medium have not met with success and the most common expedient is to premix the nutrient salts in a sterile manner and to place the fresh eggs in the salt mixture when the medium is to be prepared. Web site: http://www.delphion.com/details?pn=US04072570__ •
Process for preparation of pharmaceutical composition with enhanced activity for treatment of tuberculosis and leprosy Inventor(s): Kapil; Randhir S. (Regional Research Laboratory, Jammu 180001, IN), Kapoor; Naveen (Regional Research Laboratory, Jammu 180001, IN), Bedi; Kasturi L. (Regional Research Laboratory, Jammu 180001, IN), Singh; Gurbax (Regional Research Laboratory, Jammu 180001, IN), Johri; Ramesh K. (Regional Research Laboratory, Jammu 180001, IN), Zutshi; Usha (Regional Research Laboratory, Jammu 180001, IN), Kaul; Jawahar L. (Regional Research Laboratory, Jammu 180001, IN), Sharma; Subhash C. (Regional Research Laboratory, Jammu 180001, IN), Pahwa; Gurcharan S. (Regional Research Laboratory, Jammu 180001, IN), Dhar; Santosh K. (Regional Research Laboratory, Jammu 180001, IN), Tickoo; Manoj K. (Regional Research Laboratory, Jammu 180001, IN), Kaul; Uma (Regional Research Laboratory, Jammu 180001, IN), Singh; Surjeet (Regional Research Laboratory, Jammu 180001, IN), Singh; Rajinder (Regional Research Laboratory, Jammu 180001, IN), Tickoo; Ashok K. (Regional Research Laboratory, Jammu 180001, IN), Zutshi; Ram K. (Regional Research Laboratory, Jammu 180001, IN) Assignee(s): none reported Patent Number: 5,439,891 Date filed: October 29, 1993 Abstract: A new pharmaceutical composition for the treatment of tuberculosis and leprosy, said composition comprising piperine in combination with known antituberculosis or antileprosy drugs or the mixtures thereof. Excerpt(s): The present invention relates to an new pharmaceutical composition for the treatment of tuberculosis and leprosy. The new composition has increased therapeutic efficacy. The invention particularly relates to a pharmaceutical composition containing
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piperine anti-tuberculosis/leprotic drugs. The global problems of combating tuberculosis intensified by the country's economic problem and corresponding lack of health education which makes spitting a national pass-time and covering one's mouth, while coughing, a rare phenomenon. Of this, an estimated two million are children below the age of five. Web site: http://www.delphion.com/details?pn=US05439891__ •
Rapid amplification-based subtyping of mycobacterium tuberculosis Inventor(s): Shinnick; Thomas M. (Atlanta, GA), Plikaytis; Bonnie B. (Tucker, GA), Crawford; Jack T. (Dunwoody, GA) Assignee(s): The United States of America as represented by the Secretary of the (Washington, DC) Patent Number: 5,652,106 Date filed: October 25, 1995 Abstract: The present invention provides methods of detecting or distinguishing the DNA of an individual strain of Mycobacterium tuberculosis utilizing the polymerase chain reaction (PCR). Reproducible, unique patterns can be produced allowing the identification of unknown M. tuberculosis DNA by performing this reaction and comparing the pattern produced to the known reproducible, unique patterns. The invention further provides a kit useful to detect or distinguish the DNA of an individual strain of M. tuberculosis in a sample, comprising specific primers for use in PCR. The present invention also provides a method of determining the presence of a multidrugresistant M. tuberculosis by detecting the presence of a specific arrangement of genomic DNA. Such detection can be done using PCR or a ligase chain reaction (LCR). The present invention provides nucleic acid sequences useful in detecting multidrugresistant M. tuberculosis. Excerpt(s): The present invention relates to methods and compounds for rapid identification of clusters of epidemiologically related individual strains of Mycobacterium tuberculosis by a DNA amplification strategy of multiple copy elements of M. tuberculosis. Additionally provided is a method for detecting the presence of M. tuberculosis RFLP-type 021-2072 (or strain W). Tuberculosis remains a major source of morbidity and mortality throughout the world and is increasing in the United States today. The resurgence of tuberculosis in the United States is largely related to the human immunodeficiency virus (HIV) epidemic. Because of the reduction in cellmediated immunity in HIV-infected persons, active disease may develop quickly after exposure to Mycobacterium tuberculosis (Barnes et al., 1991). As the number of hospitalized patients infected with HIV and tuberculosis increases, the risk of nosocomial infection with M. tuberculosis increases not only among patients, but also among health care providers (Pearson et al., 1992). An important factor in the control of tuberculosis is the ability to identify outbreaks and track the transmission of a particular strain of M. tuberculosis. The standard procedure for distinguishing strains of M. tuberculosis isolates has been phage typing; however, a more sensitive molecular approach has been described recently (Cave et al., 1991). This approach takes advantage of the facts that M. tuberculosis strains carry multiple copies of an insertion sequence, IS6110, and that the precise locations of the IS6110 elements in the M. tuberculosis genome varies significantly from strain to strain, providing a unique DNA fingerprint for each M. tuberculosis strain. The IS6110-restriction fragment length polymorphism (RFLP) technique has been shown to be a reliable and reproducible method for
Patents 421
differentiating M. tuberculosis strains (Cave et al., 1991; Otal et al., 1991; van Soolingen et al.), and a recent report utilized this technique to study the epidemiology of multidrug-resistant tuberculosis among hospitalized HIV-infected patients (Edlin et al., 1992). This method allows for the grouping of isolates into fingerprint types. Web site: http://www.delphion.com/details?pn=US05652106__ •
Rapid detection of antibiotic resistance in mycobacterium tuberculosis Inventor(s): Telenti; Amalio (Gerzensee, CH), Honore; Nadine (Colombes, FR), Bodmer; Thomas (Ersigen, CH), Zhang; Ying (London, GB), Young; Douglas (Ruislip, GB), Cole; Stewart (Clamart, FR), Heym; Beate (Ville d'Avray, FR) Assignee(s): Institut Pasteur (Paris, FR) Patent Number: 5,851,763 Date filed: October 12, 1994 Abstract: A process for the detection of resistance to an antibiotic in a mycobacterium comprises detecting a mutation in a gene selected from the group consisting of the katG gene or fragment thereof, the rpoB gene or fragment thereof, and the rpsI gene or fragment thereof. The process is useful for detecting in vitro the presence of nucleic acids of a Mycobacterium tuberculosis resistant to isoniazid. Excerpt(s): This application is a National stage application filed under 35 U.S.C.sctn. 371 based on International Application PCT/EP/01063, filed Apr. 30, 1993, which is based upon U.S. application Ser. No. 07/929,206, filed Aug. 14, 1992, now U.S. Pat. No. 5,633,131, issued May 27, 1997, which is a continuation-in-part application of U.S. application Ser. No. 07/875,940, filed Apr. 30, 1992, now abandoned and French applications No. FR 93 04545, filed Apr. 16, 1993, and No. FR 92 11098, filed Sep. 17, 1992. This invention relates to the rapid detection of strains of Mycobacterium tuberculosis that are resistant to antibiotics, particularly isoniazid, rifampicin and streptomycin. More particularly, this invention relates to a method of detecting antibiotic resistance in Mycobacterium tuberculosis, e.g. either as a result of mutations in the relevant genes or by nucleic acid hybridization. This invention also relates to a nucleic acid probe and a kit for carrying out the nucleic acid hybridization. The invention further relates to the chromosomal location of the katG gene (SEQ ID NO:45) and its nucleotide sequence. Despite more than a century of research since the discovery of Mycobacterium tuberculosis, the aetiological agent of tuberculosis, by Robert Koch, this disease remains one of the major causes of human morbidity and mortality. There are an estimated 3 million deaths annually attributable to tuberculosis (Snider, 1989), and although the majority of these are in developing countries, the disease is assuming renewed importance in the West due to the increasing number of homeless people and the impact of the AIDS epidemic (Chaisson et al., 1987; Snider and Roper, 1992). Web site: http://www.delphion.com/details?pn=US05851763__
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Rapid detection of isoniazid resistance in mycobacterium tuberculosis probes for selecting nucleic acid encoding isoniazid resistance, and methods and kits Inventor(s): Zhang; Ying (London, GB2), Heym; Beate (Paris, FR), Cole; Stewart T. (Clamart, FR), Young; Douglas B. (Middlesex, GB) Assignee(s): Institut Pasteur (Paris, FR), Medical Research Council (London, GB), Assistance Publique (Paris, FR), Universite Paris VI (Paris, FR) Patent Number: 5,633,131 Date filed: August 14, 1992 Abstract: Multi-drug resistant strains of Mycobacterium tuberculosis represent a considerable threat to public health worldwide. Resistance to isoniazid (INH), a key component of anti-tuberculosis regimens, is often associated with loss of catalase activity and virulence. The katG gene, encoding HPI catalase-peroxidase, mediates INHsensitivity and that the high level resistance encountered clinically may be due to deletions, insertions or point mutations which reduce or eliminate the expression of the catalase gene in the chromosomal region encompassing katG. INH-resistant strains of Mycobacterium tuberculosis are detected by nucleic acid hybridization with a unique nucleic acid sequence or by amplification techniques. Excerpt(s): Despite more than a century of research since the discovery of Mycobacterium tuberculosis, the aetiological agent of tuberculosis, by Robert Koch, this disease remains one of the major causes of human morbidity and mortality. There are an estimated 3 million deaths annually attributable to tuberculosis (Snider 1989), and although the majority of these are in developing countries, the disease is assuming renewed importance in the West due to the increasing number of homeless people and the impact of the AIDS epidemic (Chaisson et al., 1987; Snider and Roper, 1992). Isonicotinic acid hydrazide or isoniazid (INH) has been used in the treatment of tuberculosis for the last forty years due to its exquisite potency against the members of the "tuberculosis" groups--Mycobacterium tuberculosis, M. bovis and M. africanum (Middlebrook, 1952; Youatt, 1969). Neither the precise target of the drug, nor its mode of action are known and INH treatment results in the perturbation of several metabolic pathways. There is substantial evidence indicating that INH may act as an antimetabolite of NAD and pyridoxal phosphate (Bekierkunst and Bricker, 1967; Sriprakash and Ramakrishnan, 1970; Winder and Collins, 1968, 1969, 1970), and other data indicating that the drug blocks the synthesis of the mycolic acids, which are responsible for the acid-fast character of mycobacterial cell walls (Winder and Collins 1970; Quemard et al., 1991). Shortly after its introduction, INH-resistant isolates of Mycobacterium tuberculosis emerged and, on characterization, were often found to have lost catalase-peroxidase activity and to show reduced virulence in guinea pigs (Middlebrook et al., 1954; Kubica et al., 1968; Sriprakash and Ramakrishnan, 1970). Very recently, INH-resistance has acquired new significance owing to a tuberculosis epidemic in the USA due to multi-drug resistant (MDR) variants of M. tuberculosis (CDC, 1990; 1991a, b) and the demonstration that such strains were responsible for extensive nosocomial infections of HIV-infected individuals and health care workers (Snider and Roper, 1992). In view of the gravity of this problem, there exists a need in the art to determine the relationship between INH-resistance and catalase-peroxidase production. Web site: http://www.delphion.com/details?pn=US05633131__
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Rapid detection of mycobacterium tuberculosis Inventor(s): Herold; Christopher D. (205 12th St., Del Mar, CA 92014), O'Hagan; Michael (1160 Via Espana, La Jolla, CA 92037) Assignee(s): none reported Patent Number: 5,776,723 Date filed: February 8, 1996 Abstract: A rapid, sensitive method for the detection of M. tuberculosis. A sample suspected of containing M. tuberculosis is extracted, derivatized and analyzed for the presence of two particular characterizing compounds specific to M. tuberculosis. One preferred analytical method involves a fuzzy matching process. Excerpt(s): A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all rights whatsoever. The present invention relates to rapid detection of mycobacteria. More specifically, the invention relates to the detection of two characterizing compounds specific to Mycobacterium tuberculosis. Tuberculosis (TB), a chronic, recurrent infection most common in the lungs, is caused by several species of mycobacteria, the most common of which is M. tuberculosis. TB has reached global epidemic proportions with approximately one-third of the world's population infected and is the largest cause of death arising from a single pathogen. With global control of TB remaining at the 1990 level, it is estimated that 30 million people will die from TB in the last decade of the 20th century (Tuberculosis: Pathogenesis, Protection and Control, Snider et al., eds., ASM Press, Washington, D.C., 1995). Web site: http://www.delphion.com/details?pn=US05776723__
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Rapid immunoassay to detect infection with Mycobacterium tuberculosis Inventor(s): Simonson; Lloyd Grant (Spring Grove, IL), Ralls; Stephen Alden (McLean, VA) Assignee(s): The United States of America as represented by the Secretary of the Navy (Washington, DC) Patent Number: 6,599,691 Date filed: February 24, 1997 Abstract: A rapid, non-invasive, semi-quantitative immunoassay of saliva has been developed to aid in the diagnosis of diseases, e.g., using saliva to detect subjects actively or previously infected with Mycobacterium tuberculosis, a causative organism of tuberculosis. The semi-quantitative assay comprises spotting disease-related antigens on the surface of a solid substrate; contacting the solid substrate with a saliva sample which, in positive subjects, contains primary antibodies to the disease-related antigens; contacting the primary antibodies with a label capable of being detected; and detecting and reading the label whereby exposure to the antigens is determined. The device for conducting these assays is a frame or support which holds a solid substrate capable of immobilizing the antigens of interest while permitting drainage of other materials or fluids away from the immobilized antigens. A less rapid, quantitative assay has also been developed by adapting the rapid, semi-quantitative assay to an enzyme linked
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immunosorbant assay thereby providing a quantitative assay capable of assessing multiple saliva samples simultaneously. Excerpt(s): This invention relates to a rapid immunoassay kit and method for semiquantitatively detecting antibodies in human saliva to antigens of disease-related microorganisms, e.g., antibodies to Mycobacterium tuberculosis. This invention also encompasses an alternative embodiment that permits quantitative, though less rapid, detection of antibodies in saliva by adapting the methodology of the semi-quantitative immunoassay to an enzyme linked immunosorbant assay (ELISA). Within this invention, this alternative embodiment is referred to as the quantitative immunoassay, or similar, to distinguish it from the rapid, semi-quantitative immunoassay. Though not substantially related to the invention described herein, there have been several efforts of peripheral interest. Ebersole has described a SEROLOGICAL METHOD FOR THE IDENTIFICATION OF MICROORGANISMS in U.S. Pat. No. 4,458,014 for the identification of diseases of the mouth. Chen et al. have described in U.S. Pat. No. 4,866,167 a DETECTION OF HUMAN ORAL CELLS BY NUCLEIC ACID HYBRIDIZATION to detect oral bacterial species. The methods of both Ebersole and Chen et al. are technically complex, time consuming, not rapid and are not based on detecting antibodies in saliva to antigens of disease-related microorganisms. Olson et al. have described an IMMUNOLOGICAL COLOR CHANGE TEST INVOLVING TWO DIFFERENTLY COLORED REAGENT SPOTS in U.S. Pat. No. 4,639,419. Their patent describes a substantially different methodology than that described herein. This test is an agglutination reaction directed toward identifying antigenic material wherein a colored substrate and colored reagent combine, in positive reactions, to give the appearance of a third color. Web site: http://www.delphion.com/details?pn=US06599691__ •
Recombinant M. tuberculosis auxotrophic for leucine and vaccines using same Inventor(s): Bloom; Barry R. (Hastings on Hudson, NY), Hondalus; Mary K. (Northborough, MA), Jacobs, Jr. William R. (City Island, NY) Assignee(s): Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) Patent Number: 6,562,348 Date filed: July 8, 1999 Abstract: The present invention provides a recombinant M. tuberculosis mycobacterium that is auxotrophic for leucine. The present invention also provides a vaccine comprising a recombinant M. tuberculosis mycobacterium that is auxotrophic for leucine, as well as a method for treating or preventing tuberculosis in a subject comprising administering to the subject a recombinant M. tuberculosis mycobacterium that is auxotrophic for leucine in an amount effective to treat or prevent tuberculosis in the subject. Excerpt(s): Approximately one third of the world's population is infected with Mycobacterium tuberculosis (MTB), the causative agent of human tuberculosis (TB). MTB is responsible for 2-3 million deaths annually, giving it the dubious distinction of being the leading cause of death due to a single infectious agent. In addition, TB ranks seventh in causes of global mortality and disability, and if current predictions prove correct, it will remain among the top 10 causes of disease, well into the next century (Murray and Lopez, Lancet, 349:1498-1504 (1997)). Directly observed treatment, shortcourse (DOTS) is the tactic proposed by the World Health Organization (WHO) to control the global TB crisis (Murray and Solomon, PNAS USA, 95:13881-13886 (1998)).
Patents 425
DOTS has proven to be an effective strategy in several national TB control programs, with cure rates approaching 90% (Lancet, 347:358-362 (1996)). However, since global implementation of DOTS programs is occurring at a slow-moving pace, it is likely that additional measures will be needed to stem the tide of TB mortality. It has been estimated that the introduction of a new vaccine of only 50% efficacy could decrease the incidence of TB by 36 million cases, saving 9 million lives (Murray and Salomon, 1998). Thus, by coupling efficacious vaccination with effective treatment, greater success in global TB management would be anticipated. Bacille Calmette-Guerin (BCG), an attenuated strain of M. bovis, is the currently available vaccine for the prevention of tuberculosis. It was created empirically by repeated passage in the laboratory, and for reasons that are as yet undefined, it is avirulent in immunocompetent hosts. In several animal models of infection, BCG has been demonstrated to induce protective immunity against MTB. Since its implementation in 1928 as a TB vaccine, more doses of BCG have been administered than any other vaccine, as an estimated 3 billion people have received BCG vaccination for the prevention of tuberculosis. Although the use of BCG is unquestionably safe in immunocompetent individuals, it has shown itself to be of variable efficacy. While in certain populations, vaccination with BCG has been highly effective in preventing tuberculosis, in others it has failed miserably. In the largest clinical trial that took place in India involving more that 100,000 persons, BCG exhibited a calculated protective efficacy of zero. Thus, the generation of an improved vaccine(s) to replace BCG and to prevent tuberculosis is urgently needed. Relative to wildtype M. tuberculosis, 15-16 regions of the MTB genome are not represented in BCG. Eleven of these segments cannot be found even in virulent strains of M. bovis; of the remaining 5, 4 are missing from all BCG strains examined. It is probable that one or more of the 38 open reading frames (ORFs) specifically missing from BCG are required for virulence. Of interest, is the finding that a number of predicted transcriptional regulators identified by the H37Rv genome sequencing project (Cole, et al., Nature, 393:537-544 (1998)) would be located in these BCG deletions. The loss of a regulatory protein would be expected to affect multiple genetic loci and could lead to deranged gene expression in vivo. Consistent with this hypothesis, is the demonstration that reintroduction of one of these deleted regions into BCG results in the repression of at least 10 proteins and the upregulated expression of others. It is conceivable that potentially immunogenic and immunoprotective antigens might be missing from or inappropriately expressed in BCG, and therefore, compromising the immune response generated from this vaccine. For example, it has been noted that the gene for ESAT 6, a highly immunogenic, secreted protein of M. tuberculosis, is located within one of these deleted chromosomal regions. It has been demonstrated that protective immunity against experimental tuberculosis can be provided by prior immunization with supernatants containing a mixture of MTB secreted antigens, of which ESAT 6 is one. It is possible, that if one or more of the proteins encoded within the deleted regions were present at vaccination, the immune response elicited might be more efficacious. Web site: http://www.delphion.com/details?pn=US06562348__
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Recombinant polypeptides and peptides, nucleic acids coding for the same and use of these polypeptides and peptides in the diagnostic of tuberculosis Inventor(s): Content; Jean (Rhode St Genese, BE), De Wit; Lucas (Puurs, BE), De Bruyn; Jacqueline (Beersel, BE), Van Vooren; Jean-Paul (St-Pieters Leeuw, BE) Assignee(s): N.V. Innogenetics S.A. (Ghent, BE) Patent Number: 5,916,558 Date filed: May 22, 1995 Abstract: The invention relates to recombinant polypeptides and peptides which can also be used for the diagnosis of tuberculosis. The invention also relates to a process for preparing the above polypeptides and peptides, which are in a state of biological purity such that they can be used as part of the active principle in the preparation of vaccines against tuberculosis. The invention additionally relates to nucleic acids coding for said polypeptides and peptides. Excerpt(s): The invention relates to recombinant polypeptides and peptides, which can be used for the diagnosis of tuberculosis. The invention also relates to a process for preparing the above-said polypeptides and peptides, which are in a state of biological purity such that they can be used as part of the active principle in the preparation of vaccines against tuberculosis. It also relates to nucleic acids coding for said polypeptides and peptides. Furthermore, the invention relates to the in vitro diagnostic methods and kits using the above-said polypeptides and peptides and to the vaccines containing the above-said polypeptides and peptides as active principle against tuberculosis. Web site: http://www.delphion.com/details?pn=US05916558__
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Regulation of a sigma factor from Mycobacterium tuberculosis Inventor(s): DeMaio; James (Tacoma, WA), Bishai; William R. (Baltimore, MD) Assignee(s): The Johns Hopkins University (Baltimore, MD) Patent Number: 5,824,546 Date filed: March 27, 1996 Abstract: Two genes, orfX and orfY, regulate sigF expression and sigF activity in M. tuberculosis. M. tuberculosis sigF, orfX, and orfY are used in screening methods for potential therapeutic agents which regulate the growth of M. tuberculosis. Excerpt(s): The present invention is broadly directed to reagents and methods for developing novel therapeutics for treating active and latent M tuberculosis. Tuberculosis is the leading cause of death due to infection, causing an estimated 2.5 million deaths and 7.5 million cases per year worldwide (1). In the United States, rates of tuberculosis began to increase in 1985 after 40 years of steady decline. In addition, a number of American cities are reporting high rates of infection by multiply drug resistant tuberculosis. Such mycobacteria cause a high mortality rate because available antibiotics are ineffective (2). About 90% of individuals who become infected with M. tuberculosis do not have immediate symptoms but develop a positive reaction to the tuberculin skin test and carry the bacteria in a dormant or latent state (3). Over a lifetime, these individuals have a 10% risk of developing reactivation tuberculosis in which, after years of quiescence, the tubercle bacilli resume growth and cause classic pulmonary tuberculosis as well as other forms of disease. One billion people, roughly one-third of the world's population, have latent tuberculosis (4). Individuals with latent tuberculosis
Patents 427
currently require prolonged therapy because antimycobacterial drugs work poorly against dormant bacilli. Web site: http://www.delphion.com/details?pn=US05824546__ •
Repetitive DNA sequence specific for mycobacterium tuberculosis to be used for the diagnosis of tuberculosis Inventor(s): Bates; Joseph H. (Little Rock, AR), Crawford; Jack T. (Atlanta, GA), Eisenach; Kathleen D. (Little Rock, AR), Cave; M. Donald (Little Rock, AR) Assignee(s): The Board of Trustees of the University of Arkansas (Little Rock, AR) Patent Number: 5,183,737 Date filed: October 1, 1991 Abstract: A novel composition and/or methods for the diagnosis of tuberculosis wherein the composition comprises a repetitive DNA segment that is specific for members of the Mycobacterium tuberculosis complex. The DNA segment repeats in the chromosome of Mycobacterium tuberculosis complex, and is conserved in all copies of the chromosomes. A method comprises using an entire repetitive DNA sequence, or any part thereof, as a hybridization probe for the direct detection of Mycobacterium tuberculosis complex in clinical material. In another method, a smaller portion of an entire repetitive DNA sequence is amplified using polymerase chain reaction, yielding a 123 base-pair product. Excerpt(s): The present invention relates to a specific DNA sequence. More precisely, the present invention relates to a composition comprising a specific DNA sequence that is unique to a pathogenic microorganism. The present invention further relates to the utilization of the composition to detect the pathogenic microorganism in clinical material. Tuberculosis, an infectious disease caused by the microorganism Mycobacterium tuberculosis, continues to remain a major global health problem. In the United States, tuberculosis still persists as a significant health problem, particularly in underprivileged and minority populations, among immigrants from high-risk countries, and in other high-risk groups, such as individuals with human immunodeficiency viral infections. A definitive diagnosis of tuberculosis depends upon the isolation of Mycobacterium tuberculosis (sometimes referred to hereinafter as "M. tuberculosis") from the secretions or tissues of an infected individual in conjunction with clinical findings of the disease. Because of the length of time required for isolation of M. tuberculosis and the subsequent diagnosis of tuberculosis, a long-standing goal of researchers has been to develop a rapid, sensitive, and specific test for the detection of the organism in clinical specimens. Such a test could substantially decrease the time required to definitively diagnose tuberculosis, and assist the health care provider in administering the appropriate therapeutic treatment. Web site: http://www.delphion.com/details?pn=US05183737__
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SecA gene of mycobacterium tuberculosis and related methods and compositions Inventor(s): Owens; Marie U. (Tucker, GA), Quinn; Frederick D. (Decatur, GA), King; C. Harold (Rex, GA), Schmidt; Michael G. (Mt. Pleasant, SC) Assignee(s): The United States of America as represented by the Department of Health (Washington, DC) Patent Number: 5,885,828 Date filed: February 14, 1997 Abstract: An isolated nucleic acid encoding a SecA protein of M. tuberculosis is provided. This nucleic acid can be a native coding sequence for the SecA protein of M. tuberculosis. A specific example of the isolated nucleic acid is one that encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:2. An isolated fragment of the secA gene that is specific for M. tuberculosis is provided. A purified SecA protein of Mycobacterium tuberculosis is provided. The purified SecA protein of Mycobacterium tuberculosis comprises the polypeptide having the sequence set forth in the Sequence Listing as SEQ ID NO:2. Fragments of the M. tuberculosis SecA protein are provided. A purified mutant SecA protein of Mycobacterium tuberculosis is provided. The invention provides purified mutant M. tuberculosis expressing the mutant SecA protein of the invention. The invention also provides methods of screening for putative M. tuberculosis virulence factors translocated by the SecA protein. Excerpt(s): Mycobacterium tuberculosis remains one of the leading world health problems despite attempts at modern chemotherapy and vaccination. Tuberculosis is blamed for 2-3 million deaths each year worldwide, and is being diagnosed in increasing measure in developed countries, a phenomenon attributed to the AIDS epidemic. This resurgence of tuberculosis has magnified the need to understand the molecular mechanisms involved in the pathogenesis of M. tuberculosis. M. tuberculosis is a facultative intracellular pathogen that establishes respiratory infection following inhalation of the bacilli into the alveoli of the lungs. The tubercle bacilli establish themselves intracellularly in monocytes, macrophages and reticuloendothelial cells. Cell to cell spread may be accomplished through the lysis of a previously infected host cell. Additionally, the organism is able to survive and grow in the extracellular spaces of lung tissue containing liquefaction residue. Despite the huge toll in life and resources taken by M. tuberculosis, universally useful vaccines and diagnostic tests for active tuberculosis are currently unavailable. The development of more appropriate candidates is critical, especially with the current rapid spread of the disease world-wide. Recent studies have implicated the importance of extracellular mycobacterial proteins as virulence factors. By examining the secretion process present in mycobacteria, it may be possible to identify virulence factors that are expressed during human infection and may lead to the development of more effective vaccinations, treatment options as well as a more specific and rapid diagnosis of the disease. In this regard, public protein export has been well characterized in Escherichia coli. Yet, only recently have homologs for several of the Sec factors including SecA have been identified in Gram positive species and now, the Mycobacteria. Web site: http://www.delphion.com/details?pn=US05885828__
Patents 429
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Specific detection of the mycobacterium tuberculosis Inventor(s): Guesdon; Jean-Luc (Sevres, FR), Thierry; Dominique (Boulogne, FR) Assignee(s): Institut Pasteur (Paris, FR) Patent Number: 5,776,693 Date filed: June 5, 1995 Abstract: The invention relates to a nucleic acid fragment derived from the Mycobacterium tuberculosis genome, characterized in that it contains one of the sequences I, II, III and IV, defined in the following manner: I: a sequence chosen from one of the sequences A to H: A: 5'-CCCGCGGCAAAGCCCGCAGGACCACGATCG-3' (SEQ ID NO. 1); B: 5'-CGACCCGCCAGCCCAGGATCCTGCGAGCGT-3' (SEQ ID NO. 2); C: 5'-GGCGGGTCCAGATGGCTTGCTCGATCGCGT-3' (SEQ ID NO. 3); D: 5'-GTTGGCGGGTCCAGATGGCTTGCTCGATCG-3' (SEQ ID NO. 4); E: 5'-TCAAAGGGTTTGACAAATTAATGATTGGTC-3' (SEQ ID NO. 5); F: 5'-TCGTGTACAAAATGTGGACAAGTA-3' (SEQ ID NO. 6); G: 5'-TCGACGGACGTCGTGACCAGAAGTC-3' (SEQ ID NO. 7); H: 5'-GTCGACACGCCTTCTGCACGGGAAGTCCTT-3' (SEQ ID NO. 8). II: a sequence containing at least 10 consecutive bases of one of the sequences A to F And having a total length of approximately 20 to 40 bases;III: a sequence having a length of 20 to 40 bases which hybridizes with the sequence I or with the sequence II, and which preferably displays at least 80% homology with these sequences;IV: a sequence complementary to one of the sequences I, II and III. Excerpt(s): The invention relates to a specific nucleic acid sequence of Mycobacterium tuberculosis, as well as to particular fragments of this sequence capable of playing the role of nucleic acid primers in the amplification of DNA originating from Mycobacterium in a biological sample. The invention also relates to a method for the detection of Mycobacterium tuberculosis in a biological sample, this method making use of the said nucleic acid primers. The mycobacteria correspond to the genus Mycobacterium which comprises at least 54 different species. Among the latter, about 10 are pathogenic or opportunistic pathogens for man or animals. M. tuberculosis is the agent responsible for tuberculosis. Web site: http://www.delphion.com/details?pn=US05776693__
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Super fast tuberculosis diagnosis and sensitivity testing method Inventor(s): Ledley; Robert S. (1002 La Grande Rd., Silver Spring, MD 20903) Assignee(s): none reported Patent Number: 5,922,282 Date filed: June 7, 1995 Abstract: Very rapid diagnosis and sensitivity testing can significantly stem the growing Tuberculosis epidemic in the United States, caused by susceptible AIDs patients and the occurrence of antibiotic resistant mycobacilli. Thus I have invented an automated computerized microscope, the ATBD unit, and slide module to diagnose and test patient's sputum by examining individual living mycobacteria from the patient sample with no culturing required. The diagnosis and sensitivity testing is accomplished in
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minutes or hours, instead of the current weeks to months. The system inserts a plasmid, specific for M. tuberculosis, carrying the luciferase gene into the mycobacteria by improved electroporesis on the slide. Luminescence indicates tuberculosis. Then the mycobacteria are bathed in antibiotics, and if the luminescence is not turned off, the patient's bacteria are resistant. A phage carrying the luciferase gene can also be used to infect the M.TB. Finally, the invention can be applied to any mycobacteriological infection to do diagnosis sensitivity testing even when the species is not known. Excerpt(s): My invention is a complex multi-component apparatus using several technologies in a cross-disciplinary manner, which, in addition to performing very rapid tuberculosis diagnosis and sensitivity, can contribute importantly to establishing a new approach to clinical microbiology. The purpose of this invention is to automatically be capable of diagnosing tuberculosis and performing antibiotic sensitivity testing on the mycobacteria within hours, rather than taking many weeks or months. This is one of the top objectives of the United States' tuberculosis control and research programs. Public health officials fear a resurgence of Tuberculosis due to AIDS patients, most of whom get Tuberculosis, and also, most importantly, due to the antibiotic resistance being developed by the Tuberculosis mycobacteria themselves. By making the diagnosis and sensitivity testing rapidly, this resurgence can be aborted because patients would be treated on the day that they came for the diagnosis. Otherwise the patients are either hospitalized for at least $800.00 a day while waiting for the diagnosis, or they are let out into the community where they infect others, or they are inappropriately treated with antibiotics before the sensitivity diagnosis is made, which has helped breed resistant bacteria. ›1,2! It is a serious and rapidly growing problem, especially due to AIDs patient's vulnerability not only to mycobacterium tuberculosis, but to other types of mycobacteria, such as avium, kansasii, etc. Web site: http://www.delphion.com/details?pn=US05922282__ •
Test substance for tuberculosis Inventor(s): Kniker; William T. (San Antonio, TX) Assignee(s): Lincoln Laboratories, Inc. (Decatur, IL) Patent Number: 3,969,497 Date filed: May 5, 1971 Abstract: A new test substance for use in skin testing for tuberculosis, which substance is produced from Mycobacterium tuberculosis (M.tb.) culture filtrate or bacillary extract. The culture filtrate or extract is first fractionated by means of chromatography. Resultant fractions are then further fractionated so as to produce subfractions which contain at least one M.tb. specific antigen and are substantially free of antigens crossreactive with atypical mycobacteria. At least two of these subfractions may then be combined to produce a mix or new test substance, containing a plurality of M.tb. specific antigens only, capable of stimulating lymphocytes in individuals previously sensitized to M. tuberculosis antigens. Excerpt(s): This invention relates to an improved antigenic substance for testing for tuberculosis and to the method for preparing such antigenic substance. It has been known for many years that exposure of a human being to the disease commonly known as tuberculosis, resulting from an infection by Mycobacterium tuberculosis (M. tb.) may be tested for by an intradermal injection of antigenic material derived from tubercle bacilli or their products. The antigenic material, tuberculin, induces sensitized
Patents 431
lymphocytes to initiate a delayed hypersensitivity response at the site of the injection. The subsequent swelling at that site is known as edema or induration, and the reddening in the area is known as erythema. After a selected lapse of time, generally 48 to 72 hours, the size of the edematous swelling is measured and compared to previously established statistical standards that relate size of reaction after a particular dose of antigen to probability and recentness of prior infection with M. tb. Thus, an evaluation is made as to whether the injectee is a "positive" or "negative" reactor. A number of antigenic materials or tuberculins exist or have been suggested, and a number of intradermal injectors have been used. The classical standard of injector is a needle and syringe using a technique known throughout medical literature as the "Mantoux test", a technique that requires considerable skill both in administration and in evaluating the results. Other injectors and techniques include and have included a simple scratch test, the "Vollmer" patch test, multiple scratch scarifications by an instrument known as the Heaf gun (also known by the Trademark "Sterneedle"), or by simultaneous skin puncture and injection as effected by instruments known as "Mono-Vacc" of Lincoln Laboratories and "Tine Test" of Lederle Laboratories. For reasons that are unimportant here, the Mantoux test is generally accepted as a standard diagnostic test while use of the other instruments is generally considered a "screening" test useful as a first test in screening from a large group of humans being tested, those who appear to be clearly positive reactors. Some of the test noted, such as the Vollmer patch test, have been discarded as unreliable. Web site: http://www.delphion.com/details?pn=US03969497__ •
Tuberculosis vaccine Inventor(s): Andersen; Peter (Bronshoj, DK), Andersen;.ANG.se Bengaard (Bronshoj, DK), Sorensen; Anne Lund (Bronshoj, DK), Haslov; Kaare (Soborg, DK) Assignee(s): Statens Seruminstitut (Copenhagen, DK) Patent Number: 5,955,077 Date filed: June 5, 1995 Abstract: The invention relates to novel secreted antigens from mycobacteria capable of evoking early (within 4 days) immunological responses from T-helper cells in the form of gamma-interferon release in memory immune animals after rechallenge infection with mycobacteria of the tuberculosis complex. The antigens are present in short term filtrates (ST-CF) from cultured mycobacteria belonging to the tuberculosis complex. One of these antigens, a polypeptide with an apparent molecular weight of 6 kDa, has been identified, and the DNA encoding the polypeptide has been cloned and sequenced. The antigens of the invention are believed useful especially in vaccines, but also in diagnostic compositions, especially for diagnosing infection with virulent mycobacteria. Also disclosed are nucleic acid fragments encoding the antigens as well as methods of immunizing animals/humans and methods of diagnosing tuberculosis. Excerpt(s): The present invention relates to a novel vaccine for immunizing an animal, including a human being, against tuberculosis. The invention further relates to methods and means for the diagnosis of tuberculosis. Human tuberculosis caused by Mycobacterium tuberculosis is a severe global health problem responsible for approximately 3 million deaths annually (NIH report). The worldwide incidence of new tuberculosis cases has been progressively falling for the last decade but the recent years has markedly changed this trend due to the advent of AIDS and the appearance of multidrug resistant strains of M. tuberculosis (Rieder). The only vaccine presently
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available is BCG, a vaccine which efficacy remains a matter of controversy. BCG generally induces a high level of acquired resistance in animal models of tuberculosis (Smith), but several human trials in developing countries have failed to demonstrate significant protection (Fine). Web site: http://www.delphion.com/details?pn=US05955077__
Patent Applications on Tuberculosis As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to tuberculosis: •
1'-Acetoxychavicol acetate for tuberculosis treatment Inventor(s): Kittakoop, Prasat; (Prathumthani, TH), Kirdmanee, Chalermpol; (Bangkok, TH), Palittapongarnpim, Prasit; (Bangkok, TH), Rukseree, Kamolchanok; (Bangkok, TH) Correspondence: Mr. Prasit Palittapongarnpim; 113 Thailand Science Park, Paholyothin Rd. Klong 1, Klong Luang; Pathumthani; 12120; TH Patent Application Number: 20020192262 Date filed: May 23, 2002 Abstract: 1'-Acetoxychavicol acetate is a compound not known before to possess antituberculous activity. The above data revealed that the compound was active against the standard H37Ra strain as well as several clinical isolates at the concentration well below the toxic concentration against various mammalian cells. The compound is therefore potentially useful as an therapeutic and preventive agent for tuberculosis as well as an antiseptic agent against the bacteria. Excerpt(s): Many investigators reported growth-inhibiting activities of 1-acetoxychavicol acetate against many organisms. It could inhibit the growth of various fungi (Jassen, A. M. and Scheffer, J. J. C. 1985), including many dermatophytic fungi such as Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton concentricum and Epidermophyton floccosum with the minimal inhibitory concentrations (MIC) between 50-250.mu.g/ml. It also inhibited the growth of several other fungi such as Rhizopus stolonifer, Penicillium expansum, Aspergilus niger, albeit with higher MIC. This compound could not inhibit the growth of the yeast Candida albicans, and many bacteria, such as Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis but could slightly inhibit the growth of Staphylococcus aureus. There has been no existing report on the inhibitory activity against the growth of M. tuberculosis and other mycobacterium of this compound. 1'-Acetoxychavicol acetate can inhibit the formation of many tumor and cancer in mice experimental models, such as skin cancer (Murakami, A. et.al., 1996), bile duct cancer (Miyauchi, M. et.al. 2000), esophageal cancer (Kawabata, K. et.al. 2000), large intestinal cancer (Tanaka, T. et.al. 1997 and Tanaka, T. et.al. 1997), oral cancer (Ohnishi, M. et.al. 1996) and liver tumor (Kobayashi, Y. et.al. 1998). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
10
This has been a common practice outside the United States prior to December 2000.
Patents 433
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A METHOD FOR PREPARING MASSIVELY RmlC PROTEIN AND PURIFIED RmlC PROTEIN OF MYCOBACTERIUM TUBERCULOSIS BY IT Inventor(s): Lee, Tae-Yoon; (Taegu-shi, KR) Correspondence: MERCHANT & GOULD PC; P.O. BOX 2903; MINNEAPOLIS; MN; 55402-0903; US Patent Application Number: 20030166234 Date filed: March 22, 2002 Abstract: This invention relates to a mass preparation method of RmlC protein and the purified RmlC protein by the said method. RmlC is a gene product of rmlC, which is one of the biosynthesis genes of rhamnose that is an important element that consists cell wall of Mycobacterium tuberculosis. To be more specific, this invention improves the following disadvantage of recombinant RmlC protein of Mycobacterium tuberculosis previously reported that contains unnecessary 15 amino acids into the natural RmlC protein. This invention relates to a recombinant plasmid, a recombinant E. coli that is transformed by the plasmid, preparation method of Mycobacterium tuberculosis RmlC recombinant protein using the recombinant E. coli, purification method of recombinant RmlC protein, and the RmlC protein purified by the said method. Excerpt(s): This invention relates to a mass preparation method of RmlC protein, a gene product of rmlC that is one of the genes synthesizing rhamnose, which is an important element that constitutes cell wall of Mycobacterium tuberculosis. To be more specific, this invention relates to an improvement of disadvantages such as expression efficiency reduction of RmlC protein for the development of anti-tuberculosis drug(s) because of the fusion of 15 unnecessary amino acids into Mycobacterium tuberculosis RmlC recombinant protein as reported previously (Stern R. J. et al. Microbiology 145:663671(1999)), problems of crystal formation because of the fusion of unnecessary amino acids when crystal of RmlC protein is formed, and extension of required time because of the fusion of unnecessary amino acids when the structure of RmlC protein is determined by X-ray crystallography. This method contains a recombinant plasmid that expresses RmlC protein itself without unnecessary amino acids and a method that can produce RmlC protein of Mycobacterium tuberculosis in large quantities that contains enzymatic activity of the corresponding RmlC protein, a recombinant E. coli transformed by the plasmid, a preparation method of Mycobacterium tuberculosis RmlC recombinant protein using E. coli, a purification method of recombinant RmlC protein prepared by said method, and the RmlC protein purified by said method. Approximately 1.7 billion people, 32% of the world population, are infected by tuberculosis. There are 8 million new patients every year and about 34% of them, 2.7 million, died from this serious disease. In Korea, it is estimated that there are approximately 0.7 million tuberculosis patients, 0.14 million new patients every year, and 4,000 people died from the disease. Therefore, tuberculosis remains as a serious health problem. Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis and currently the prevalence is increasing worldwide as a complication, of acquired immunodeficiency syndrome(AIDS). Also, many of the recent Mycobacterium tuberculosis has multipledrug resistance that makes tuberculosis treatment more difficult. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Agar medium for the growth of Mycobacterium tuberculosis Inventor(s): Heifets, Leonid; (Denver, CO), Sanchez, Tracy; (Lafayette, CO) Correspondence: Angela Dallas-Pedretti; SHERIDAN ROSS P.C. 1560 Broadway, Suite 1200; Denver; CO; 80202-5141; US Patent Application Number: 20010055787 Date filed: March 20, 2001 Abstract: A novel agar medium for the isolation, sub-cultivation, and indirect or direct drug-susceptibility testing of Mycobacterium tuberculosis is disclosed. Also disclosed are methods of isolating and growing Mycobacterium tuberculosis and methods of drug-resistance screening using the agar medium of the invention. Excerpt(s): This application claims the benefit of priority under 35 U.S.C.sctn. 119(e) from U.S. Provisional Application Ser. No. 60/190,701, filed Mar. 20, 2000, and entitled "New Agar Medium For Mycobacterium tuberculosis". The entire disclosure of U.S. Provisional Application Ser. No. 60/190,701 is incorporated herein by reference. This invention relates to a novel agar medium for the isolation, sub-cultivation, and indirect or direct drug-susceptibility testing of Mycobacterium tuberculosis. The invention also relates to methods of isolating and growing Mycobacterium tuberculosis and to methods of drug-resistance screening using the agar medium of the invention. At first glance, it seems that nothing is new in the cultivation of Mycobacterium tuberculosis. The first attempts of M. tuberculosis cultivation on agar medium go back to the report by Fannie and Walter Hesse in 1881. In 1882, Robert Koch used blood serum coagulated on glass slides for M. tuberculosis cultivation. Apparently, he was not too much concerned about the biosafety of such a procedure. He later improved this method, which was called the "plate technique", by adding peptone, some salts and glycerol. Also, in 1882, Richard Petri invented the petri dish to be used instead of a glass slide. These attempts at cultivation on a transparent type of media were interrupted in 1903 with introduction of the first egg-based media by Dorset (Dorset, Science. 17:374, 1903), followed by a variety of egg-based media recipes (American Trudeau Society, Handbook of Tuberculosis Laboratory Methods, Washington, D.C., 1962; IUAT, Bull Int Union Tuberc Lung Dis. 24:78, 1954; Jensen, Abteilung Originale. 125:222-239, 1932; Ogawa et al., Kekkaku. 24:13-29, 1949; Petragnani, Bollettino dell'Istituto sieroterapico Milanese. 5:173-185,1926; Petroff, J. Exp. Med. 21:38-42, 1915; Stonebrink, Acta Tuberc. Scand. 35:67-80, 1958). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compositions and methods for detecting multidrug resistant strains of M. tuberculosis having mutations in genes of the mutT family Inventor(s): Gicquel, Brigitte; (Paris, FR) Correspondence: FINNEGAN, HENDERSON, FARABOW, GARRETT &; DUNNER LLP; 1300 I STREET, NW; WASHINGTON; DC; 20006; US Patent Application Number: 20030129619 Date filed: August 13, 2002 Abstract: The present invention pertains to polynucleotides derived from M. tuberculosis genes imparting resistance to antibiotics and chemically related compounds. This invention also relates to the use of the polynucleotides as
Patents 435
oligonucleotide primers or probes for detecting M. tuberculosis strains that are resistant to antibiotics and related compounds in a biological sample. Kits containing the primers and probes are also provided. Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application No. 60/311,824, filed Aug. 14, 2001, and U.S. Provisional Patent Application No. 60/313,523, filed Aug. 21, 2001, the disclosures of each of which are incorporated herein by reference in their entirety. The present invention pertains to polynucleotides derived from Mycobacterium tuberculosis (M. tuberculosis) genes that aid in imparting resistance to antibiotics and chemically related compounds. This invention also relates to the use of the polynucleotides as oligonucleotide primers or probes for detecting M. tuberculosis strains that are resistant to antibiotics and related compounds in a biological sample. The present invention is also directed to diagnostic kits for detecting specific strains of M. tuberculosis expected to be contained in a biological sample. Tuberculosis remains the world's leading infectious cause of adult deaths due to a single pathogen. Outbreaks of Multidrug-Resistant (MDR) tuberculosis defined as resistant to rifampicin and isoniazid are numerous, with low rates of treatment response and very high mortality. Some of these outbreaks involve patients with HIV infection (1, 2). In some reports, strains with a particular genotype have been identified, such as the "W" strain, which caused a major outbreak in New York (3). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compositions and methods for the prevention, treatment and detection of tuberculosis and other diseases Inventor(s): Leishman, Kathryn; (Los Angeles, CA) Correspondence: HELLER EHRMAN WHITE & MCAULIFFE LLP; 1666 K STREET,NW; SUITE 300; WASHINGTON; DC; 20006; US Patent Application Number: 20030108927 Date filed: October 7, 2002 Abstract: Methods and compositions are provided for the prevention and treatment of infectious diseases such as syphilis, tuberculosis, pneumonia, other bacterial infections, AIDS, and other viral infections. Many of the compositions are active against carbon monoxide dehydrogenase ("CODH"), and include substances such as antigens, antibodies specific for CODH, and other inhibitors of CODH such as nickel and molybdenum metal chelators. The methods and compositions are particularly suited for treatment of diseases from previously under recognized anaerobic or facultative anaerobic pathogens such as Mycobacterium tuberculosis and Mycobacterium pneumonia. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 10/018,243, filed Dec. 18, 2001, which is a continuation of international application no. PCT/US00/16679, filed Jun. 19, 2000, which receives priority from provisional applications 60/206,518 filed May 22, 2000 and 60/194,766 filed Apr. 3, 2000. All prior applications are incorporated by reference in their entireties. This invention relates to compositions and methods for detecting, preventing and treating infectious diseases such as Mycobacterium tuberculosis ("M. TB"), M. pneumonia ("M. TP"), and to new classes of antibiotics effective against anaerobic and facultative anaerobic microorganisms. Treatment and prophylaxis of infectious diseases have been advanced tremendously by the discovery of antibiotics and vaccines. The discovery and implementation of antibiotics to kill
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bacteria has greatly increased human life span and the discovery of the role of the immune system in warding off and reversing viral disease has been exploited to great benefit by vaccination programs against those diseases. Despite those great successes, however, new modalities of action for antibiotics against the bacteria are needed in view of the development of resistance to those same antibiotics. At the same time, mankind's creativity and understanding of the molecular biology behind disease is challenged anew by the AIDS crisis. Despite almost two decades of intensive research there is still no cure for AIDS, though it appears that effective treatment for various infections, including HIV, that 30% , afflict AIDS patients prolongs their lives. Thus, modem society is faced with two major challenges: the prevention, treatment and detection of intractable disease such as tuberculosis, syphilis, and AIDS and the development of antibiotics that utilize new molecular modalities against bacteria that resist the old treatments. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compounds and methods for diagnosis and immunotherapy of tuberculosis Inventor(s): Ovendale, Pamela; (Everett, WA), Jen, Shyian; (Seattle, WA), Lodes, Michael; (Seattle, WA), Skeiky, Yasir; (Seattle, WA), Campos-Neto, Antonio; (Bainbridge Island, WA) Correspondence: TOWNSEND AND TOWNSEND AND CREW, LLP; TWO EMBARCADERO CENTER; EIGHTH FLOOR; SAN FRANCISCO; CA; 94111-3834; US Patent Application Number: 20020098200 Date filed: February 26, 2001 Abstract: Compounds and methods for diagnosing tuberculosis or for inducing protective immunity against tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one immunogenic portion of one or more Mycobacterium proteins and DNA molecules encoding such polypeptides. Diagnostic kits containing such polypeptides or DNA sequences and a suitable detection reagent may be used for the detection of Mycobacterium infection in patients and biological samples. Antibodies directed against such polypeptides are also provided. In addition, such compounds may be formulated into vaccines and/or pharmaceutical compositions for immunization against Mycobacterium infection. Excerpt(s): The present application claims priority to patent application Ser. No. 60/185,037, filed Feb. 25, 2000; and patent application Ser. No. 60/223,828, filed Aug. 8, 2000, herein each incorporated by reference in its entirety. The present application is related to U.S. patent application Ser. Nos. 08/859,381, filed May 20, 1997 (abandoned); 08/858,998, filed May 20, 1997 (abandoned); 09/073,010, filed May 5, 1998; and 09/073,009, filed May 5, 1998; and to PCT application Nos. PCT/US98/10407, filed May 20, 1998; and PCT/US98/10514, filed May 20, 1998, herein each incorporated by reference in its entirety. Not applicable. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compounds and methods for diagnosis of tuberculosis Inventor(s): Campos-Neto, Antonio; (Bainbridge Island, WA), Houghton, Raymond; (Bothell, WA), Reed, Steven G. (Bellevue, WA), Dillon, Davin C. (Redmond, WA), Skeiky, Yasir A.W. (Seattle, WA), Lodes, Michael J. (Seattle, WA), Vedvick, Thomas S. (Federal Way, WA), Hendrickson, Ronald C. (Seattle, WA), Twardzik, Daniel R. (Bainbridge Island, WA) Correspondence: TOWNSEND AND TOWNSEND AND CREW, LLP; TWO EMBARCADERO CENTER; EIGHTH FLOOR; SAN FRANCISCO; CA; 94111-3834; US Patent Application Number: 20030135026 Date filed: July 10, 2002 Abstract: Compounds and methods for diagnosing tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one antigenic portion of one or more M. tuberculosis proteins, and DNA sequences encoding such polypeptides. Diagnostic kits containing such polypeptides or DNA sequences and a suitable detection reagent may be used for the detection of M. tuberculosis infection in patients and biological samples. Antibodies directed against such polypeptides are also provided. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/024,753, filed Feb. 18, 1998; which is a continuation-in-part of U.S. application Ser. No. 08/942,341, filed Oct. 1, 1997; which is a continuation-in-part of U.S. application Ser. No. 08/818,111, filed Mar. 13, 1997, which is a continuation-in-part of U.S. application Ser. No. 08/729,622 filed Oct. 11, 1996; which claims priority from PCT Application No. PCT/US 96/14675, filed Aug. 30, 1996; and is a continuation-in-part of U.S. application Ser. No. 08/680,574, filed Jul. 12, 1996; which is a continuation-in-part of U.S. application Ser. No. 08/658,800 filed Jun. 5, 1996; which is a continuation-in-part of U.S. application Ser. No. 08/620,280, filed Mar. 22, 1996, now abandoned; which is a continuation-in-part of U.S. application Ser. No. 08/532,136, filed Sep. 22, 1995, now abandoned; which is a continuation of U.S. application Ser. No. 08/523,435, filed Sep. 1, 1995, now abandoned. The present invention relates generally to the detection of Mycobacterium tuberculosis infection. The invention is more particularly related to polypeptides comprising a Mycobacterium tuberculosis antigen, or a portion or other variant thereof, and the use of such polypeptides for the serodiagnosis of Mycobacterium tuberculosis infection. Tuberculosis is a chronic, infectious disease, that is generally caused by infection with Mycobacterium tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compounds and methods for immunotherapy and diagnosis of tuberculosis Inventor(s): Hendrickson, Ronald C. (Seattle, WA), Lodes, Michael J. (Seattle, WA), Twardzik, Daniel R. (Bainbridge Island, WA), Houghton, Raymond; (Bothell, WA), Campos-Neto, Antonio; (Bainbridge Island, WA), Dillon, Davin C. (Redmond, WA), Reed, Steven G. (Bellevue, WA), Vedvick, Thomas S. (Federal Way, WA), Skeiky, Yasir A.W. (Seattle, WA) Correspondence: TOWNSEND AND TOWNSEND AND CREW, LLP; TWO EMBARCADERO CENTER; EIGHTH FLOOR; SAN FRANCISCO; CA; 94111-3834; US Patent Application Number: 20030143243 Date filed: February 25, 2002 Abstract: Compounds and methods for inducing protective immunity against tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one immunogenic portion of one or more M. tuberculosis proteins and DNA molecules encoding such polypeptides. Such compounds may be formulated into vaccines and/or pharmaceutical compositions for immunization against M. tuberculosis infection, or may be used for the diagnosis of tuberculosis. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 9/025,197, filed Feb. 18, 1998; which is a continuation-in-part of U.S. application Ser. No. 08/942,578, filed Oct. 1, 1997; which is a continuation-in-part of U.S. application Ser. No. 08/818,112, filed Mar. 13, 1997; which is a continuation-in-part of U.S. application Ser. No. 08/730,510, filed Oct. 11, 1996; which claims priority from PCT Application No. PCT/US 96/14674, filed Aug. 30, 1996; and is a continuation-in-part of U.S. application Ser. No.08/680,574, filed Jul. 12, 1996; which is a continuation-in-part of U.S. application Ser. No. 08/659,683, filed Jun. 5, 1996; which is a continuation-in-part of U.S. application Ser. No. 08/620,874, filed Mar. 22, 1996, now abandoned; which is a continuation-in-part of U.S. application Ser. No. 08/533,634, filed Sep. 22, 1995, now abandoned; which is a continuation-in-part of U.S. application Ser. No. 08/523,436, filed Sep. 1, 1995, now abandoned. The present invention relates generally to detecting, treating and preventing Mycobacterium tuberculosis infection. The invention is more particularly related to polypeptides comprising a Mycobacterium tuberculosis antigen, or a portion or other variant thereof, and the use of such polypeptides for diagnosing and vaccinating against Mycobacterium tuberculosis infection. Tuberculosis is a chronic, infectious disease, that is generally caused by infection with Mycobacterium tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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COMPOUNDS FOR DIAGNOSIS OF TUBERCULOSIS AND METHODS OF THEIR USE Inventor(s): DILLON, DAVIN C. (REDMOND, WA), ALDERSON, MARK R. (BAINBRIDGE ISLAND, WA), SKEIKY, YASIR A.W. (SEATTLE, WA), CAMPOSNETO, ANTONIO; (BAINBRIDGE ISLAND, WA) Correspondence: PENNIE & EDMONDS; 1155 AVENUE OF THE AMERICAS; NEW YORK; NY; 100362711 Patent Application Number: 20010012888 Date filed: May 5, 1998 Abstract: Compounds and methods for diagnosing tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one antigenic portion of one or more M. tuberculosis proteins, and DNA sequences encoding such polypeptides. Diagnostic kits containing such polypeptides or DNA sequences and a suitable detection reagent may be used for the detection of M. tuberculosis infection in patients and biological samples. Antibodies directed against such polypeptides are also provided. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 08/858,998, filed May 20, 1997. The present invention relates generally to the detection of Mycobacterium tuberculosis infection. The invention is more particularly related to polypeptides comprising a Mycobacterium tuberculosis antigen, or a portion or other variant thereof, and the use of such polypeptides for the serodiagnosis of Mycobacterium tuberculosis infection. Tuberculosis is a chronic, infectious disease, that is generally caused by infection with Mycobacterium tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, serious complications and death typically result. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Desaturase antigen of mycobacterium tuberculosis Inventor(s): Gicquel, Brigitte; (Paris, FR), Jackson, Mary; (Paris, FR) Correspondence: FINNEGAN, HENDERSON, FARABOW, GARRETT &; DUNNER LLP; 1300 I STREET, NW; WASHINGTON; DC; 20005; US Patent Application Number: 20020192781 Date filed: December 7, 2000 Abstract: The present invention relates to the isolation of a new gene, des, which encodes a M. tuberculosis protein named DES. The des gene appears to be conserved among different Mycobacteria species. The amino acid sequence of the DES protein contains two sets of motifs that are characteristic of the active sites of enzymes from the class II diiron-oxo protein family. Among this family of proteins, DES shares significant homology with soluble stearoyl-ACP desaturases. DES is a highly antigenic protein, which is recognized by human sera from patients infected with M. tuberculosis and M. leprae but not by sera from tuberculous cattle. Thus, the DES protein provides a useful tool for the serodiagnostic analysis of tuberculosis.
440 Tuberculosis
Excerpt(s): Tuberculosis and leprosy, caused by the bacilli from the Mycobacterium tuberculosis complex and M. leprae respectively are the two major mycobacterial diseases. Pathogenic mycobacteria have the ability to survive within host phagocytic cells. From the interactions between the host and the bacteria results the pathology of the tuberculosis infection through the damages the host immune response causes on tissues (Andersen & Brennan, 1994). Alternatively, the protection of the host is also dependent on its interactions with mycobacteria. Identification of the bacterial antigens involved in these interactions with the immune system is essential for the understanding of the pathogenic mechanisms of mycobacteria and the host immunological response in relation to the evolution of the disease. It is also of great importance for the improvement of the strategies for mycobacterial disease control through vaccination and immunodiagnosis. Through the years, various strategies have been followed for identifying mycobacterial antigens. Biochemical tools for fractionating and analysing bacterial proteins permitted the isolation of antigenic proteins selected on their capacity to elicit B or T cell responses (Romain et al., 1993; Sorensen et al., 1995). The recent development of molecular genetic methods for mycobacteria (Jacobs et al., 1991; Snapper et al., 1990; Hatful, 1993; Young et al., 1985) allowed the construction of DNA expression libraries of both M. tuberculosis and M. leprae in the.lambda.gt11 vector and their expression in E. coli. The screening of these recombinant libraries using murine polyclonal or monoclonal antibodies and patient sera led to the identification of numerous antigens (Braibant et al., 1994; Hermans et al., 1995; Thole & van der Zee, 1990). However, most of them turned out to belong to the group of highly conserved heat shock proteins (Thole & van der Zee, 1990; Young et al., 1990). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Detection of rpoB sequences of Mycobacterium tuberculosis Inventor(s): Delgado, Francisco D. (San Diego, CA), Jucker, Markus T. (Poway, CA), Brentano, Steven T. (Santee, CA), Cleuziat, Philippe; (L'Isle D'Abeau, FR) Correspondence: GEN PROBE INCORPORATED; 10210 GENETIC CENTER DRIVE; SAN DIEGO; CA; 92121 Patent Application Number: 20030108921 Date filed: September 18, 2002 Abstract: A method of detecting rpoB sequences of Mycobacterium tuberculosis present in a biological sample that includes steps of amplifying the M. tuberculosis rpoB sequence in vitro in a nucleic acid amplification mixture that includes specific disclosed primer sequences, and detecting the amplified sequences using multiple probes that provide sequence information by their specific hybridization to portions of the amplified nucleic acid. Compositions for amplifying and detecting in vitro the rpoB sequences of M. tuberculosis in a sample are disclosed. Excerpt(s): This application claims the benefit of U.S. provisional application No. 60/323,485, filed Sep. 18, 2001, under 35 U.S.C. 119(e). This invention relates to in vitro diagnostic detection of pathogenic bacteria, and specifically relates to compositions and assays for detecting nucleic acid sequences associated with rifampin resistance of Mycobacterium Tuberculosis by using in vitro nucleic acid amplification of the rpoB gene and detection of amplified products. Rifampin (RIF), an antibiotic synthesized from rifamycin B, is a key component of drug therapy against Mycobacterium tuberculosis. Rifampin has a unique site of action on the beta subunit of prokaryotic RNA polymerase. In Escherichia coli, missense mutations and short deletions in the
Patents 441
central region of the RNA polymerase subunit gene (rpoB) result in strains resistant to rifampin (Lisityn et al., 1984, Mol. Gen. Genet. 196 :173-174). Similarly, in M. tuberculosis a wide variety of mutations in the rpoB gene have been identified that confer rifampin resistance (Telenti et al., 1993, Lancet 341: 647-650). More than 90% of rifampin-resistant M. tuberculosis isolates are also resistant to isoniazid, and, therefore, rifampin resistance is a valuable surrogate marker for multiple drug resistance. Thus, there is a need for tests that can detect rapidly the genetic basis for rifampin resistance for diagnosis that leads to appropriate treatment of infected individuals. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
DNA molecule fragments encoding for cellular uptake of mycobacterium tuberculosis and uses thereof Inventor(s): Riley, Lee W. (New York, NY), Chong, Pele; (Richmond Hill, CA) Correspondence: Michael L. Goldman, Esq. NIXON PEABODY LLP; Clinton Square; P. O. Box 31051; Rochester; NY; 14603; US Patent Application Number: 20010019716 Date filed: January 4, 2001 Abstract: The present invention relates to a DNA molecule conferring on Mycobacterium tuberculosis an ability to enter mammalian cells and to survive within macrophages. Peptides, proteins, or polypeptides (e.g. the Mycobacterium cell entry protein or Mcep) encoded by this gene fragment are useful in vaccines to prevent infection by Mycobacterium tuberculosis, while the antibodies raised against these peptides, proteins, or polypeptides can be employed in passively immunizing those already infected by the organism. These proteins, peptides, polypeptides, and antibodies may be utilized in diagnostic assays to detect Mycobacterium tuberculosis in tissue or bodily fluids. The peptides, proteins, or polypeptides of the present invention can be associated with various other therapeutic materials, for administration to mammals, particularly humans, to achieve uptake of those materials by such cells. Synthetically constructed peptides based on the disclosed amino acid sequences exhibit the same mammalian cell uptake activity observed with Mcep. Excerpt(s): The present invention relates to a DNA molecule encoding for uptake of Mycobacterium tuberculosis and its use in drugs, vaccines, and diagnostic tests. Tuberculosis is the leading cause of death in the world with an estimated 9 million new cases of tuberculosis and 2.9 million deaths occurring from the disease each year. In the United States, the steadily declining incidents of tuberculosis has been reversed since 1985. This problem is compounded by the increasing incidence of drug-resistant strains of Mycobacterium tuberculosis. Recent outbreaks of tuberculosis have involved settings in which a large number of HIV-infected persons resided in close proximity (e.g., AIDS wards in hospitals, correctional facilities, and hospices). Transmission of tuberculosis to health care workers occurred in these outbreaks; 18 to 50% of such workers showed a conversion in their skin tests. See F. Laraque et. al., "Tuberculosis in HIV-Infected Patients," The AIDS Reader (September/October 1992), which is hereby incorporated by reference. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Fragments of nucleic acids specific to mycobacteria which are members of the M. tuberculosis complex and their applications for the detection and the differential diagnosis of members of the M. tuberculosis complex Inventor(s): Magdalena, Juana; (Bournville, GB), Locht, Camille; (Bruxelles, BE), Supply, Philip; (Tournai, BE) Correspondence: Charles A. Muserlian; c/o Bierman, Muserlian and Lucas; 600 Third Avenue; New York; NY; 10016; US Patent Application Number: 20030124546 Date filed: February 28, 2002 Abstract: A fragment of a nucleic acid specific to mycobacteria of M. tuberculosis complex having a nucleotide sequence of SEQ ID No: 1 and SEQ ID No: 2 and their complimentary sequences. Excerpt(s): The present invention relates to sequences of nucleic acids of mycobacteria belonging to the M. tuberculosis complex. The invention likewise relates to sequences of in vitro detection of strains of mycobacteria belonging to the M. tuberculosis complex as well as to a method for a differential diagnosis of strains of the M. tuberculosis complex, especially for differentiating the presence of the BCG from that of other members of the complex in a sample. Approximately, 1.7 billion people or 1/3 of the world population are infected with M. tuberculosis (Sudre et al., 1992). In 1990, the estimated number of cases of tuberculosis was 8 million, including 2.9 million deaths (Sudre et al., 1992). These last few years, the number of cases of tuberculosis in the Unites States and in Europe has increased by 3 to 6% per annum, principally in populations at high risk such as patients suffering from AIDS, chronic alcoholics, the homeless and drug addicts (Barnes et al., 1991). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Fusion proteins of mycobacterium tuberculosis antigens and their uses Inventor(s): Campos-Neto, Antonio; (Bainbridge Island, WA), Reed, Steven G. (Bellevue, WA), Skeiky, Yasir A. (Bellevue, WA), Dillon, Davin C. (Redmond, WA), Alderson, Mark; (Bainbridge, WA) Correspondence: TOWNSEND AND TOWNSEND AND CREW, LLP; TWO EMBARCADERO CENTER; EIGHTH FLOOR; SAN FRANCISCO; CA; 94111-3834; US Patent Application Number: 20030147911 Date filed: February 5, 2003 Abstract: The present invention relates to fusion proteins containing at least two Mycobacterium tuberculosis antigens. In particular, it relates to bi-fusion proteins which contain two individual M. tuberculosis antigens, tri-fusion proteins which contain three M. tuberculosis antigens, tetra-fusion proteins which contain four M. tuberculosis antigens, and penta-fusion proteins which contain five M. tuberculosis antigens, and methods for their use in the diagnosis, treatment and prevention of tuberculosis infection. Excerpt(s): The present application is a continuation-in-part of co-pending application Ser. No. 09/223,040 filed Dec. 30, 1998, and of co-pending application Ser. No. 09/056,556 filed Apr. 7, 1998, which is a continuation-in-part of co-pending application Ser. No. 09/025,197 filed Feb. 18, 1998, which is a continuation-in-part of co-pending
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application Ser. No. 08/942,578 filed Oct. 1, 1997, which is a continuation-in-part of copending application Ser. No. 08/818,112, filed Mar. 13, 1997, each of which is incorporated by reference herein in its entirety. The present invention relates to fusion proteins containing at least two Mycobacterium tuberculosis antigens. In particular, it relates to bi-fusion proteins which contain two individual M. tuberculosis antigens, trifusion proteins which contain three M. tuberculosis antigens, tetra-fusion proteins which contain four M. tuberculosis antigens, and penta-fusion proteins which contain five M. tuberculosis antigens, and methods for their use in the diagnosis, treatment and prevention of tuberculosis infection. Tuberculosis is a chronic infectious disease caused by infection with M. tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If untreated, serious complications and death typically result. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Hybrids of M. tuberculosis antigens Inventor(s): Andersen, Peter; (Bronshoj, DK), Rasmussen, Peter Birk; (Frederiksberg, DK), Olsen, Anja Weinreich; (Soborg, DK), Skjot, Rikke Louise Vinther; (Hedehusene, DK) Correspondence: Thomas J. Kowalski; c/o FROMMER LAWRENCE & HAUG LLP; 745 Fifth Avenue; New York; NY; 10151; US Patent Application Number: 20020176867 Date filed: March 13, 2001 Abstract: The present invention discloses fusion proteins of the immunodominant antigens ESAT-6 and Ag85B from Mycobacterium tuberculosis or homologues thereof, and a tuberculosis vaccine based on the fusion proteins, which vaccine induces efficient immunological memory. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 09/246,191, filed Dec. 30, 1998, which claims priority from U.S. provisional application No. 60/070,488, filed Jan. 5, 1998. Reference is also made to: the concurrently-filed US application of Andersen et al., Ser. No. ______(attorney docket 670001-2002.4); U.S. application Ser. No. 09/289,388 filed Apr. 12, 1999, which is a continuation of U.S. application Ser. No. 08/465,640 filed Jun. 5, 1995, now U.S. Pat. No. 5,955,077, issued Sep. 21, 1999, which is a continuation-in-part of U.S. Ser. No. 08/123,182 filed Sep. 20, 1993, now abandoned, and a continuation-in-part of PCT/DK94/00273, filed Jul. 1, 1994, published as WO95/01441, and claiming priority from Danish application 0798/93, filed Jul. 2, 1993; U.S. application Ser. No. 09/050,739 filed Mar. 30, 1998, which is claims priority from U.S. provisional application Ser. No. 60/044,624 filed Apr. 18, 1997; Andersen et al., application Ser. No. 09/791,171, filed Feb. 20, 2001, as a divisional of U.S. application Ser. No. 09/050,739; and commonly-owned U.S. Patent No. 6,120,776. Each of these patents, patent applications and patent publications, as well as all documents cited in the text of this application, and references cited in the documents referred to in this application (including references cited in the aforementioned patents, patent applications and patent publications or during their prosecution) are hereby incorporated herein by reference. The present application discloses new fusion proteins of the immunodominant antigens ESAT-6 and Ag85B from Mycobacterium tuberculosis
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or homologues thereof, and a tuberculosis subunit vaccine comprising at least one fusion protein. The vaccine induced efficient immunological memory. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Isolated and purified nonpeptide antigens from mycobacterium tuberculosis Inventor(s): Liu, Gui; (Medford, MA), Beltz, Gerald; (Lexington, MA), LeClair, Kenneth; (Needham, MA), Kensil, Charlotte; (Milford, MA), Cox, Daniel; (Medway, MA) Correspondence: PENNIE AND EDMONDS; 1155 AVENUE OF THE AMERICAS; NEW YORK; NY; 100362711 Patent Application Number: 20020044951 Date filed: April 4, 2001 Abstract: Nonpeptide antigens were isolated and purified from Mycobacterium tuberculosis. The antigens were used in vaccine compositions, pharmaceutical compositions and methods to elicit an immune response to Mycobacterium tuberculosis in a mammal. Excerpt(s): The invention described herein is related to vaccine compositions that are used to elicit an immune response specific for Mycobacterium tuberculosis in a mammal, as well as methods to elicit the immune response specific for Mycobacterium tuberculosis. The invention also pertains to immunogenic or vaccine compositions comprising at least one nonpeptide antigen isolated from Mycobacterium tuberculosis, wherein the isolated nonpeptide antigen elicits a specific immune response against Mycobacterium tuberculosis, and may further comprise one or more T-cell stimulating compounds. Several inventive isolated and purified nonpeptide antigens from the mycobacteria Mycobacterium tuberculosis are described herein. Immunity from a bacterial pathogen may be mediated by a protein, but may also be mediated by a nonpeptide antigen such as a polysaccharide or a lipid. Some lipid, glycolipid, and phospholipid antigens have already been identified from various Mycobacterium species. These include mycolic acid, inositol-containing phospholipids (e.g., lipoarabinomannan (LAM) and phosphatidylinositol mannosides (PIMs)), and mycolyl glycolipids (e.g., glucose monomycolate (GMM)), all of which may be purified from mycobacterial cell walls (Beckman, et al., Nature 372:691 (1994); Sieling, et al., Science 269:227 (1995); and Moody, et al., Science 278:283 (1997)). Some of these molecules share similar structural features consisting of a relatively hydrophilic polar head group linked to a single or dual branched hydrophobic acyl chain(s). It has been hypothesized that these molecules may be presented by the CD1 pathway of antigen presentation. A nonpeptide antigen (e.g., from bacteria or parasites) is ingested by an antigen presenting cell ("APC") (e.g., macrophage, B-cell or dendritic cell) and may then be presented in conjunction with a CD1 molecule, to thereby induce T-cell proliferation. (Porcelli, et al., Current Opinion in Immunology 8:510-516 (1996)). This pathway is referred to herein as the "CD1 antigen-presenting pathway." These lipid or nonpeptide antigens are processed independently from the major histocompatability complex ("MHC") peptide antigen-presenting pathway. The immune response that results from the CD1 antigen presenting pathway is referred to as a "CD1-restricted response." The immunologic role of CD1 presentation of hydrophobic nonpeptide antigens has been demonstrated in M. tuberculosis infection. The presentation of mycobacterial lipid and glycolipid antigens by CD1 molecules initiates an MHC-independent pathway of host defense against mycobacterial infection in vivo by both cytolytic- and cytokine-based mechanisms. Specifically, CD8.sup.+ or CD8.sup.-/CD4.sup.- (double negative) T-cells recognize
Patents 445
nonpeptide microbial antigens when presented in the context of CD1 molecules. These CD1-restricted T-cells are cytolytic and kill mycobacterial infected monocytes (Stenger, et al., Science 276:1684 (1997)). CD8.sup.+, CD1-restricted M. tuberculosis specific T-cell lines derived from the blood of human donors produce Th1-type cytokines, such as interferon, which may facilitate control of mycobacterial infections, and may play a role in clearing intracellular microbial infections. Nonpeptide antigens may also induce an immune response through an MHC-dependent pathway of presentation, for example through Class II MHC, particularly if it is presented in association with a protein antigen. It is well-known that a potent immune response can be raised to a nonpeptide antigen that is conjugated to a protein carrier such as keyhole limpet hemocyanin that provides T-cell help and cytokine stimulation through T-cell recognition of carrier peptide bound to Class II MHC on APC. An example is the T-cell dependent immune response raised against T-independent pneumococcal polysaccharide antigens chemically conjugated to a T-cell dependent protein carrier such as tetanus toxoid, CRM.sub.197 (nontoxic mutant diptheria toxin), or OMPC (outer membrane protein complex of Neisseria meningitidis) (R. Eby, Pharmaceutical Bioechnology 6: 695714(1995). Another example is the T-cell dependent immune response to LOS (lipooligosaccharide) from nontypeable Haemophilus influenzae after conjugation to a protein carrier (Gu, et al., Vaccine 18:1264-1272 (2000)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
M. tuberculosis antigens Inventor(s): Skjot, Rikke Louise Vinther; (Hedehusene, DK), Andersen, Peter; (Bronshoj, DK) Correspondence: Thomas J. Kowalski; c/o FROMMER LAWRENCE & HAUG LLP; 745 Fifth Avenue; New York; NY; 10151; US Patent Application Number: 20030147897 Date filed: March 13, 2001 Abstract: The present invention is based on the identification and characterization of a number of novel M. tuberculosis derived proteins and protein fragments. The invention is directed to the polypeptides and immunologically active fragments thereof, the genes encoding them, immunological compositions such as vaccines and skin test reagents containing the polypeptides. Excerpt(s): U.S. application Ser. No. 09/246,191, filed Dec. 30, 1998, which claims priority from U.S. provisional 60/070,488 filed Jan. 5, 1998. Reference is also made to commonly-owned U.S. Pat. No. 6,120,776. Each of these patents, patent applications and patent publications, as well as all documents cited in the text of this application, and references cited in the documents referred to in this application (including references cited in the aforementioned patents, patent applications and patent publications or during their prosecution) are hereby incorporated herein by reference. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for detecting mycobacterium tuberculosis by PCR amplification of REP13E12 repeated sequence Inventor(s): Lee, Tae-Yoon; (Daegu-shi, KR), Lee, Jai-Youl; (Daegu-shi, KR), Kim, SungKwang; (Daegu-shi, KR), Lee, Jong-Seok; (Daegu-shi, KR) Correspondence: MERCHANT & GOULD; P O BOX 2903; MINNEAPOLIS; MN; 554020903; US Patent Application Number: 20010023065 Date filed: February 16, 2001 Abstract: A method for detecting Mycobacterium tuberculosis by the polymerase chain reaction (PCR) amplification of the REP13E12 repeated sequence, and more particularly, to a method for detecting Mycobacterium tuberculosis in clinical specimen by the PCR amplification of all or some of the REP1 3E1 2 repeated sequence is provided. Since the Mycobacterium tuberculosis detecting method by the PCR amplification for amplifying the REP13E12, which is the repeated sequence cloned from the microbial cells of Mycobacterium tuberculosis, which are separated from Korea, shows excellent sensitivity and specificity, it is possible to effectively detect Mycobacterium tuberculosis in specimen using the method. Excerpt(s): The present invention relates to a method for detecting Mycobacterium tuberculosis by the polymerase chain reaction (PCR) amplification of the REP13E12 repeated sequence, and more particularly, to a method for specially detecting the Mycobacterium tuberculosis in clinical specimen with high sensitivity by the PCR amplification of all or some of the REP1 3E1 2 repeated sequence. Tuberculosis is a very severe infectious disease, by which 1/3 of the world population, that is, about 1,700,000,000 are infected, by which about 800,000,000 patients are newly infected every year, and from which 34% of the new patients, that is 2,700,000, die. It is estimated that the tuberculosis patients of about 700,000 exist in our country. It is reported that 140,000 patients are newly infected by tuberculosis every year and that 5,000 patients die from tuberculosis. This is a very severe public health problem. Tuberculosis is a chronic infectious disease caused by the Mycobacterium tuberculosis. The prevalence rate of tuberculosis is increasing all over the world as well as in our country as a complication of acquired immune deficiency syndrome (AIDS). Since many of recently generated Mycobacterium tuberculosis have multiple tolerances to tuberculosis drugs, it is more difficult to cure tuberculosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for identifying mycobacterium tuberculosis and mycobacteria other than tuberculosis, together with detecting resistance to an antituberculosis drug of mycobateria obtained by mutation of rpoB gene Inventor(s): Kim, Sang-Jae; (Seoul, KR), Cho, Sang-Nae; (Seoul, KR), Bang, Hye Eun; (Seoul, KR), Lee, Hyeyoung; (Seoul, KR), Bai, Gill-Han; (Seongnam-shi, KR) Correspondence: POWELL GOLDSTEIN FRAZER & MURPHY LLC; PO Box 97223; Washington; DC; 20090-7223; US Patent Application Number: 20030108881 Date filed: January 30, 2002
Patents 447
Abstract: The present invention provides a method for identifying Mycobacterium tuberculosis and non-tuberculosis Mycobacterium (MOTT), and for the determination of drug susceptibility of M. tuberculosis based on detection of mutations in the rpoB gene. Excerpt(s): This application claims priority to the foreign application KR 2001-43450 filed Jul. 19, 2001. The present invention relates to a method for identifying Mycobacterium tuberculosis (hereinafter, referred to as `M. tuberculosis`) and Mycobacterium Other Than Tuberculosis (hereinafter, referred to as `MOTT`), and for the determination of resistance of M. tuberculosis to an antituberculosis drug obtained by the mutation of the rpoB gene. Tuberculosis is a chronic wasting disease caused by M. tuberculosis. Worldwide, it ranks the first in mortality and morbidity among infectious diseases (Global Tuberculosis Programme. Global Tuberculosis Control, WHO Report 1997. World Health Organization, 1997). Carriers of M. tuberculosis presently number about 1.9 billion, a third of the world population, and about 8-10 million of these carriers develop into new tuberculosis patients per year, and about 3 million of patients die of tuberculosis per year (Dolin P. J., Raviglion M. C., Kochi, A. (1994) Global tuberculosis incidence and mortality during 1990-2000. Bull World Health Organization. 72(2): 213-220; Kochi, A. (1992) The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle. SCI. 72:1-6; Styblo K. Epidemiology of Tuberculosis the Hague, Royal Netherland Tuberculosis Association (1991), p. 83 in: Minister of Health and Welfare, The Korean National Tuberculosis Association. Measures for Tuberculosis Control in 2000s, p5, 1997). Also, about a half of the population in Korea are carriers of M. tuberculosis, and about 150,000 persons develop into new tuberculosis patients per year, and about 14,000 patients per year die of tuberculosis (Sreevatsan S. Stockbauer K E, Pan X, Kreiswirth B N, Mogha S L, Jacobs W R Jr, Telenti A, Musser J M. (1997) Ethambutol resistance in M. tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 41:1677-1681). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of diagnosing multidrug resistant tuberculosis Inventor(s): Barry, Clifton E. III; (Bethesda, MD), DeBarber, Andrea E. (Rockville, MD), Mdluli, Khisimuzi; (Seattle, WA), Bekker, Linda-Gail; (New York, NY) Correspondence: TOWNSEND AND TOWNSEND AND CREW, LLP; TWO EMBARCADERO CENTER; EIGHTH FLOOR; SAN FRANCISCO; CA; 94111-3834; US Patent Application Number: 20030013090 Date filed: June 22, 2001 Abstract: The invention relates to the discovery that a putative gene of Mycobacterium tuberculosis with no previously identified function is responsible for the ability of the bacterium to activate thioamide drugs. Since M. tuberculosis has a low rate of synonymous mutations, all mutations in this gene, identified as Rv3854c and now termed "EtaA," are expected to inhibit the ability of a bacterium with the mutation to activate a thioamide or thiocarbonyl drug. Thus, detecting a bacterium with a mutation in this gene indicates that the bacterium is resistant to treatment with thioamides. Excerpt(s): This application claims priority from U.S. Provisional Application Ser. No. 60/214,187, filed Jun. 26, 2000, the contents of which are incorporated by reference for all purposes. The World Health Organization ("WHO") estimates that as much as onethird of the world's population is infected with tuberculosis. In 1998, the latest year for which estimates are available, Mycobacterium tuberculosis ("MTb") infected 7.25 million
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people and resulted in 2.9 million fatalities (Farmer, P. et al., Int J Tuberc Lung Dis 2:869 (1998)). Underlying these statistics is an emerging epidemic of multiple drug-resistant ("MDR") tuberculosis that severely undermines control efforts and is transmitted indiscriminately across national borders (Viskum, K. et al., Int J Tuberc Lung Dis 1:299 (1997); Bass, J. B. et al., Am J Respir Crit Care Med 149:1359 (1994)). Resistance to any of the front-line drugs generally bodes poorly for the patient, who then is committed to a regimen of less active "second-line" therapies. Where multidrug resistance is suspected, the WHO recommends that three or more drugs be administered at the same time, to decrease the chance that the organism will be able to develop resistance to all of the agents. One of the most efficacious of the second-line drugs is the thioamide ethionamide (ETA) (Farmer, P. et al., supra). Like the front-line drug, isoniazid (INH), ETA is specific for mycobacteria and is thought to exert a toxic effect on mycolic acid constituents of the cell wall of the bacillus (Rist, N. Adv Tuberc Res 10:69 (1960); Banerjee, A. et al., Science 263:227 (1994)). Current tuberculosis therapies include a large number of "prodrugs" that must be metabolically activated to manifest their toxicity upon specific cellular targets (Barry, C. B., III et al., Biochem Pharm 59:221 (2000)). The best characterized example of this is the activation of INH by the catalase-peroxidase KatG, generating a reactive form that then inactivates enzymes involved in mycolic acid biosynthesis (Slayden, R. A. et al., Microbes and Infection (2000) (in press); Heym, B. et al., Tubercle Lung Dis 79:191 (1999)). The majority of clinically observed INH resistance is associated with the loss of this activating ability by the bacillus (Musser, J. M., Clin Microbiol Rev 8:496 (1995)), but such strains typically retain their sensitivity toward ETA, suggesting that ETA activation requires a different enzyme than KatG (Rist, N., Adv. Tub. Res. 10, 69 (1960)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
METHODS OF TREATING AND PROTECTING AGAINST TUBERCULOSIS USING A MONOCLONAL ANTIBODY SELECTIVE FOR MYCOBACTERIUM TUBERCULOSIS Inventor(s): CASADEVALL, ARTURO; (PELHAM, NY), GLATMAN-FREEDMAN, AHARONA; (IRVINGTON, NY) Correspondence: AMSTER ROTHSTEIN AND EBENSTEIN; 90 PARK AVENUE; NEW YORK; NY; 10016 Patent Application Number: 20010007660 Date filed: June 4, 1997 Abstract: The present invention is directed to compositions comprising a monoclonal antibody that reacts with surface epitopes of M. tuberculosis, methods of treating tuberculosis by passively immunizing a subject using the antibody compositions, antigenic determinants for use as a vaccine to protect against M. tuberculosis infection, and a method of using the vaccine to prevent infections of M. tuberculosis. Excerpt(s): Tuberculosis continues to be a major worldwide health problem and is responsible for most incidences of death by an infectious agent. The worldwide incidence of tuberculosis was estimated by the World Health Organization to be 8.8 million in 1995, with a mortality estimate of 3.0 million persons, and is expected to rise to 10.2 million by the year 2000 (Dolin, et al., Bull. WHO. 72:213-220 (1994)). The tuberculosis problem has been compounded by the development of the AIDS epidemic and the growing number of HIV-related cases of tuberculosis (Dolin, et al., Bull. WHO. 72:213-220 (1994)). Effective treatment of tuberculosis is generally prolonged, especially
Patents 449
in patients also infected with HIV. In the past, infection with drug-sensitive strains of the M. tuberculosis complex had been cured with certain antibiotics, including isoniazid, rifampicin, ethionamide and pyrazinamide. However, resistance to isoniazid and other antibiotics has developed in many strains of M. tuberculosis. The only licensed vaccine, the BCG vaccine, is controversial in regard to its efficacy, and its effectiveness varies markedly from country to country. This has resulted in the continued search for an effective vaccine against M. tuberculosis. Mycobacterium tuberculosis is an intracellular pathogen, thought not to be reached by antibody immunity. Recent studies suggest that some IgA antibodies can neutralize viruses inside cells (Mazanec, et al. 1992) and that monoclonal antibodies inhibit intracellular Toxoplasma gondii (Mineo, et al. 1994). It is known that patients with tuberculosis mount high levels of serum antibodies (Favez, et al. 1966). This antibody response is polyclonal and may contain protective, non-protective, and enhancing antibodies. In such a case, monoclonal antibody technology can be used to identify the protective antibodies. Passive antibody therapy was used to treat tuberculosis in the pre-antibiotic era in the form of serum therapy. The results of that treatment were equivocal, but some investigators published positive results (Maragliano 1896, Paquin 1895, and Marmorek 1903). Since that time, antimicrobial therapy has been the only treatment available for tuberculosis. The rise in antimicrobial resistance, however, has created a sense of urgency for the development of alternative methods of therapy for tuberculosis. The present invention provides for compositions comprising a monoclonal antibody that reacts with a surface epitope of M. tuberculosis, methods of treating tuberculosis by passively immunizing a subject using the antibody composition, and antigenic determinates for use as a vaccine to protect against M. tuberculosis infection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
MHC class I associated peptides for prevention and treatment of tuberculosis Inventor(s): Hunt, Donald F. (Charlottesville, VA), White, Forest M. (Charlottesville, VA), Philip, Ramila; (Charlottesville, VA), Ross, Mark M. (Charlottesville, VA), Engelhard, Victor H. (Charlottesville, VA), Flyer, David; (Olney, MD) Correspondence: CARELLA, BYRNE, BAIN, GILFILLAN, CECCHI,; STEWART & OLSTEIN; 6 Becker Farm Road; Roseland; NJ; 07068; US Patent Application Number: 20020192229 Date filed: December 13, 2001 Abstract: The present invention relates to compositions and methods for the prevention, treatment, and diagnosis of tuberculosis, and discloses peptides, polypeptides, and polynucleotides that can be used to stimulate a CTL response against tuberculosis. The peptide and/or proteins of the invention may be used as a therapeutic drug to stimulate the immune system to recognize and eliminate M. tuberculosis in infected cells or as a vaccine for the prevention of disease. Antibodies that react with the immunogens of the invention, as well as methods of using these antibodies for prevention and treatment of disease, are also disclosed. Excerpt(s): This application claims priority of U.S. Provisional Applications 60/264,978, filed Jan. 30, 2001 and 60/255,292, filed Dec. 13, 2000, the disclosures of which are hereby incorporated by reference in their entirety. The present invention relates generally to the field of immunogens whose structures incorporate peptides derived from Mycobacterium tuberculosis and to methods of using such peptide as a basis for the prevention and treatment of diseases such as tuberculosis. The mammalian immune
450 Tuberculosis
system has evolved a variety of mechanisms to protect the host from microorganisms, an important component of this response being mediated by cells referred to as T cells and by antibodies derived from B cells. In combating bacterial infections, antibodies are especially important but likewise are specialized T cells that function primarily by recognizing and killing infected cells. The latter also function by secreting soluble molecules called cytokines that mediate a variety of functions of the immune system. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Molecular differences between species of the M. tuberculosis complex Inventor(s): Behr, Marcel; (Montreal, CA), Wilson, Michael A. (Santa Clara, CA), Small, Peter; (Stanford, CA), Schoolnik, Gary; (Stanford, CA) Correspondence: PAMELA J. SHERWOOD; Bozicevic, Field and Francis LLP; Suite 200; 200 Middlefield Road; Menlo Park; CA; 94025; US Patent Application Number: 20020176873 Date filed: June 27, 2001 Abstract: Specific genetic deletion are identified in mycobacteria isolates, including variations in the M. tuberculosis genome sequence between isolates, and numerous deletion present in BCG as compared to M. tb. These deletions are used as markers to distinguish between pathogenic and avirulent strains, and as a marker for particular M. tb isolates. Deletions specific to vaccine strains of BCG are useful in determining whether a positive tuberculin skin test is indicative of actual tuberculosis infection. The deleted sequences may be re-introduced into BCG to improve the efficacy of vaccination. Alternatively, the genetic sequence that corresponds to the deletion(s) are deleted from M. bovis or M. tuberculosis to attenuate the pathogenic bacteria. Excerpt(s): Tuberculosis is an ancient human scourge that continues to be an important public health problem worldwide. It is an ongoing epidemic of staggering proportions. Approximately one in every three people in the world is infected with Mycobacterium tuberculosis, and has a 10% lifetime risk of progressing from infection to clinical disease. Although tuberculosis can be treated, an estimated 2.9 million people died from the disease last year. There are significant problems with a reliance on drug treatment to control active M. tuberculosis infections. Most of the regions having high infection rates are less developed countries, which suffer from a lack of easily accessible health services, diagnostic facilities and suitable antibiotics against M. tuberculosis. Even where these are available, patient compliance is often poor because of the lengthy regimen required for complete treatment, and multidrug-resistant strains are increasingly common. Prevention of infection would circumvent the problems of treatment, and so vaccination against tuberculosis is widely performed in endemic regions. Around 100 million people a year are vaccinated with live bacillus CalmetteGuerin (BCG) vaccine. BCG has the great advantage of being inexpensive and easily administered under less than optimal circumstances, with few adverse reactions. Unfortunately, the vaccine is widely variable in its efficacy, providing anywhere from 0 to 80% protection against infection with M. tuberculosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Patents 451
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MONOCLONAL ANTIBODIES TO MYCOBACTERIUM TUBERCULOSIS AND A MODIFIED ELISA ASSAY Inventor(s): CASADEVALL, ARTURO; (PELHAM, NY), GLATMAN-FREEDMAN, AHARONA; (IRVINGTON, NY) Correspondence: AMSTER ROTHSTEIN AND EBENSTEIN; 90 PARK AVENUE; NEW YORK; NY; 10016 Patent Application Number: 20020034763 Date filed: June 4, 1997 Abstract: The present invention provides for monoclonal antibodies, the hybridoma cell lines which produce these antibodies, and the use of such monoclonal antibodies in the detection of M. tuberculosis. More specifically, the present invention provides for monoclonal antibodies that react with surface epitopes of M. tuberculosis and the use of these monoclonal antibodies for detecting and diagnosing M. tuberculosis. Also provided by the present invention is a modified ELISA assay for detection of microorganisms, and a modified ELISA assay employing the monoclonal antibodies of the present invention for detecting M. tuberculosis. Excerpt(s): Tuberculosis continues to be a major worldwide health problem and is responsible for most incidences of death by an infectious agent. The worldwide incidence of tuberculosis was estimated by the World Health Organization to be 8.8 million in 1995, with a mortality estimate of 3.0 million persons, and is expected to rise to 10.2 million by the year 2000 (Dolin, et al., Bull. WHO. 72: 213-220 (1994)). The tuberculosis problem has been compounded by the development of the AIDS epidemic and the growing number of HIV-related cases of tuberculosis (Dolin, et al., Bull. WHO. 72: 213-220 (1994)). As the incidence of tuberculosis increases, major problems also develop concerning this disease. For example, the lack of a sensitive and rapid laboratory method of diagnosing tuberculosis makes it difficult to differentiate between M. tuberculosis and M. avium-intracellulare, both of which are frequently present in HIV infected patients. Multiple methods of detection of M. tuberculosis employing polyclonal and monoclonal antibodies have been described (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Friedman, et al., Am. Rev. Respir. Dis. 140: 668-671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901-904 (1986); Mason, et al., Tubercle Lung Dis. 74:195-199 (1993); Papa, et al., Res. Microbiol. 143: 327-331 (1992); Sada, et al., Lancet 2 651-652 (1983); Schoningh, et al., J. Clin. Microbiol. 28: 708-713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991) Watt, et al., J Infect Dis. 158:681-686 (1988);, Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., Clin. Microbiol. 23: 822-825 (1986)), but none have acquired a widespread role in the diagnosis of tuberculosis as these antibodies crossreact with other mycobacterial strains (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Friedman, et al., Am. Rev. Respir. Dis. 140:668 -671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901-904 (1986); Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., J. Clin. Microbiol. 23:822 -825 (1986)). In addition, in order to obtain significant results, a large amount of mycobacteria or mycobacterial antigen is required (Cho, et al., J. Clin. Microbiol. 30:3065 -3069 (1992); Mason, et al., Tubercle Lung Dis. 74:195-199 (1993); Papa, et al., Res. Microbiol. 143: 327-331 (1992); Schoningh, et al., J. Clin. Microbiol. 28:708 -713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991)). Improvements in antibody-based diagnostic tests for the detection of M. tuberculosis would require specific antibody reagents with high affinity for mycobacterial antigens. Several monoclonal antibodies have been generated against surface components of M. tuberculosis (Cho, et al., Yonsei Med. J. 31:333-338 (1990);
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Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Mauch, et al., J. Clin. Microbiol. 26:1691-1694 (1988)) but they are often cross reactive with other strains or cytoplasmic fractions (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Mauch, et al., J. Clin. Microbiol. 26:1691-1694 (1988)). There is thus a need for a monoclonal antibody that selectively binds to M. tuberculosis and does not cross react with other strains of mycobacteria. An additional problem concerns the protocol used for detecting M. tuberculosis. The protocols described thus far for detecting mycobacteria, such as direct ELISA (Mason, et al., Tubercle Lung Dis. 74:195-199 (1993); Schoningh, et al., J. Clin. Microbiol. 28: 708-713 (1990); Verstijnen, et al., J. Clin. Microbiol. 29:1372-1375 (1991)), capture ELISA (Cho, et al., Yonsei Med. J. 31:333-338 (1990); Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Friedman, et al., Am. Rev. Respir. Dis. 140: 668-671 (1989); Kadival, et al., J. Clin. Microbiol. 23: 901-904 (1986); Rattan, et al., Tubercle Lung Dis. 74: 200-203 (1993); Sada, et al., Lancet 2 651-652 (1983); Watt, et al., J Infect Dis. 158:681-686 (1988); Wu, et al., Chin. J. Microbiol. Immunol. 22:173-180 (1989); Yanez, et al., J. Clin. Microbiol. 23: 822825 (1986)) and DOT ELISA (Cho, et al., J. Clin. Microbiol. 30: 3065-3069 (1992); Papa, et al., Res. Microbiol. 143: 327-331 (1992)), are deficient in many areas. For example, none of the methods listed above allow for visualization of single captured microorganisms. Furthermore, many of these methods require the use of polyclonal immunoglobulins which have the potential disadvantages of lot to lot variation, reliance on animal sources and unwanted cross-reactivities. Accordingly, there is an outstanding need for a method of detecting M. tuberculosis which eliminates the problems existing in current methods of detection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Mycobacterial proteins, microorganisms producing them and their use for vaccines and for the detection of tuberculosis Inventor(s): Pescher, Pascale; (Paris, FR), Marchal, Gilles; (Ivry Sur Seine, FR), Romain, Felix; (Fontenay les Briis, FR), Laqueyrerie, Anne; (Paris, FR) Correspondence: OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC; FOURTH FLOOR; 1755 JEFFERSON DAVIS HIGHWAY; ARLINGTON; VA; 22202; US Patent Application Number: 20030054008 Date filed: November 2, 2001 Abstract: Mycobacterium tuberculosis protein having a molecular weight of 28,799 Da, and hybrid protein containing at least portions of its sequence.These proteins may in particular be used in vaccines or for the detection of specific tuberculosis antibodies. Excerpt(s): The object of the present invention is mycobacterial proteins and microorganisms producing them. It also relates to the use of these proteins in vaccines or for the detection of tuberculosis. At present, a definite diagnosis made by the demonstration of cultivatable bacilli in a sample taken from the patient is only obtained in less than half the cases of tuberculosis. Even for pulmonary tuberculosis, which represents 80 to 90% of the tuberculosis cases, and which is the form of the disease for which the detection of the bacilli is the easiest, the examination of expectorations is only positive for less than half the cases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Patents 453
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Mycobacterium tuberculosis CYP51 polypeptides and nucleic acids and therapeutic and screening methods relating to same Inventor(s): Waterman, Michael R. (Nashville, TN), Bellamine, Aouatef; (Nashville, TN) Correspondence: JENKINS & WILSON, PA; 3100 TOWER BLVD; SUITE 1400; DURHAM; NC; 27707; US Patent Application Number: 20020052031 Date filed: July 20, 2001 Abstract: A cytochrome p450 14.alpha.-demethylase enzyme isolated from Mycobacterium tuberculosis designated as MT CYP51. A crystalline form of MT CYP51 is also disclosed. Nucleic acid molecules encoding MT CYP51 are also disclosed. Recombinant host cells, recombinant nucleic acids and recombinant proteins are also disclosed, along with methods of producing each. Isolated and purified antibodies to MT CYP51, and methods of producing the same, are also disclosed. MT CYP51 is characterized as having 14.alpha.-demethylase biological activity. Thus, therapeutic and drug screening methods pertaining to this activity are also disclosed. Excerpt(s): The present invention relates generally to isolated and purified polypeptides and to isolated and purified nucleic acids encoding such polypeptides. More particularly, the present invention relates to isolated and purified Mycobacterium tuberculosis CYP51 polypeptides and isolated and purified nucleic acid molecules encoding the same. The cytochrome P450 enzyme cytochrome P450 14.alpha.demethylase (CYP45014DM) catalyzes 14.alpha.-demethylation of different sterols via three successive oxidations at the C-32 methyl group. CYP45014DM is thus involved in cholesterol, ergosterol and phytosterol biosynthesis in animals, fungi and plants, respectively. In animals, for example, the demethylation reaction catalyzed by CYP45014DM results in the formation of formic acid and 4,4-dimethyl-5.alpha. cholesta8,14-,24-trien-3.beta.-- ol from lanosterol. Although the function of this enzyme has been conserved between different species, CYP45014DM substrate specificity is narrow. It has been reported that yeast and animals utilize lanosterol and dihydrolanosterol while filimentus fungi utilize eburicol (24-methylene lanosterol). Plant CYP45014DM's, however, use only obtusifoliol as a substrate. Currently, this enzyme is the only CYP450 enzyme found in three different phyla: animals, fungi and plants. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Mycobacterium tuberculosis DNA sequences encoding immunostimulatory peptides and methods for using same Inventor(s): Nano, Francis E. (Victoria, CA) Correspondence: Klarquist Sparkman, LLP; One World Trade Center, Suite 1600; 121 SW Salmon Street; Portland; OR; 97204; US Patent Application Number: 20030049263 Date filed: November 28, 2001 Abstract: Nucleotide sequences isolated from Mycobacterium tuberculosis are disclosed. These sequences encode immunostimulatory peptides. Also disclosed are vaccine preparations formulated using these peptides. Excerpt(s): This application is a continuation-in-part of co-pending U.S. application No. 08/990,823, filed Dec. 15, 1997, which is incorporated herein by reference. The
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08/990,823 application claims priority from PCT application No. U.S. 96/10375, filed Jun. 14, 1996, which claims priority from U.S. Provisional application No.60/000,254, filed Jun. 15, 1995, all of which are incorporated herein by reference. Over the past few years the editors of the Morbidity and Mortality Weekly Report have chronicled the unexpected rise in tuberculosis cases. It has been estimated that one billion people are infected with M. tuberculosis worldwide, with 7.5 million active cases of tuberculosis. Even in the United States, tuberculosis continues to be a major problem especially among the homeless, Native Americans, African-Americans, immigrants, and the elderly. HIV-infected individuals represent the newest group to be affected by tuberculosis. Of the 88 million new cases of tuberculosis expected in this decade, approximately 10% will be attributable to HIV infection. The emergence of multi-drug resistant strains of M. tuberculosis has complicated matters further and even raises the possibility of a new tuberculosis epidemic. In the U.S. about 14% of M. tuberculosis isolates are resistant to at least one drug, and approximately 3% are resistant to at least two drugs. M. tuberculosis strains have even been isolated that are resistant to all seven drugs in the repertoire of drugs commonly used to combat tuberculosis. Resistant strains make treatment of tuberculosis extremely difficult: for example, infection with M. tuberculosis strains resistant to isoniazid and rifampin leads to mortality rates of approximately 90% among HIV-infected individuals. The mean time to death after diagnosis in this population is 4-16 weeks. One study reported that, of nine immunocompetent health care workers and prison guards infected with drug-resistant M. tuberculosis, five died. The expected mortality rate for infection with drug-sensitive M. tuberculosis is 0%. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel peroxiredoxin defense system from mycobacterium tuberculosis Inventor(s): Bryk, Ruslana; (New York, NY), Nathan, Carl F. (Larchmont, NY), Lima, Christopher D. (New York, NY) Correspondence: Michael L. Goldman, Esq. NIXON PEABODY LLP; Clinton Square; P.O. Box 31051; Rochester; NY; 14603-1051; US Patent Application Number: 20030190325 Date filed: January 15, 2003 Abstract: The present invention relates to methods of preventing and treating tuberculosis in a subject infected with Mycobacterium tuberculosis. The method involves inhibiting AhpD in the subject under conditions effective to make the pathogen susceptible to antimicrobial reactive nitrogen intermediates or reactive oxygen intermediates. The present invention also relates to methods of preventing and treating tuberculosis in a subject infected with Mycobacterium tuberculosis involving inhibiting dihydrolipoamide dehydrogenase or dihydrolipoamide succinyltransferase in Mycobacterium tuberculosis in the subject under conditions effective to make the pathogen susceptible to antimicrobial reactive nitrogen intermediates or reactive oxygen intermediates. Also disclosed are methods for identifying candidate compounds suitable for treatment or prevention of tuberculosis. Methods of producing an AhpD crystal suitable for X-ray diffraction as well as methods for designing a compound suitable for treatment or prevention of tuberculosis and compounds suitable for treatment or prevention of tuberculosis are also disclosed. Excerpt(s): This application claims the benefit of U.S. patent application Ser. No. 60/348,844, filed Jan. 16, 2002, which is hereby incorporated by reference in its entirety.
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The present invention relates to prevention and treatment of tuberculosis in a subject infected with Mycobacterium tuberculosis by inhibiting AhpD, dihydrolipoamide dehydrogenase, and/or dihydrolipoamide succinyltransferase to impart susceptibility to antimicrobial reactive nitrogen intermediates or reactive oxygen intermediates. A method of producing an AhpD crystal suitable for X-ray diffraction and a compound suitable for treatment or prevention of tuberculosis in a subject are also disclosed. Mycobacterium tuberculosis infects about one-third of the human population, persists for decades, and causes disease in a small fraction of those infected. Despite the low disease rate, Mycobacterium tuberculosis is the single leading cause of death from bacterial infection and accounts for an extraordinary proportion of the chronic infectious morbidity and mortality of humankind. Mycobacterium tuberculosis provokes inflammation that leads human macrophages to express the high output isoform of nitric oxide synthase (iNOS or NOS2). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Nucleic acid fragments and polypeptide fragments derived from M. tuberculosis Inventor(s): Rasmussen, Peter Birk; (Kobenhaven O, DK), Rosenkrands, Ida; (Kobenhaven O, DK), Nielsen, Rikke; (Frederiksberg C, DK), Florio, Walter; (Frederiksberg C, DK), Andersen, Peter; (Bronshoj, DK), Weldingh, Karin; (Kobenhaven N, DK), Oettinger, Thomas; (Hellerup, DK) Correspondence: FROMMER LAWRENCE & HAUG LLP; 745 FIFTH AVENUE; NEW YORK; NY; 10151; US Patent Application Number: 20020094336 Date filed: February 20, 2001 Abstract: The present invention is based on the identification and characterization of a number of M. tuberculosis derived novel proteins and protein fragments (SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 17-23, 42, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72-86, 88, 90, 92, 94, 141, 143, 145, 147, 149, 151, 153, and 168-171). The invention is directed to the polypeptides and immunologically active fragments thereof, the genes encoding them, immunological compositions such as vaccines and skin test reagents containing the polypeptides. Another part of the invention is based on the surprising discovery that fusions between ESAT-6 and MPT59 are superior immunogens compared to each of the unfused proteins, respectively. Excerpt(s): The present invention relates to a number of immunologically active, novel polypeptide fragments derived from the Mycobacterium tuberculosis, vaccines and other immunologic compositions containing the fragments as immunogenic components, and methods of production and use of the polypeptides. The invention also relates to novel nucleic acid fragments derived from M. tuberculosis which are useful in the preparation of the polypeptide fragments of the invention or in the diagnosis of infection with M. tuberculosis. The invention further relates to certain fusion polypeptides, notably fusions between ESAT-6 and MPT59. Human tuberculosis (hereinafter designated "TB") caused by Mycobacterium tuberculosis is a severe global health problem responsible for approximately 3 million deaths annually, according to the WHO. The worldwide incidence of new TB cases has been progressively falling for the last decade but the recent years has markedly changed this trend due to the advent of AIDS and the appearance of multidrug resistant strains of M. tuberculosis. The only vaccine presently available for clinical use is BCG, a vaccine which efficacy remains a matter of controversy. BCG generally induces a high level of acquired resistance in
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animal models of TB, but several human trials in developing countries have failed to demonstrate significant protection. Notably, BCG is not approved by the FDA for use in the United States. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Polynucleotide functionally coding for the LHP protein from Mycobacterium tuberculosis, its biologically active derivative fragments, as well as methods using the same Inventor(s): Rasmussen, Peter Birk; (Bergsgade, DK), Berthet, Francois-Xavier; (Paris, FR), Anderson, Peter; (Bronshoj, DK), Gicquel, Brigitte; (Paris, FR) Correspondence: OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC; FOURTH FLOOR; 1755 JEFFERSON DAVIS HIGHWAY; ARLINGTON; VA; 22202; US Patent Application Number: 20030092899 Date filed: May 8, 2002 Abstract: The present invention is directed to a polynucleotide carrying an open reading frame coding for an antigenic polypeptide from Mycobacterium tuberculosis, named lhp, which is placed under the control of its own regulation signals which are functional in mycobacteria, specially in mycobacteria belonging to the Mycobacterium tuberculosis complex and also in fast growing mycobacteria such as Mycobacterium smegmatis. The invention is also directed to the polypeptide LHP encoded by lhp and most preferably to suitable antigenic portions of LHP as well as to oligomeric polypeptides containing more than one unit of LHP or an antigenic portion of LHP. The invention concerns also immunogenic and vaccine compositions containing a polypeptide or an oligomeric polypeptide such as defined above, as well as antibodies directed specifically against such polypeptides that are useful as diagnostic reagents. In another embodiment, the present invention is directed to a polynucleotide carrying the natural regulation signals of lhp which is useful in order to express heterologous proteins in mycobacteria. Finally, the present invention is directed to oligonucleotides comprising at least 12 consecutive nucleotides from the regulation sequence of lhp which are useful as reagents for detecting the presence of Mycobacterium tuberculosis in a biological sample. Excerpt(s): This application is a filed May 8, 2002, allowed, which claims priority from Provisional Application, U.S. Application Serial No. 60/052,631 filed Jul. 16, 1997. The entire disclosure of this application is incorporated herein-by-reference. The present invention is directed to a polynucleotide comprising an open reading frame coding for a polypeptide from Mycobacterium tuberculosis, named LHP capable of inducing an immune response in a host. lhp is placed under the control of its own regulation signals which are functional in mycobacteria, especially in mycobacteria belonging to the Mycobacterium tuberculosis complex and also in fast growing mycobacteria such as Mycobacterium smegmatis and also in E. coli. The Mycobacterium tuberculosis complex has its usual meaning, i.e. the complex of mycobacteria causing tuberculosis which are Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti and the vaccine strain M. bovis BCG. The invention is also directed to the polypeptide LHP encoded by lhp and most preferably to suitable antigenic portions of LHP as well as to oligomeric polypeptides containing more than one unit of LHP or an antigenic portion of LHP. The invention concerns also immunogenic and vaccine compositions containing a polypeptide or an oligomeric polypeptide such as defined above or live recombinant attenuated mycobacteria transformed with a polynucleotide according to the present invention. The invention
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also concerns antibodies directed specifically against such polypeptides that are useful as diagnostic reagents. In another embodiment, the present invention is directed to a polynucleotide carrying the natural regulation signals of lhp which is useful in order to express heterologous proteins in mycobacteria as well as functionally active regulatory polynucleotides derived from said regulatory region. Finally, the present invention is directed to oligonucleotides comprising at least 12 consecutive nucleotides which are useful as reagents for detecting the presence of Mycobacterium tuberculosis in a biological sample. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
POLYNUCLEOTIDE TUBERCULOSIS VACCINE Inventor(s): ULMER, JEFFREY; (CHALFONT, PA), MONTGOMERY, DONNA; (CHALFONT, PA), LIU, MARGARET A. (ROSEMONT, PA), HUYGEN, KRIS; (BRUSSELS, BE), CONTENT, JEAN; (RHODE-SAINT-GENESE, BE) Correspondence: JOHN W WALLEN III; MERCK & CO INC; PATENT DEPT; P O BOX 2000; RAHWAY; NJ; 070650907 Patent Application Number: 20020032162 Date filed: January 22, 1998 Abstract: Genes encoding Mycobacterium tuberculosis (M.tb) proteins were cloned into eukaryotic expression vectors to express the encoded proteins in mammalian muscle cells in vivo. Animals were immunized by injection of these DNA constructs, termed polynucleotide vaccines or PNV, into their muscles. Immune antisera was produced against M.tb antigens. Specific T-cell responses were detected in spleen cells of vaccinated mice and the profile of cytokine secretion in response to antigen 85 was indicative of a T.sub.h1 type of helper T-cell response (i.e., high IL-2 and IFN-.gamma.). Protective efficacy of an M.tb DNA vaccine was demonstrated in mice after challenge with M.bovis BCG, as measured by a reduction in mycobacterial multiplication in the spleens and lungs of M.tb DNA-vaccinated mice compared to control DNA-vaccinated mice or primary infection in naive mice. Excerpt(s): A major obstacle to the development of vaccines against viruses and bacteria, particularly those with multiple serotypes or a high rate of mutation, against which elicitation of neutralizing antibodies and/or protective cell-mediated immune responses is desirable, is the diversity of the external proteins among different isolates or strains. Since cytotoxic T-lymphocytes (CTLs) in both mice and humans are capable of recognizing epitopes derived from conserved internal viral proteins [J. W. Yewdell et al., Proc. Natl. Acad. Sci. (USA) 82, 1785 (1985); A. R. M. Townsend, et al., Cell 44, 959 (1986); A. J. McMichael et al., J. Gen. Virol. 67, 719 (1986); J. Bastin et al., J. Exp. Med. 165, 1508 (1987); A. R. M. Townsend and H. Bodmer, Annu. Rev. Immunol. 7, 601 (1989)], and are thought to be important in the immune response against viruses [Y. -L. Lin and B. A. Askonas, J. Exp. Med. 154, 225 (1981); I. Gardner et al., Eur. J. Immunol. 4, 68 (1974); K. L. Yap and G. L. Ada, Nature 273, 238 (1978); A. J. McMichael et al., New Engl. J. Med. 309, 13 (1983); P. M. Taylor and B. A. Askonas, Immunol. 58, 417 (1986)], efforts have been directed towards the development of CTL vaccines capable of providing heterologous protection against different viral strains. It is known that CTLs kill virallyor bacterially-infected cells when their T cell receptors recognize foreign peptides associated with MHC class I and/or class II molecules. These peptides can be derived from endogenously synthesized foreign proteins, regardless of the protein's location or function within the pathogen. By recognition of epitopes from conserved proteins, CTLs
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may provide heterologous protection. In the case of intracellular bacteria, proteins secreted by or released from the bacteria are processed and presented by MHC class I and II molecules, thereby generating T-cell responses that may play a role in reducing or eliminating infection. Most efforts to generate CTL responses have either used replicating vectors to produce the protein antigen within the cell [J. R. Bennink et al., ibid. 311, 578 (1984); J. R. Bennink and J. W. Yewdell, Curr. Top. Microbiol. Immunol. 163, 153 (1990); C. K. Stover et al., Nature 351, 456 (1991); A. Aldovini and R. A. Young, Nature 351, 479 (1991); R. Schafer et al., J. Immunol. 149, 53 (1992); C. S. Hahn et al., Proc. Natl. Acad. Sci. (USA) 89, 2679 (1992)], or they have focused upon the introduction of peptides into the cytosol [F. R. Carbone and M. J. Bevan, J. Exp. Med. 169, 603 (1989); K. Deres et al., Nature 342, 561 (1989); H. Takahashi et al., ibid. 344, 873 (1990); D. S. Collins et al., J. Immunol. 148, 3336 (1992); M. J. Newman et al., ibid. 148, 2357 (1992)]. Both of these approaches have limitations that may reduce their utility as vaccines. Retroviral vectors have restrictions on the size and structure of polypeptides that can be expressed as fusion proteins while maintaining the ability of the recombinant virus to replicate [A. D. Miller, Curr. Top. Microbiol. Immunol. 158, 1 (1992)], and the effectiveness of vectors such as vaccinia for subsequent immunizations may be compromised by immune responses against vaccinia [E. L. Cooney et al., Lancet 337, 567 (1991)]. Also, viral vectors and modified pathogens have inherent risks that may hinder their use in humans [R. R. Redfield et al., New Engl. J. Med. 316, 673 (1987); L. Mascola et al., Arch. Intern. Med. 149, 1569 (1989)]. Furthermore, the selection of peptide epitopes to be presented is dependent upon the structure of an individual's MHC antigens and, therefore, peptide vaccines may have limited effectiveness due to the diversity of MHC haplotypes in outbred populations. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Process for the preparation of a vaccine for the treatment of tuberculosis and other intracellular infections diseases and the vaccine produced by the process Inventor(s): Agrewala, Javed Naim; (Chandigarh, IN), Sharma, Naresh; (Chandigarh, IN) Correspondence: Joseph J. Crimaldi; Renner, Otto, Boisselle & Sklar, LLP; Keith Building, 19th Floor; 1621 Euclid Avenue; Cleveland; OH; 44115-2191; US Patent Application Number: 20020136738 Date filed: March 23, 2001 Abstract: The present invention relates to a process for the preparation of a vaccine against tuberculosis and other intracellular pathogens, this vaccine is targeted against intracellular pathogens, more particularly the pathogen Mycobacterium tuberculosis and Salmonella in this case. Excerpt(s): The present invention relates to a process for the preparation of a vaccine against tuberculosis and other intracellular pathogens. This vaccine is targeted against intracellular pathogens, more particularly the pathogen Mycobacterium tuberculosis and Salmonella in this case. The utility of the present invention is to develop a vaccine against the intracellular pathogens, which are causative agent of tuberculosis, brucellosis, leishmaniasis, leisteriosis, leprosy, malaria, typhoid, trypanosomiasis and streptococcus and HIV-infection. The pathogen Mycobacterium tuberculosis (M. tuberculosis) the subject matter of this invention is a causative agent of tuberculosis. In this invention M. tuberculosis was allowed to grow in the allogeneic and syngeneic macrophages and macrophage cell lines. The macrophages-M. tuberculosis complex was
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then irradiated to kill the macrophages as well as the mycobacterium. Tuberculosis is a chronic infectious disease that continues to kill some 3 million people a year. About 8 million new cases arise every year and the number continues to increase. About onethird of the world population is infected with M. tuberculosis. The emergence of AIDS has reactivated tuberculosis in millions of dormant individuals, causing a sharp rise in the number of cases and deaths. M. tuberculosis is therefore responsible for the highest morbidity rate among all infectious agents. The only available vaccine BCG is both unpredictable and highly variable. Doubtful efficacy of BCG vaccination has put the scientific community to urgently develop effective means of vaccination against the M. tuberculosis (Bloom, B. R. et. al., Annu. Rev. Immunol. 10:1992:453). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Rapid lateral flow assay for determining exposure to mycobacterium tuberculosis and other mycobacteria Inventor(s): Simonson, Lloyd G. (Spring Grove, IL) Correspondence: BANNER & WITCOFF, LTD. TEN SOUTH WACKER DRIVE; SUITE 3000; CHICAGO; IL; 60606; US Patent Application Number: 20030143652 Date filed: January 30, 2002 Abstract: An assay method and kit is disclosed for detecting the presence of at least one predesignated, target antibody to a mycobacterium in a sample selected from one or more patient bodily fluids. The method comprises the following steps: (a) contacting the sample of one or more patient bodily fluids with at least one mycobacterium antigen on a lateral-flow assay membrane to bind to the target antibody in the sample; (b) previously, simultaneously or subsequently to step (a), binding the at least one mycobacterium antigen with a conjugated label producing a detectable signal; and (c) detecting the signal whereby the presence of the target antibody is determined in the sample by the intensity or presence of the signal. The method can further comprise the step of evaluating immunization status of the patient from whom the sample came by comparing the signal or lack thereof with immunizations previously received by the patient and in comparison to a known standard control. In a preferred embodiment, the mycobacterium antigen specifically binds to Mycobacterium tuberculosis specific antibodies. Preferably, the immunoassay of the present invention comprises a lateralflow assay comprising a membrane, a conjugated label pad, and at least one mycobacterium antigen bound to the membrane. In a preferred embodiment, the at least one mycobacterium antigen is selected from the group consisting of 38 kDa and 16 kDa antigens. Excerpt(s): The present invention relates to a rapid test method and assay for determining the presence of antibodies in a patient to disease-related antigens, e.g., antibodies to Mycobacterium tuberculosis, and other mycobacterial antigens. Antibodies are naturally produced biomolecules that react specifically with usually foreign biomolecules called antigens. Disease-related microbial infections, e.g., Mycobacterium tuberculosis, which causes tuberculosis (TB), are usually characterized by the production of antibodies to the specific disease-related antigens. Antibodies are also produced with other diseases and afflictions, e.g., autoimmune diseases, wherein there is often a destructive antibody response to the host. In the case of autoimmune diseases, the host supplies the disease-related antigen, a host tissue. In this case, the corresponding host antibody synthesis may have been initiated by either a foreign
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substance or by a host tissue not normally encountered by the host's immune system. Subsequent antibody production may proceed in the absence of the foreign substance, due to similar structural nature of the host tissue. Herein the term "disease-related antigen" includes microbial antigens and antigens associated with the host antibody response in autoimmune diseases. Infectious diseases are widespread in the world. Military personnel, including Navy and Marine personnel, are at particular risk because of their global deployment. According to the World Health Organization, the infectious disease tuberculosis caused by Mycobacterium tuberculosis (MTB) kills about three million people every year. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
RECOMBINATION M. TUBERCULOSIS MYCOBACTERIUM AUXOTROPHIC FOR LEUCINE AND VACCINES USING SAME Inventor(s): BLOOM, BARRY R. (HASTINGS ON HUDSON, NY), HONDALUS, MARY K. (NORTHBOROUGH, MA), JACOBS, WILLIAM R. JR. (CITY ISLAND, NY) Correspondence: CRAIGE J ARNOLD; AMSTER ROTHSTEIN & EBENSTEIN; 90 PARK AVENUE; NEW YORK; NY; 10016 Patent Application Number: 20020068067 Date filed: July 8, 1999 Abstract: The present invention provides a recombinant M. tuberculosis mycobacterium that is auxotrophic for leucine. The present invention also provides a vaccine comprising a recombinant M. tuberculosis mycobacterium that is auxotrophic for leucine, as well as a method for treating or preventing tuberculosis in a subject comprising administering to the subject a recombinant M. tuberculosis mycobacterium that is auxotrophic for leucine in an amount effective to treat or prevent tuberculosis in the subject. Excerpt(s): Approximately one third of the world's population is infected with Mycobacterium tuberculosis (MTB), the causative agent of human tuberculosis (TB). MTB is responsible for 2-3 million deaths annually, giving it the dubious distinction of being the leading cause of death due to a single infectious agent. In addition, TB ranks seventh in causes of global mortality and disability, and if current predictions prove correct, it will remain among the top 10 causes of disease, well into the next century (Murray and Lopez, Lancet, 349:1498-1504 (1997)). Directly observed treatment, shortcourse (DOTS) is the tactic proposed by the World Health Organization (WHO) to control the global TB crisis (Murray and Solomon, PNAS USA, 95:13881-13886 (1998)). DOTS has proven to be an effective strategy in several national TB control programs, with cure rates approaching 90% (Lancet, 347:358-362 (1996)). However, since global implementation of DOTS programs is occurring at a slow-moving pace, it is likely that additional measures will be needed to stem the tide of TB mortality. It has been estimated that the introduction of a new vaccine of only 50% efficacy could decrease the incidence of TB by 36 million cases, saving 9 million lives (Murray and Salomon, 1998). Thus, by coupling efficacious vaccination with effective treatment, greater success in global TB management would be anticipated. Bacille Calmette-Guerin (BCG), an attenuated strain of M. bovis, is the currently available vaccine for the prevention of tuberculosis. It was created empirically by repeated passage in the laboratory, and for reasons that are as yet undefined, it is avirulent in immunocompetent hosts. In several animal models of infection, BCG has been demonstrated to induce protective immunity against MTB. Since its implementation in 1928 as a TB vaccine, more doses of BCG have been administered than any other vaccine, as an estimated 3 billion people have
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received BCG vaccination for the prevention of tuberculosis. Although the use of BCG is unquestionably safe in immunocompetent individuals, it has shown itself to be of variable efficacy. While in certain populations, vaccination with BCG has been highly effective in preventing tuberculosis, in others it has failed miserably. In the largest clinical trial that took place in India involving more that 100,000 persons, BCG exhibited a calculated protective efficacy of zero. Thus, the generation of an improved vaccine(s) to replace BCG and to prevent tuberculosis is urgently needed. Relative to wildtype M. tuberculosis, 15-16 regions of the MTB genome are not represented in BCG. Eleven of these segments cannot be found even in virulent strains of M. bovis; of the remaining 5, 4 are missing from all BCG strains examined. It is probable that one or more of the 38 open reading frames (ORFs) specifically missing from BCG are required for virulence. Of interest, is the finding that a number of predicted transcriptional regulators identified by the H37Rv genome sequencing project (Cole, et al., Nature, 393:537-544 (1998)) would be located in these BCG deletions. The loss of a regulatory protein would be expected to affect multiple genetic loci and could lead to deranged gene expression in vivo. Consistent with this hypothesis, is the demonstration that reintroduction of one of these deleted regions into BCG results in the repression of at least 10 proteins and the upregulated expression of others. It is conceivable that potentially immunogenic and immunoprotective antigens might be missing from or inappropriately expressed in BCG, and therefore, compromising the immune response generated from this vaccine. For example, it has been noted that the gene for ESAT 6, a highly immunogenic, secreted protein of M. tuberculosis, is located within one of these deleted chromosomal regions. It has demonstrated that protective immunity against experimental tuberculosis can be provided by prior immunization with supernatants containing a mixture of MTB secreted antigens, of which ESAT 6 is one. It is possible, that if one or more of the proteins encoded within the deleted regions were present at vaccination, the immune response elicited might be more efficacious. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Structure of isocitrate lyase enzyme from mycobacterium tuberculosis and inhibitory agents to combat persistent infection Inventor(s): Sharma, Sujata; (Pearland, TX), Jacobs, William R. JR. (Bronx, NY), Sacchettini, James C. (College Station, TX), Russell, David G. (Ithaca, NY), Sharma, Vivek; (Pearland, TX), Honer Zu Bentrup, Kerstin A. (New Orleans, LA), McKinney, John D. (New York, NY) Correspondence: Scott Reese, Ph.D. Howrey, Simon, Arnold & White, L.L.P. 750 Bering Drive; Houston; TX; 77057-2198; US Patent Application Number: 20030018166 Date filed: August 3, 2001 Abstract: The invention provides methods and compositions for use in identifying inhibitors of biochemical pathways important for persistent infection, allowing the identification and/or design of improved therapeutics for treating persistent infections by pathogenic microbes. Particularly disclosed is the importance of the glyoxylate shunt to the persistent phase of various infectious agents, including Mycobacteria, such as M. tuberculosis, and the identification of preferred targets for drug development, including the enzymes isocitrate lyase (ICL) and malate synthase. Crystals and three-dimensional structures of M. tuberculosis ICL, without ligand and in complex with two inhibitors are also disclosed, for exemplary use in the design of inhibitors and therapeutic agents.
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Excerpt(s): The present invention generally relates to the fields of pathogenic microbes and to therapeutic agents for treating persistent infections, including infection by M. tuberculosis. Through rigorous definition of an important pathway for persistent infection, the invention provides preferred targets for drug development from the glyoxylate shunt pathway, such as the isocitrate lyase and malate synthase enzymes. Exemplary embodiments of the invention concern crystals and three-dimensional structures of M. tuberculosis isocitrate lyase in complex with inhibitors, for particular use in the design of inhibitors and therapeutic agents. Although modem medicine has provided many weapons to combat disease, infection by pathogenic microbes still poses a significant threat to human life. In recent times, an increasing number of microbes have developed resistance to many commonly used antimicrobial agents, thereby contributing to a new spread of disease. Mycobacteria are examples of microbial pathogens that exhibit persistent infection. Mycobacterium tuberculosis, the causative agent of the tuberculosis (TB) disease, exhibits a penetrance in the human population that is rivaled by few other pathogens. Tuberculosis remains the largest cause of death in the world from a single infectious disease and causes many fatalities in developing countries. The success of M. tuberculosis is dependent on its ability to persist and maintain chronic infection in humans (Parrish et al., 1998). During chronic tuberculosis, the bacteria exist in diverse metabolic states that are not targeted by conventional antimycobacterials (Mitchison, 1980). Lengthy regimens of anti-TB drugs are necessary and are currently the only way to even approach killing of the persistent bacteria. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
TB diagnostic based on antigens from M. tuberculosis Inventor(s): Weldingh, Karin; (Vaerlose, DK), Hansen, Christina Veggerby; (Manchester, GB), Okkels, Li Mei Meng; (Bagsvaerd, DK), Skjot, Rikke Louise Vinther; (Hedehusene, DK), Rasmussen, Peter Birk; (Copenhagen, DK), Florio, Walter; (Carrara, IT), Andersen, Peter; (Bronshoj, DK) Correspondence: BIRCH STEWART KOLASCH & BIRCH; PO BOX 747; FALLS CHURCH; VA; 22040-0747; US Patent Application Number: 20030165525 Date filed: May 2, 2002 Abstract: The present invention is based on the identification and characterization of a number of novel M. tuberculosis derived proteins and protein fragments. The invention is directed to the polypeptides and immunologically active fragments thereof, the genes encoding them, immunological compositions such as diagnostic reagents containing the polypeptides. Excerpt(s): U.S. patent application Ser. No. 10/060,428, filed Jan. 29, 2002, which claims priority from U.S. application Ser. No. 09/415,884, filed Oct. 8, 1999, which claims priority from U.S. Provisional Application No. 60/116,673, filed Jan. 21, 1999; U.S. Provisional Application No. 60/070,488, filed Jan. 5, 1988; U.S. Provisional Application No. 60/044,624, filed Apr. 18, 1997; Danish Patent Application No. DK 1997 00376, filed Apr. 2, 1997; Danish Patent Application No. DK 1997 01277, filed Nov. 1, 1997 and Danish Patent Application No. DK 1998 01281, filed Oct. 8, 1998. Each of these patent applications as well as all documents cited in the text of this application, and references cited in the documents referred to in this application (including references cited in the aforementioned patent applications or during their prosecution) are hereby incorporated herein by reference. The present invention relates to a number of
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immunologically active, novel polypeptide fragments derived from Mycobacterium tuberculosis, diagnostics and other immunologic compositions containing the fragments as immunogenic components, and methods of production and use of the polypeptides. The invention also relates to novel nucleic acid fragments derived from M. tuberculosis which are useful in the preparation of the polypeptide fragments of the invention or in the diagnosis of infection with M. tuberculosis. The invention further relates to certain fusion polypeptides. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
TEST KIT FOR TUBERCULOSIS DIAGNOSIS BY DETERMINING ALANINE DEHYDROGENASE Inventor(s): KOLK, AREND; (BRAUNSCHWEIG, DE), HUTTER, BERND; (BRAUNSCHWEIG, DE), SINGH, MAHAVIR; (BRAUNSCHWEIG, DE), FLOHE, LEOPOLD; (WOLFENBUTTEL, DE) Correspondence: MARSHALL O'TOOLE GERSTEIN; MURRAY & BORUN; 6300 SEARS TOWER; 233 SOUTH WACKER DRIVE; CHICAGO; IL; 606066402 Patent Application Number: 20030162171 Date filed: July 28, 1999 Abstract: Tuberculosis is an infectious disease which kills more than three million people every year. Although both a vaccine and various methods of diagnosis and treatment are available, the efficacy of these measures is in urgent need of improvement given that the number of new cases is once again on the increase. Research focuses, among other things, on the characterization of antigens secreted in the early stages of the infection as they constitute the first point of contact of the immune system with the pathogen. The 40 KD-antigen described herein is present in vivo as a hexamer and, despite its high molecular weight and lack of a signal sequence, is present extracellularly after only a few days of growth. Functionally, it is an L-alanine dehydrogenase and reacts with the monoclonal antibody HBT-10 directed against this protein. HBT-10 was the first known antibody specific to a protein of M. tuberculosis which did not crossreact with the vaccine strain M. bovis BCG. Excerpt(s): Isolated lambda gt11 clones containing the complete AlaDH coding DNA of M. tuberculosis or parts thereof are known from Anderson et al. (1992). The isolated mycobacterial AlaDH insert from lambda AA67 was used as the hybridisation probe in that work. The 40 kD antigen with which this work is concerned is in many respects an interesting subject for detailed studies. The antigen had already been cloned into an expression vector for Escherichia coli (Konrad & Singh, unpublished). The expression and purification of the recombinant protein was therefore to be optimised. Using a homogeneous protein fraction, the crucial biochemical parameters of the enzyme were then to be determined. Previous experience has shown that it is possible to infer the physiological function of an enzyme from such data. The question that this posed was whether the hypothetical function of the enzyme in cell wall biosynthesis could be confirmed or disproved. If disproved, other possible functions were to be elicited. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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TUBERCULOSIS ANTIGENS AND METHODS OF USE THEREFOR Inventor(s): HENDRICKSON, RONALD C. (SEATTLE, WA), HOUGHTON, RAYMOND L. (BOTHELL, WA), LODES, MICHAEL J. (SEATTLE, WA) Correspondence: SEED INTELLECTUAL PROPERTY LAW GROUP PLLC; 701 FIFTH AVE; SUITE 6300; SEATTLE; WA; 98104-7092; US Patent Application Number: 20030027774 Date filed: March 18, 1999 Abstract: Compounds and methods for the diagnosis and treatment of tuberculosis are disclosed. Compounds include the M. tuberculosis antigens Mtb-81 and Mtb-67.2, immunogenic portions thereof and polynucleotides that encode such portions. Such compositions may be used, for example, for the immunotherapy and serodiagnosis of M. tuberculosis infection. Excerpt(s): The present invention relates generally to the detection and treatment of tuberculosis. The invention is more specifically related to polypeptides comprising at least a portion of a Mycobacterium tuberculosis antigen, or a portion or other variant thereof, and to the use of such polypeptides for the serodiagnosis and immunotherapy of M. tuberculosis infection. Tuberculosis is a chronic, infectious disease that is generally caused by infection with Mycobacterium tuberculosis. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about eight million new cases and three million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If left untreated, M. tuberculosis infection generally results in serious complications and death. Inhibiting the spread of tuberculosis requires accurate, early diagnosis of the disease. The most common method of diagnosis is a skin test, which involves intradermal exposure to tuberculin PPD (protein-purified derivative). Antigen-specific T cell responses result in measurable indubation at the injection site within 48-72 hours after injection, which indicates exposure to mycobacterial antigens. Although the tuberculin test is used throughout the world, it suffers from problems with sensitivity and specificity. For example, individuals vaccinated with Bacillus Calmette-Guerin (BCG) cannot be distinguished from infected individuals. In addition, tuberculosis is a frequent occurrence in AIDS patients, but the sensitivity of the tuberculin skin test is substantially reduced during HIV infection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Tuberculosis vaccine Inventor(s): Kaufmann, Stefan H.E. (Berlin, DE), Hess, Jurgen; (Baiersdorf, DE) Correspondence: ARENT FOX KINTNER PLOTKIN & KAHN, PLLC; Suite 600; 1050 Connecticut Avenue, N.W. Washington; DC; 20036-5339; US Patent Application Number: 20020177569 Date filed: September 10, 2001 Abstract: The present invention relates to novel recombinant vaccines providing protective immunity against tuberculosis. Further, the present invention refers to novel recombinant nucleic acid molecules, vectors containing said nucleic acid molecules, cells
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transformed with said nucleic acid molecules and polypeptides encoded by said nucleic acid molecules. Excerpt(s): The present invention relates to novel recombinant vaccines providing protective immunity especially against tuberculosis. Further, the present invention refers to novel recombinant nucleic acid molecules, vectors containing said nucleic acid molecules, cells transformed with said nucleic acid molecules and polypeptides encoded by said nucleic acid molecules. Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a significant global problem. It is estimated that one third of the world's population is infected with M. tuberculosis (Kochi, 1991). In many countries the only measure for TR control has been vaccination with M. bovis bacille Calmette-Gurin (BCG). The overall vaccine efficacy of BCG against TB, however, is about 50% with extreme variations ranging from 0% to 80% between different field trials (Roche et al., 1995). Thus, BCG should be improved, e.g. by genetic engineering, to provide a vaccine for better TB control (Murray et al., 1996; Hess and Kaufmann, 1993). The widespread emergence of multiple drug-resistant M. tuberculosis strains additionally underlines the urgent requirement for novel TB vaccines (Grange, 1996). M. tuberculosis belongs to the group of intracellular bacteria that replicate within the phagosomal vacuoles of resting macrophages, thus protection against TB depends on T cell-mediated immunity (Kaufmann, 1993). Several studies in mice and humans, however, have shown that mycobacteria stimulate antigen-specific, major histocompatibility complex (MHC) class II- or class I-restricted CD4 and CD8 T cells, respectively (Kaufmann, 1993). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with tuberculosis, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “tuberculosis” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on tuberculosis. You can also use this procedure to view pending patent applications concerning tuberculosis. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 7. BOOKS ON TUBERCULOSIS Overview This chapter provides bibliographic book references relating to tuberculosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on tuberculosis include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “tuberculosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on tuberculosis: •
Tuberculosis Education and Training Resource Guide Contact: CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: To help the nation eliminate tuberculosis (TB), this resource guide was developed as a cooperative effort between the Centers for Disease Control and Prevention (CDC) National Prevention Information Network (NPIN) and the CDC Division of Tuberculosis Elimination to give health departments, lung associations, and other providers of healthcare and health education knowledge of and access to available materials on TB education, training, and public awareness. The guide contains six sections. (1) Educational Materials (Patient and Public Education and Professional Education): Materials listed in this section are drawn from the NPIN Educational Materials Database and include fact sheets, guides, reports, and videos. (2) Consensus Guidelines: Guidelines listed in this section discuss TB prevention, control, and screening. (3) Journal Articles: Articles listed in this section discuss TB prevention
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worldwide as a means of eliminating TB in the United States. (4) Internet Resources: This section presents select Internet sites that provide information on TB and related health issues and sites that link users directly to TB-related journals and newsletters. (5) Organizations: The national and international organizations listed in this section promote TB prevention, develop training programs, and advocate for adequate public and private response. (6) Funding Opportunities: The organizations listed in this section have funded, or are currently funding, TB research programs or programs that provide TB education, prevention, and support services. •
WHO Report 2003: Global Tuberculosis Control: Surveillance, Planning, Financing Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph is a World Health Organization (WHO) annual report on the progress in global Tuberculosis (TB) control and in implementing the directly observed therapy, short course (DOTS) strategy. The monograph presents data on case notifications for 2001, treatment results for patients registered in 2000, the status of DOTS implementation by the end of 2001, and the latest data on progress made by countries during 2002. It also includes an analysis of plans, finances, and constraints on DOTS expansion for 22 high-burden countries (HBC). The annexes present the data collection forms for surveillance and financing; profiles of HBCs; country data by region; world maps showing estimated TB incidence rates for 2001, implementation of DOTS, 2001, and TB notification rates 2001; comparison of cases notified and registered for treatment in 2000; and trends in treatment success and DOTS detection rates, 19942001.
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Tuberculosis Prevention Guide for Homeless Service Providers Contact: Homeless Health Care Los Angeles, 2330 Beverly Blvd, Los Angeles, CA, 90057, (213) 744-0724, http://www.hhcla.org. Summary: This monograph, for health professionals who serve homeless persons, can be used as a guide in developing policies and procedures to decrease the risk of tuberculosis (TB) in homeless person facilities. The monograph discusses the epidemiology of TB among homeless persons in Los Angeles. It outlines how TB is transmitted, the difference between TB infection (LTBI) and TB disease, and TB risk factors. It examines treatments for persons with TB, persons co-infected with TB and the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), pregnant women with TB, and individuals with multidrug-resistant TB.
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Timebomb: The Global Epidemic of Multi-Drug-Resistant Tuberculosis Contact: McGraw Hill, Order Services, POBox 545, Blacklick, OH, 43004. Summary: This monograph provides health professionals, organizations, and government agencies with information on the developing epidemic of multidrugresistant tuberculosis (MDRTB). It reviews the history of TB and discusses its transmission and treatment. It examines how the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic has influenced the reemergence of TB by facilitating the spread of MDRTB. It presents specific information on TB and MDRTB in Russia, the relationship between treatment of TB and the spread of MDRTB, and socioeconomic and political forces that have contributed to the spread of
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MDRTB. The monograph discusses the epidemiology of TB and MDRTB in New York City, directly observed therapy, short-course (DOTS) role in the prevention of MDRTB, the development of MDRTB, and reasons why there have been relatively few developments in TB treatment over the past three decades. •
Interventions for Tuberculosis Control and Elimination Contact: International Union Against Tuberculosis and Lung Disease, 68 Boulevard Saint-Michel, Paris, (011) 33144320360, http://www.iuatld.org. Summary: This monograph, for managers of national tuberculosis control programs, largely in low-income countries, discusses the medical treatments for tuberculosis (TB) as a means of prevention and elimination. The monograph examines typical first- and second-line treatments of TB, the use of prophylactic treatment in people exposed to TB, the use of vaccination and the effectiveness of the Bacille Calmette-Guerin (BCG) vaccination in TB, adjunctive treatment with corticosterioids, active agents other than essential drugs and drug classes, and current vaccine development strategies.
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Nomas Para la Prevencion de la Transmision de la Tuberculosis en los Establecimientos de Asistencia Sanitaria en Condiciones de Recursos Limitados Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph presents information about the prevention of tuberculosis (TB) in health care facilities based upon three levels of infection control: the administrative, environmental, and personal respiratory levels. The monograph includes seven chapters: (1) Pathogenesis and Transmission of TB, (2) Risk of Nosocomial Transmission of Mycobacterium tuberculosis to Health Care Workers in Resource-Limited Countries, (3) An Introduction to Infection Control Strategies, (4) Administrative Control Measures, (5) Environmental Control Measures, (6) Personal Respiratory Protection, and (7) Laboratory Safety.
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The Global Plan to Stop Tuberculosis Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph presents the Global Partnership to Stop TB's (GPSTB) fiveyear strategic plan to eliminate tuberculosis (TB) as a public health problem. The GPSTB is a network of country partners, international organizations, public and private donors, governmental and non-governmental organizations (NGOs), and academic institutions, (more than 200 organizations in all) working together. The partnership is hosted by the World Health Organization (WHO). The monograph explains the purpose, objectives, structure, plan costs, and the strategies and mechanisms to achieve the goal. The four strategic objectives of the GPSTB are to (1) expand the currently available anti-TB strategy of Directly Observed Therapy, Short-course (DOTS) so that all people with TB have access to effective diagnosis and treatment; (2) adapt this current strategy to meet emerging challenges of HIV and TB drug resistance; (3) improve existing tools by developing new diagnostics, new drugs, and new vaccines, (4) and strengthen the GPSTB partnership so that proven TB-control strategies are effectively applied.
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Reported Tuberculosis in the United States, 2001 Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This monograph presents summary data for tuberculosis (TB) cases reported to the Division of TB Elimination (DTBE), Centers for Disease Control and Prevention (CDC), during 2001. Reports of TB cases are submitted to the DTBE by 60 reporting areas (50 states, the District of Columbia, New York City, Puerto Rico, and other jurisdictions in the Pacific and Caribbean). This report contains six major sections. (1) The first section presents trends in overall TB case counts and case rates by selected demographic and clinical characteristics. (2) The second section provides overall TB case counts and case rates for the US by selected demographic characteristics for 2001. (3) The third section provides TB case counts and case rates by state with tables of selected demographic and clinical characteristics. (4) The fourth section provides data collected as part of the expanded system (e.g., initial drug resistance, HIV status) by reporting area. (5) The fifth section provides TB case counts and case rates by metropolitan statistical areas with tables of selected demographic and clinical characteristics. (6) The sixth section presents figures from the annual surveillance slide set, which emphasize key recent trends in TB epidemiology in the US. The current case definition and 'Recommendations for Counting Reported Tuberculosis Cases' are provided in the Appendices. Data show that during 2001, a total of 15,989 TB cases (5.6 cases per 100,000 population) were reported to CDC from 50 states and the District of Columbia, representing a 2% decrease from 1999 and a 40% decrease from 1992, when the number of cases peaked during the resurgence of TB in the United States.
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Taking Precautions Against Tuberculosis: Health-Care Staff Handbook Contact: Channing L. Bete Company Incorporated, 200 State Rd, South Deerfield, MA, 01373-0200, (800) 477-4776, http://www.channing-bete.com. Summary: This study guide, for health professionals, provides information about the prevention of tuberculosis (TB) in healthcare settings. It discusses the risk factors for TB; national agencies involved in TB precautions; standard and transmission-based precautions to prevent the spread of TB; engineering and policy controls for health care facilities to prevent TB; and how to prevent transmission from patients to health professionals through the use of patient care guidelines, personal protective equipment (e.g., gloves), and sanitation and hygiene. The study guide provides an overview of health professional staff screening for TB.
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Georgia Tuberculosis Reference Guide Contact: Georgia Department of Human Resources, Division of Public Health, Tuberculosis Program, 2 Peachtree St NW 12th Fl, Atlanta, GA, 30303-3186, (404) 6572634, http://dhr.st. Emory University School of Medicine, Division of Infectious Diseases, 69 Butler Street SE, Atlanta, GA, 30303, (404) 616-6145. Summary: This reference guide serves as a basic clinical guide to tuberculosis (TB) infection, disease, and control for health professionals. It contains standards and guidelines based on the work and experience of the American Thoracic Society, the Centers for Disease Control and Prevention, the Infectious Disease Society of America,
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the New York City Department of Health, and the Atlanta TB Prevention Coalition. Specific topics include the classification system for TB, tuberculin skin testing, treatment of latent TB infection, current TB disease therapy, TB prevention and treatment during pregnancy, childhood TB, TB and nursing homes, the Bacille Calmette-Guerin (BCG) vaccination, TB infection control in hospitals, community TB control, and Georgia's Department of Human Resources' community guidelines for respiratory isolation of patients with active TB in the community. •
Tuberculosis Case Management for Nurses: Self-Study Modules Contact: New Jersey Medical School National Tuberculosis Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, National Tuberculosis Center, Second Fl East Wing, 225 Warren St, Newark, NJ, 07103-3620, (973) 972-3270, http://www.umdnj.edu/ntbc. Summary: This monograph provides guidelines for the case management of persons with tuberculosis (TB). The monograph is separated into four study modules covering general public health and public nursing issues; the fundamentals of TB case management; leadership skills of the nurse case manager; and case management of the pediatric patient with TB.
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Tuberculosis Update and Tuberculin Skin Testing Certification Contact: Mississippi Department of Health, Tuberculosis Control Branch, PO Box 1700, Jackson, MS, 39215-1700, (601) 576-7700. Summary: This teaching guide provides information about tuberculosis (TB), how it develops, symptoms, treatment, and tuberculin skin testing. The guide was designed to be used in a one-day instructional seminar and contains a general outline and a list of objectives. It has information about the history of TB, treatments used in the past, and describes the epidemiology of TB today (globally, in the United States, and in Mississippi (MS)). It explains how TB is spread, and how it develops from a TB infection to active TB disease. It examines which groups are at the highest risk for getting TB. The guide explains the tuberculin skin test, the classification system used in its interpretation, the booster phenomenon, Bacillus Calmette-Guerin (BCG) vaccination, and how they affect the interpretation of the skin test. It discusses preventive therapy, diagnostic tests used to determine TB infection or active TB, and opportunistic infections that cause TB infection to develop into active TB. Medical therapies for active TB and Directly Observed Therapy (DOT) are explained.
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Involving Private Practitioners in Tuberculosis Control: Issues, Interventions, and Emerging Policy Framework Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph describes the major characteristics of the private health sector role in tuberculosis (TB) care and presents efforts to address the issue. The monograph reports the result of a global situation assessment initiated by the World Health Organization (WHO) in 1999 to investigate the extent and nature of private involvement in TB care. Twenty-three countries in the six WHO regions were visited as part of the assessment. The assessment confirmed a substantial TB caseload and unsatisfactory management practices among private practitioners. The report argues
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that private sector involvement in TB care should be addressed and provides a framework for that purpose. The options available to the National Tuberculosis Programmes (NTBs) include provision of TB care exclusively through the public sector and active inclusion of the private health sector. The report argues that inclusion of the private health sector in the delivery of TB care is one of the most promising options for NTBs in high-burden TB countries. •
WHO Report 2001: Global Tuberculosis Control Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph is an annual report that charts the progress in TB control and in implementing the World Health Organization (WHO) directly observed therapy, short course (DOTS) strategy. The report presents data available in January 2001 on case notifications for 1999, treatment results for patients registered in 1998, and the status of DOTS implementation by the end of 1999. This information is supplemented, with the latest data on progress made by countries during 2000. New figures were compared with those in previous reports paying special attention to progress in countries with the largest numbers or TB cases. The report concludes that progress in global TB control accelerated slightly between 1997 and 1998, however much more effort will be needed if DOTS programs are to reach global targets by 2005.
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Ending Neglect: The Elimination of Tuberculosis in the United States Contact: National Academy Press, 2101 Constitution Ave NW, Box 285, Washington, DC, 20055, (202) 334-3313. Summary: This monograph provides government and nongovernment entities involved in tuberculosis (TB) elimination with background on the pathology of TB, its history and status in the United States, and the public and private response, with illustrative case studies. It explores strategies to ensure that success in curbing TB will not lead to another period of neglect and yet another resurgence; the case for targeted TB screening in high-risk populations and treatment of latent infection, including privacy issues and implications for immigration; and research needs in diagnosis, treatment, and prevention.
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Management of Tuberculosis : A Guide for Low Income Countries Contact: International Union Against Tuberculosis and Lung Disease, 68 Boulevard Saint-Michel, Paris, (011) 33144320360, http://www.iuatld.org. Summary: This tuberculosis (TB) guide is for use in low-income countries and written for health professionals, governmental, and international agencies, and organizations. The guide contains a description of TB and its identification; treatment modalities including directly observed therapy, short-course (DOTS) and preventive therapy; and patient care. The treatment of TB and the organization and management of TB services and the structure within which these services can be delivered, even under the most stringent socio-economic conditions are outlined. The rationale for developing a community TB program is discussed and a technical guide for smear microscopy is provided.
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Cross-Cultural Tuberculosis Guide : Cultural Influences on TB-Related Beliefs and Practices of Filipinos, Vietnamese, Chinese, and Koreans Summary: This monograph provides information about tuberculosis (TB) practices and beliefs among Asian Americans and seeks to provide a better understanding of how patients perceive TB. It provides a 'biopsychosocial' perspective on tuberculosis, which expands the focus beyond the infectious mycobactreriums and looks at the distribution of TB in the US; how people perceive TB; what it means to have TB; and how best to motivate TB-infected persons toward treatment. It discusses how culture has influenced the spread and prevention of TB among four demographic groups: Filipinos, Vietnamese, Chinese, and Koreans. It discusses reasons for non-adherence to TB medications and provides a summary of key cultural issues and provider responses. The monograph makes recommendations regarding how to improve culturally competent TB-related communication with Asian Americans.
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A Clinician's Guide to Tuberculosis Contact: Lippincott Wilkins and Williams Publishers, Philadelphia Office, 530 Walnut St, Philadelphia, PA, 19106-3621, (215) 521-8300, http://www.lww.com. Summary: This monograph sets forth guidelines for the treatment of patients with tuberculosis (TB). The monograph reviews the history and epidemiology of TB. It discusses TB transmission, diagnosis, and treatment in adults and children as well as persons with the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The monograph explains that because HIV destroys the immune cells, it enables latent TB to be reactivated in or a new TB infection to be acquired by persons with HIV/AIDS. The monograph discusses multidrug-resistant TB (MDRTB), the goals of preventive therapy, the effectiveness of existing vaccinations against TB, and the prevention of TB among healthcare workers and institutions through universal precautions.The monograph also discusses the 1998 Centers for Disease Control and Prevention's revised recommendatons on the prevention and treatment of TB among HIV-infected persons and uses cases of hypothetical patients to examine treatment options and review factors in choosing regimens.
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Tuberculosis Control in Prisons: A Manual for Programme Managers Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph sets forth guidelines for the development, management, and evaluation of tuberculosis (TB) control programs for correctional facilities. The monograph discusses the need for a TB control program in correctional facilities, different TB control strategies, and how to integrate these strategies into other disease control programs. It explains how to design a TB control policy, the elements of an effective TB control policy, and how to evaluate a TB control program in correctional facilities.
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Anti-Tuberculosis Drug Resistance in the World: Report No. 2: Prevalence and Trends Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop
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Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This report gives the results of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance (DRS), conducted between 1996 and 1999, three years after the initial survey of 35 geographical settings, with the aim of collecting worldwide information on drug resistance of Mycobacterium tuberculosis. The report includes the following data: (1) information collected in the period 1996-1999 on the prevalence of drug resistance from 58 geographical settings; (2) trends on drug resistance from 28 geographical settings; (3) data from 17 geographical settings on the levels of drug resistance according to place of birth; (4) individual patient data from 11 geographical settings to assess determinants of drug resistance; (5) and ecological data from all 72 geographical settings that participated in the Global Project since 1994. The report discusses the project’s background and methodology and provides statistical results and a discussion of the findings. The findings describe the magnitude of anti-tuberculosis drug resistance; the relationship between drug resistance and TB control indicators; the impact of migration on drug resistance; and the impact of age, HIV, and prior TB treatment on the magnitude of drug resistance. Data confirm that prior anti-tuberculosis therapy is a strong predictor of drug resistance. The report also includes copies of the forms used in data collection and individual country profiles. •
Guidelines for Establishing DOTS-Plus Pilot Projects for the Management of Multidrug-Resistant Tuberculosis (MDR-TB) Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph presents guidelines developed by the Scientific Panel of the Working Group on Directly Observed Treatment, short-course (DOTS)-Plus for multidrug-resistant tuberculosis (MDR-TB). The World Health Organization created the Working Group on DOTS-Plus for MDR-TB in 1999. The guidelines describe criteria and technical standards that must be in place before beginning a DOTS-Plus pilot project to treat MDR-TB patients and provide an international standard for the structure and function of pilot projects. Also, the criteria must be met before the pilot project can be supported by international provision of reserve second-line anti-TB drugs at favorable cost and by help from international expertise and monitoring. The annex section includes various strategies that may be used in DOTS-Plus pilot projects.
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Tuberculosis Control Program Staff Handbook Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This monograph provides health professionals with information on tuberculosis (TB) drugs, treating latent TB infection, and TB direct care and field services. It contains a listing of TB-related resources and services in New York City along with their contact information. It includes information for chest clinics, outreach programs, relevant local government offices, housing services, and programs for persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS).
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Core Curriculum on Tuberculosis: What the Clinician Should Know Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This curriculum present basic information about tuberculosis (TB) for health care professionals. It is intended for use as a reference manual for clinicians caring for persons with or at high risk for TB disease or infection. In addition, it was designed to be useful in developing educational programs. It contains ten chapters: (1) Introduction, (2) Transmission and Pathogenesis, (3) Epidemiology of TB in the United States, (4) Testing for TB Disease and Infection, (5) Diagnosis of TB, (6) Treatment of Latent TB Infection, (7) Treatment of TB Disease, (8) Infection Control in Health Care Settings, (9) BCG Vaccination, and (10) Community TB Control. Each chapter is followed by study questions and a selected bibliography, and continuing medical education (CME) credits, continuing nursing education (CNE) credits, and continuing education unit (CEU) credits are available for this publication.
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Epidemiologic Basis of Tuberculosis Control Contact: International Union Against Tuberculosis and Lung Disease, 68 Boulevard Saint-Michel, Paris, (011) 33144320360, http://www.iuatld.org. Summary: This monograph delineates the determinants of exposure, infection, disease, and death from tuberculosis (TB) using descriptive and etiologic epidemiological data. The monograph reviews statistics regarding exposure to TB including the number of incident cases, the duration of infection in these cases, and the number of case contact interactions per unit of time. Etiologic and descriptive epidemiology are used to asses the risk factors for infection once an exposure has occurred, the incidence and prevalence of infection, and the formation of a paradigm of the risk of infection. Risk factors for the formation of active TB once an infection has occurred, the morbidity of active TB, and the prospects for the course of the epidemic are discussed in terms of descriptive and etiologic epidemiology. These two types of epidemiology also are used to analyze the mortality of TB, the risk factors for death resulting from TB, and the expected death toll of TB in the future. Based on these findings, the monograph draws conclusions and makes recommendations for the prevention and surveillance of TB worldwide.
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Tuberculosis : Six Case Studies Contact: Charles P Felton National Tuberculosis Center at Harlem Hospital, 2238 5th Ave, New York, NY, 10037-2127, (212) 939-8254. Summary: The case studies presented in this study guide exemplify presentations of tuberculosis (TB) infection and active disease frequently encountered in general practice and are divided into teaching segments that represent a logical order of events, beginning with the initial visit and continuing through significant follow-up visits, adverse events, and final discharge. Possible recommendations or actions follow each segment. Users should check all responses that they consider appropriate. The actual recommended management decisions are contained in the Scoring and Comment section of the study guide. The six case studies involve a positive tuberculin skin test in a 29-year-old man, a positive tuberculin skin test in a 25-year-old pregnant woman, a
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positive tuberculin skin test in a 5-year-old girl (younger sister of Case 4), a positive tuberculin skin test in a 17-year-old girl (older sister of Case 3), back pain in an 80-yearold man, and a positive tuberculin skin test in a 27-year-old woman. •
Guidelines for the Prevention of Tuberculosis in Health Care Facilities in ResourceLimited Settings Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph presents information about the prevention of tuberculosis (TB) in health care facilities based upon three levels of infection control: the administrative, environmental, and personal respiratory levels. The monograph includes seven chapters: (1) Pathogenesis and Transmission of TB, (2) Risk of Nosocomial Transmission of Mycobacterium tuberculosis to Health Care Workers in Resource-Limited Countries, (3) An Introduction to Infection Control Strategies, (4) Administrative Control Measures, (5) Environmental Control Measures, (6) Personal Respiratory Protection, and (7) Laboratory Safety.
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Tuberculosis Handbook Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph is intended for staff in low- and middle-income countries who are responsible for planning, organizing, and supervising tuberculosis (TB) control activities. It provides basic information and references that are key to developing skills for (1) assessing the epidemiology of the TB burden of a country, region, or community; (2) specifying how an existing national TB program (NTP) should be revised; (3) evaluating the effectiveness of an NTP in reducing infection, morbidity, and mortality, and identifying technical and managerial elements in need of revision or reorientation; (4) analyzing the available institutional, human, and financial resources, and identifying those that can be mobilized to support NTP revision; (5) organizing logistics to ensure a regular supply of drugs and laboratory materials; (6) setting up a laboratory network; (7) planning training, health education, and communication; (8) planning supervision, monitoring, and evaluation; (9) preparing a budget and mobilizing local and external resources for an NTP; and (10) coordinating with other programs and the private sector. The monograph is divided into nine parts, corresponding to the objectives listed above.
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Guidelines for Conducting a Review of a National Tuberculosis Programme Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph provides guidelines for the appropriate government agencies of countries around the world and for national organizations to conduct an assessment of their national tuberculosis (TB) programs (NTP). NTPs must be reviewed to improve their effectiveness; raise awareness about TB; increase political commitment for TB control; develop coalitions for TB control with non-governmental organizations
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(NGO), the private sector, and donors; and increase problem solving and supervisory skills of NTP staff participating in it. Directly observed therapy, short-course (DOTS) is described as the only viable means for controlling TB and involves government commitment for an NTP. The monograph describes the three components involved in the review of an NTP: planning and preparation, conducting the review, and follow up. It also includes information about how to plan a chart and checklist for a program review; a sample of an agenda for program review, data collection tools, a checklist for a visit to a treatment center, and a press release for NTP review; the items required for preparing introductory tools, the structure of a TB program review report, the methodology for economic analysis, and the elements of a review of basic training for health professionals. •
Guidelines for the Control of Tuberculosis in Prisons Contact: World Health Organization, Communicable Diseases, Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: These guidelines provide information concerning the prevention and control of tuberculosis (TB) in correctional facilities. The guideline presents general information about TB, its methods of transmission, and how it affects the lungs. The guideline explains the reasons why TB is such a serious health concern in correctional facilities and outlines an effective TB control program in prisons, which should include administrative backing, contact tracing, TB treatment, patient monitoring, a steady supply of anti-TB drugs to these facilities, and general TB prevention efforts. The guideline also examines the effects of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) on TB prevention/control programs in prisons. It explains how to implement, monitor, and evaluate a TB control program in prisons.
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Tuberculosis and Air Travel: Guidelines for Prevention and Control Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph addresses the growing concern about TB transmission during air travel and presents guidelines produced by the World Health Organization (WHO) in collaboration with international TB experts, civil aviation authorities, and representatives of airline companies to provide airline companies, health authorities, physicians and air passengers with (1) the available scientific background on the issue of TB transmission on aircraft; (2) a review of the past practices adopted for the management of patients with infectious TB and history of air travel, and of the most commonly encountered difficulties; (3) suggestions on ways to reduce the risk of exposure to TB on board; and (4) guidance on procedures to follow when a case of infectious TB is diagnosed with a history of air travel, including tracing and screening of contacts for possible interventions. The annexes contain a summary of seven investigations of possible TB transmission on aircraft, a sample letter from a health authority asking airline companies to trace and inform passengers and crew of possible exposure to TB and a sample letter from the airline informing passengers and crew of possible exposure to TB.
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Tuberculosis Control in Refugee Situations : An Inter-Agency Field Manual Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph, for health professionals, organizations, and government agencies, discusses tuberculosis (TB) and TB control among refugees. It reviews the specific health risks posed by living in a refugee camp and the epidemiology of TB worldwide and among refugee populations. It discusses how to implement and manage TB control programs in refugee situations and presents guidelines for the prevention and surveillance of TB among refugee populations.
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Anti-Tuberculosis Drug Resistance in the World : The WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph provides findings from the First Phase of the World Health Organization's (WHO) and the International Union Against Tuberculosis (TB) and Lung Disease's (IUATLD) Global Project on anti-TB drug resistance surveillance. Data was gathered from 35 countries in five continents. Surveillance or surveys were conducted on approximately 50,000 TB cases sampled from areas representing 20% of the world's population. Findings show that (1) drug resistance was found in all countries surveyed; (2) there were several "hot spots" where multidrug-resistance (MDR) TB prevalence was high and could threaten control programs (i.e., Latvia, Estonia, Russia, the Dominican Republic, Argentina, and the Ivory Coast); (3)there was a strong correlation between both the overall quality of TB control and use of standardized short course chemotherapy and low levels of drug resistance; and (4) the MDR TB level was a useful indicator of national TB program performance.
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Guidelines for the Management of Drug-Resistant Tuberculosis Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This monograph provides guidelines from the World Health Orgnaization (WHO) on the management of multidrug-resistant tuberculosis (MDR TB). Chapter titles include Basic Principals for Management of MDR TB, Assessing the Individual Case of Apparent MDR TB, Available Drugs for MDR TB, Choosing a Chemotherapy Regimen for a Patient with Apparent MDR TB, and The Place of Surgery. The appendix provides information on second-line antituberculosis drugs.
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Treatment of Tuberculosis: Guidelines for National Programmes Contact: World Health Organization, Communicable Diseases, Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm.
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Summary: This monograph provides guidelines to national tuberculosis (TB) program managers, policy makers, nongovernmental organizations, and donor agencies about the effective management of TB control programs. The objectives of the guidelines are to (1) describe the global TB burden and the framework for effective TB control, (2) describe standardized treatment regimens according to TB case definitions and categories, (3) describe the monitoring of individual patients and how to ensure their adherence to treatment, (4) describe the special considerations in treating HIV-infected TB patients, and (5) provide information on anti-TB drug supply in the context of national pharmaceutical policies and essential drug programs. •
The White Plague : Tuberculosis, Man, and Society Contact: Rutgers University Press, 109 Church St, New Brunswick, NJ, 08901, (908) 9327365. Summary: First printed in 1952, this monograph presents the argument that the great increase in tuberculosis in the nineteenth century was intimately connected with the rise of an industrial, urbanized society and that the progress of medical science had very little to do with the marked decline in TB in the twentieth century. It examines the interrelations among disease agents, characteristics of the host, and the broader sociocultural and environmental context. This reprint includes new introductory writings by practitioners of sociology and the history of medicine.
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Tuberculosis Exposure Control and Prevention Manual Contact: Coastal Training Technologies Corporation, 500 Studio Dr, Virgina Beach, VA, 23542, (800) 725-3418, http://www.coastal.com. Summary: This manual, for health professionals, provides guidelines for the prevention of the occupational transmission of tuberculosis (TB) in healthcare settings. It discusses the basic facts about TB and outlines a workplace TB control plan. It explains how to perform workplace risk assessments and identify and manage TB patients.The manual reviews precautionary practices including the use of isolation rooms, respiratory protection, and health professional counseling and training. It cites occupational TB safety manuals set forth by the Occupational Safety and Health Administration (OSHA) and the Centers for Disease Control and Prevention (CDC) and makes recommendations regarding workplace policy documentation.
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Tuberculosis Control and Training Resource Guide Contact: Association for Professionals in Infection Control and Epidemiology, 1016 16th St NW 6th Floor, Washington, DC, 20036, (202) 296-2742. Summary: This monograph, for health professionals, businesses, and government agencies, serves as a resource guide and directory for tuberculosis control training. It provides information on program and management resources including general management assistance, prevention or control, engineering controls, and respiratory protection; training programs and materials; worker education materials or resources; non-English language resources; publications and resources for clinicians; and state and territorial health departments.
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Su Nino con Tuberculosis : Un Manual Para los Padres. [Your Child With Tuberculosis : A Guide for Parents and Guardians] Contact: Center for Pulmonary and Infectious Disease Control, University of Texas Health Center at Tyler, 11937 US Hwy 271, Tyler, TX, 75708-3154, (903) 877-7790, http://research.uthct.edu/cpidc/. Summary: This monograph explains tuberculosis (TB) infection and disease in children, how to treat it, and how to prevent it. The monograph defines TB and its causes, transmission, and how it affects the body. It briefly reviews the epidemiology of TB around the world and in the United States. TB symptoms in children are discussed. The monograph reviews the tuberculin skin test, results, and other diagnostic tests. It explains treatment methods employed in TB treatment, medications used in the treatment of TB infection and active TB, the length of the regimen, and the possible side effects the patient may experience. The monograph describes directly observed therapy (DOT), and why it is used. It discusses the diet of the child undergoing treatment for TB and the precautions that should be taken during this period. The monograph includes TB prevention information, what to do if the family moves during treatment, and other sources that can provide information about TB.
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Tuberculosis and AIDS: The Relationship Between Mycobacterium TB & the HIV Type 1 Contact: Springer Publishing Company, 536 Broadway, New York, NY, 10012-3955, (212) 431-4370. Summary: This book is a guide to the treatment of patients dually diagnosed with AIDS and tuberculosis. It updates standard knowledge about tuberculosis and discusses its relationship with HIV infection. Because of the rapid increase in tuberculosis rates throughout the United States, proper diagnosis and effective treatment have become primary-care concerns. The book provides health care professionals with help in making the proper diagnosis and planning subsequent treatment of tuberculosis, especially in patients with HIV. It explains the natural history of tuberculosis in normal hosts, then compares this information with its course in HIV-infected persons. The authors review the usual presentation of the disease in both types of hosts. The book covers epidemiology, pathogenesis, clinical presentation, diagnosis, treatment, and public health issues. The authors also provide a review of the history of tuberculosis.
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Your Child With Tuberculosis : A Guide for Parents and Guardians Contact: Center for Pulmonary and Infectious Disease Control, University of Texas Health Center at Tyler, 11937 US Hwy 271, Tyler, TX, 75708-3154, (903) 877-7790, http://research.uthct.edu/cpidc/. Summary: This monograph explains tuberculosis (TB) infection and disease in children, how to treat it, and how to prevent it. The monograph defines TB and its causes, transmission, and how it affects the body. It briefly reviews the epidemiology of TB around the world and in the United States. TB symptoms in children are discussed. The monograph reviews the tuberculin skin test, results, and other diagnostic tests. It explains treatment methods employed in TB treatment, medications used in the treatment of TB infection and active TB, the length of the regimen, and the possible side effects the patient may experience. The monograph describes directly observed therapy (DOT), and why it is used. It discusses the diet of the child undergoing treatment for TB and the precautions that should be taken during this period. The monograph includes
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TB prevention information, what to do if the family moves during treatment, and other sources that can provide information about TB. •
The Epidemiology of Tuberculosis Source: Tuberculosis: Current Concepts and Treatment, 1994. Contact: CRC Press, Incorporated, 2000 Corporate Blvd NW, Boca Raton, FL, 33431, (561) 994-0555. Summary: This book chapter reviews the general and theoretical considerations surrounding the epidemiology of tuberculosis (TB), general associations of the disease, world tuberculosis statistics, tuberculosis in the United States, infection with HIV, and drug resistant tuberculosis. The chapter opens with an overview of current tuberculosis epidemiological modeling. Reporting, outbreaks, extrapulmonary tuberculosis reinfection, the natural history of tuberculosis, and molecular epidemiology are also explored. The authors discuss factors including age, gender, race, and occupation. They also look at special risks faced by groups such as the homeless and jail inmates. The global status of tuberculosis is considered next. Recent developments in the epidemiology of tuberculosis in the United States are examined, followed by a discussion of HIV infection and its impact on the risk of tuberculosis.
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Tuberculosis: Compliance Guide & Trainer's Kit Contact: Safety Priority, 1224 Mill St, East Berlin, CT, 06023-1140, (877) 723-3806, http://holdsworth-pelton.com. Summary: This book provides information on tuberculosis (TB), including coverage of TB infection control and respiratory protection programs for minimizing risks to workers and a TB awareness training presentation. In addition, the book contains the 1990 Centers for Disease Control and Prevention (CDC) guidelines for TB control with a focus on HIV-related issues. The outline for a TB infection control plan contains these sections: understanding TB, assessing risks, identifying occupational exposure to TB, and identifying sources of exposure. The next section covers a respiratory protection plan detailing selection, use, and maintenance of respirators. A third part provides a TB awareness training presentation which encompasses understanding TB, affected workers and workplaces, and a TB infection control hierarchy. Transparencies, handouts, and post-training tests are included. The final section providing the CDC guidelines discusses related issues such as the high risk of developing active TB if one is HIV-positive. Health care workers need to prevent TB transmission when caring for HIV patients, especially when using cough-inducing procedures like sputum induction and aerosolized pentamidine (AP) treatments.
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Tuberculosis: Current Concepts and Treatment Contact: CRC Press, Incorporated, 2000 Corporate Blvd NW, Boca Raton, FL, 33431, (561) 994-0555. Summary: This book summarizes recent literature and research in the field of tuberculosis. The AIDS epidemic has played a major role in the resurgence of tuberculosis. Each contributing author has written a detailed review of a selected tuberculosis-related topic, including epidemiology, presentation, and treatment of multidrug-resistant tuberculosis, as well as environmental and public health issues. New diagnostic methods are discussed, with particular emphasis on the polymerase chain reaction and restriction fragment-length polymorphism. There are comprehensive
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presentations of pulmonary and extra-pulmonary tuberculosis as they occur in adults and children, as well as a special section on pregnancy. The influence of HIV on the epidemiology, transmission, pathophysiology, manifestations, and treatment of tuberculosis and atypical mycobacteria are reviewed. •
Tuberculosis Control : A Manual on Methods and Procedures for Integrated Programs Contact: Pan American Health Organization, 525 23rd St NW, Washington, DC, 20037, (202) 974-3000, http://www.paho.org. Summary: This manual outlines a national tuberculosis (TB) control, prevention, and treatment program that focuses less on a technological approach to TB control and more on the epidemiological, sociological, and operational dimensions of control. It discusses the establishment of a national TB program, the role of the BCG vaccine in such a program, and how to conduct case-finding and case-holding procedures. It sets forth guidelines for the creation of an effective organizational infrastructure, program planning and implementation, record keeping, surveillance, supervision and monitoring, program evaluation, and employee and volunteer training.
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Tuberculosis Education Resource Guide Contact: American Lung Association, Lung Disease Programs, 1740 Broadway, New York, NY, 10019-4374, (212) 315-8700, http://www.lungusa.org/newyork/#programs. Summary: This bibliography gives access to information on tuberculosis (TB) education, training, and public awareness materials. Entries are broken into four categories: Patient/public education written materials, patient/public education audiovisual materials, professional education written materials, and professional education audiovisual materials. Within each section, materials are classified under these subjects: General information, screening/skin testing, treatment, preventive therapy, public health program activities, TB/Human immunodeficiency virus (HIV), and other. The bibliography also includes an alphabetical listing of titles available in languages other than English.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “tuberculosis” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “tuberculosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “tuberculosis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
5th Report [session 1998-99]: Badgers and Bovine Tuberculosis: [HC]: [1998-99]: House of Commons Papers: [1998-99] by Peter Luff (1999); ISBN: 0102262993; http://www.amazon.com/exec/obidos/ASIN/0102262993/icongroupinterna
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A Century of tuberculosis : South African perspectives; ISBN: 0195705831; http://www.amazon.com/exec/obidos/ASIN/0195705831/icongroupinterna
Books 483
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A Clinician's Guide to Tuberculosis by Michael D. Iseman; ISBN: 0781717493; http://www.amazon.com/exec/obidos/ASIN/0781717493/icongroupinterna
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A Deadly Partnership: Tuberculosis in the Era of HIV by Sue Armstrong; ISBN: 011951706X; http://www.amazon.com/exec/obidos/ASIN/011951706X/icongroupinterna
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A guide to Section 16 of the Tuberculosis Act, 1948; ISBN: 0478094582; http://www.amazon.com/exec/obidos/ASIN/0478094582/icongroupinterna
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A Long Way from Home: The Tuberculosis Epidemic Among the Inuit (McGillQueen's Hannah Institute Studies in the History of Medicine, Health, And Soc) by Pat Sandiford Grygier (1994); ISBN: 0773512160; http://www.amazon.com/exec/obidos/ASIN/0773512160/icongroupinterna
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A Study of the Bovine Tuberculosis Eradication Scheme (General Research) by R. O'Connor (1986); ISBN: 0707000912; http://www.amazon.com/exec/obidos/ASIN/0707000912/icongroupinterna
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Advances in Tuberculosis Research by H. Birkhaeuser (Editor), W. Fox (Editor) (1980); ISBN: 3805529546; http://www.amazon.com/exec/obidos/ASIN/3805529546/icongroupinterna
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Anti-tuberculosis Drug Resistance in the World; ISBN: 0119862433; http://www.amazon.com/exec/obidos/ASIN/0119862433/icongroupinterna
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Anti-tuberculosis Drug Resistance in the World (The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance) (1997); ISBN: 0119517841; http://www.amazon.com/exec/obidos/ASIN/0119517841/icongroupinterna
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Anti-tuberculosis Drug Resistance in the World: The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1997-2000 (2000); ISBN: 0119863480; http://www.amazon.com/exec/obidos/ASIN/0119863480/icongroupinterna
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Antituberculosis Drugs (Handbook of Experimental Pharmacology, Vol 84) by P.F. Baker; ISBN: 0387181393; http://www.amazon.com/exec/obidos/ASIN/0387181393/icongroupinterna
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Badgers and bovine tuberculosis : review of policy : report to the Rt. Hon. Michael Jopling, MP, Minister of Agriculture, Fisheries, and Food, and the Rt. Hon. Nicholas Edwards, MP, Secretary of State for Wales by G. M. Dunnet; ISBN: 0112427618; http://www.amazon.com/exec/obidos/ASIN/0112427618/icongroupinterna
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Badgers and Bovine Tuberculosis: Minutes of Evidence, Tuesday 16 February 1999: [HC]: [1998-99]: House of Commons Papers: [1998-99] by Peter Luff (1999); ISBN: 0102173990; http://www.amazon.com/exec/obidos/ASIN/0102173990/icongroupinterna
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Badgers and Bovine Tuberculosis: Minutes of Evidence, Tuesday 16 March 1999: [HC]: [1998-99]: House of Commons Papers: [1998-99] by Peter Luff (1999); ISBN: 0102239991; http://www.amazon.com/exec/obidos/ASIN/0102239991/icongroupinterna
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Badgers and Bovine Tuberculosis: Minutes of Evidence, Tuesday 23 February 1999: [HC]: [1998-99]: House of Commons Papers: [1998-99] by Peter Luff (1999); ISBN: 0102195994; http://www.amazon.com/exec/obidos/ASIN/0102195994/icongroupinterna
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Badgers and Bovine Tuberculosis: Minutes of Evidence, Tuesday 9 February 1999: [HC]: [1998-99]: House of Commons Papers: [1998-99] by Peter Luff (1999); ISBN:
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0102157995; http://www.amazon.com/exec/obidos/ASIN/0102157995/icongroupinterna •
Badgers and Bovine Tuberculosis: Minutes of Evidence, Wednesday 10 March 1999: [HC]: [1998-99]: House of Commons Papers: [1998-99] by Peter Luff (1999); ISBN: 0102237999; http://www.amazon.com/exec/obidos/ASIN/0102237999/icongroupinterna
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Badgers Without Bias: An Objective Look at the Controversy About Tuberculosis in Badgers and Cattle by Robert W. Howard; ISBN: 0902920448; http://www.amazon.com/exec/obidos/ASIN/0902920448/icongroupinterna
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Badgers, cattle, and tuberculosis : report to the Right Honourable Peter Walker by Solly Zuckerman; ISBN: 0112403557; http://www.amazon.com/exec/obidos/ASIN/0112403557/icongroupinterna
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Bargaining for Life: A Social History of Tuberculosis, 1876-1938 (Studies in Health, Illness, and Caregiving in America) by Barbara Bates (1992); ISBN: 081221367X; http://www.amazon.com/exec/obidos/ASIN/081221367X/icongroupinterna
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BCG vaccine, tuberculosis--cancer by Sol Roy Rosenthal; ISBN: 0884162133; http://www.amazon.com/exec/obidos/ASIN/0884162133/icongroupinterna
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Below the Magic Mountain: A Social History of Tuberculosis in Twentieth-Century Britain (Oxford Historical Monographs) by Linda Bryder (1988); ISBN: 019822947X; http://www.amazon.com/exec/obidos/ASIN/019822947X/icongroupinterna
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Bovine Tuberculosis Contr O/P by Myers; ISBN: 0875270603; http://www.amazon.com/exec/obidos/ASIN/0875270603/icongroupinterna
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Captain of All These Men Of Death: The History of Tuberculosis in Nineteenth and Twentieth Century Ireland. by Greta Jones; ISBN: 904201041X; http://www.amazon.com/exec/obidos/ASIN/904201041X/icongroupinterna
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Captain of Death: The Story of Tuberculosis by Thomas M. Daniel; ISBN: 1580460704; http://www.amazon.com/exec/obidos/ASIN/1580460704/icongroupinterna
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Case Presentations in Clinical Tuberculosis by P. D. O. Davies, L. Peter Ormerod; ISBN: 0340741597; http://www.amazon.com/exec/obidos/ASIN/0340741597/icongroupinterna
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Childhood Tuberculosis: Modern Imaging and Clinical Concepts by B.J. Cremin, Douglas H. Jamieson; ISBN: 038719925X; http://www.amazon.com/exec/obidos/ASIN/038719925X/icongroupinterna
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Clinical Imaging in Non-Pulmonary Tuberculosis by Francis McGuinness, et al; ISBN: 3540659404; http://www.amazon.com/exec/obidos/ASIN/3540659404/icongroupinterna
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Clinical Studies on Tuberculosis (AZREFI Special Publications) by Darshan Bhatt (Editor), V. Balasubramanian (Editor); ISBN: 8190123815; http://www.amazon.com/exec/obidos/ASIN/8190123815/icongroupinterna
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Clinical Tuberculosis by Sir John Crofton, et al; ISBN: 0333566904; http://www.amazon.com/exec/obidos/ASIN/0333566904/icongroupinterna
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Clinical Tuberculosis by P. D. O. Davies (Editor), P. D. O. Davis (1999); ISBN: 0412803402; http://www.amazon.com/exec/obidos/ASIN/0412803402/icongroupinterna
Books 485
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Contagion and Confinement: Controlling Tuberculosis Along the Skid Road by Barron, H. Lerner, Barron H. Lemer (1998); ISBN: 0801858984; http://www.amazon.com/exec/obidos/ASIN/0801858984/icongroupinterna
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Continuing Challenge of Tuberculosis; ISBN: 0160419662; http://www.amazon.com/exec/obidos/ASIN/0160419662/icongroupinterna
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Controlling Occupational Exposures to Tuberculosis (Plant, Technology & Safety Management, No 1, 1993) (1993); ISBN: 0866883266; http://www.amazon.com/exec/obidos/ASIN/0866883266/icongroupinterna
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Cost of Tuberculosis Control in Minnesota: A Report to the Legislature by Barry Leonard (Editor) (1994); ISBN: 0788181955; http://www.amazon.com/exec/obidos/ASIN/0788181955/icongroupinterna
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DIR 77/391: Council Directive of 17 May 1977 Introducing Community Measures for the Eradication of Brucellosis, Tuberculosis and Leucosis in Cattle [compilation Including the Following Amendments (1994); ISBN: 0119748681; http://www.amazon.com/exec/obidos/ASIN/0119748681/icongroupinterna
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Disease and Class: Tuberculosis and the Shaping of Modern North American Society (Health and Medicine in American Society) by Georgina D. Feldberg (1995); ISBN: 081352217X; http://www.amazon.com/exec/obidos/ASIN/081352217X/icongroupinterna
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Disease costs of tuberculosis and syphylis in Australia : a discussion paper; ISBN: 0644455993; http://www.amazon.com/exec/obidos/ASIN/0644455993/icongroupinterna
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Drug-Resistant Tuberculosis: From Molecules to Macro-Economics by P. D. O. Davies (Editor) (2002); ISBN: 157331336X; http://www.amazon.com/exec/obidos/ASIN/157331336X/icongroupinterna
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Emergency Cervidae Tuberculosis Protection Act : hearing before the Subcommittee on Livestock of the Committee on Agriculture, House of Representatives, One Hundred Third Congress, second session, on H.R. 3417, February 3, 1994; ISBN: 0160445221; http://www.amazon.com/exec/obidos/ASIN/0160445221/icongroupinterna
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Ending Neglect: The Elimination of Tuberculosis in the United States by Institute of Medicine Committee on the Elimination of Tuberculo, et al; ISBN: 0309070287; http://www.amazon.com/exec/obidos/ASIN/0309070287/icongroupinterna
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Epidemics: Deadly Diseases Throughout History: The Plague, AIDS, Tuberculosis, Cholera, Small Pox, Polio, Influenza, Malaria (Epidemics: Deadly Diseases Throughout History Series) by Holly Cefrey, et al; ISBN: 0823992020; http://www.amazon.com/exec/obidos/ASIN/0823992020/icongroupinterna
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Estudios medicosociales sobre la tuberculosis en la España de la restauración by Jorge Molero Mesa; ISBN: 8476700776; http://www.amazon.com/exec/obidos/ASIN/8476700776/icongroupinterna
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Fevered Lives: Tuberculosis in American Culture Since 1870 by Katherine Ott (1999); ISBN: 0674299116; http://www.amazon.com/exec/obidos/ASIN/0674299116/icongroupinterna
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Fighting the Scourge of Tuberculosis by Dene C. Peters (2000); ISBN: 0864710879; http://www.amazon.com/exec/obidos/ASIN/0864710879/icongroupinterna
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Forging Partnerships to Eliminate Tuberculosis by Barry Leonard (Editor) (1995); ISBN: 0756700930; http://www.amazon.com/exec/obidos/ASIN/0756700930/icongroupinterna
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From Chaos to Coercion: Detention and the Control of Tuberculosis by Richard J. Coker; ISBN: 0312222505; http://www.amazon.com/exec/obidos/ASIN/0312222505/icongroupinterna
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From Consumption to Tuberculosis: A Documentary History (Garland Reference Library of Social Science, Vol 808) by Barbara Gutmann Rosenkrantz (Editor); ISBN: 0815306083; http://www.amazon.com/exec/obidos/ASIN/0815306083/icongroupinterna
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Genetics and Tuberculosis - No. 217 by Novartis Foundation Symposium (Author) (2000); ISBN: 047198261X; http://www.amazon.com/exec/obidos/ASIN/047198261X/icongroupinterna
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Germ Warriors: Stories of the Men and Women Who Fight the World's Worst Diseases from Tuberculosis to Smallpox by Clint Willis (Editor) (2004); ISBN: 1560255609; http://www.amazon.com/exec/obidos/ASIN/1560255609/icongroupinterna
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Grandma Cherry's Spoon: A Story of Tuberculosis by Marjorie McVicker Sutcliffe, Judy Sutcliffe (1991); ISBN: 0943164184; http://www.amazon.com/exec/obidos/ASIN/0943164184/icongroupinterna
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Groups at Risk: WHO Report on the Tuberculosis Epidemic 1996 (1996); ISBN: 0119516012; http://www.amazon.com/exec/obidos/ASIN/0119516012/icongroupinterna
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Guidelines for Conducting a Review of a National Tuberculosis Programme by Jacob Kumaresan, et al (1998); ISBN: 0119518368; http://www.amazon.com/exec/obidos/ASIN/0119518368/icongroupinterna
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Guidelines for the Management of Drug-resistant Tuberculosis by John Crofton (1997); ISBN: 0119517698; http://www.amazon.com/exec/obidos/ASIN/0119517698/icongroupinterna
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Guidelines for tuberculosis control in New Zealand, 1996; ISBN: 0478094671; http://www.amazon.com/exec/obidos/ASIN/0478094671/icongroupinterna
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Healing Tuberculosis in the Woods : Medicine and Science at the End of the Nineteenth Century by David L. Ellison (Author) (1994); ISBN: 0313290059; http://www.amazon.com/exec/obidos/ASIN/0313290059/icongroupinterna
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History of tuberculosis in Australia, New Zealand, and Papua New Guinea; ISBN: 1875495029; http://www.amazon.com/exec/obidos/ASIN/1875495029/icongroupinterna
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History of tuberculosis in the Upper Peninsula of Michigan by James R. Acocks; ISBN: 0962554502; http://www.amazon.com/exec/obidos/ASIN/0962554502/icongroupinterna
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Immunological Aspects of Leprosy, Tuberculosis and Leishmaniasis by David Humber; ISBN: 0444902511; http://www.amazon.com/exec/obidos/ASIN/0444902511/icongroupinterna
•
Improving Patient Adherence to Tuberculosis Treatment by Barry Leonard (Editor); ISBN: 0756700922; http://www.amazon.com/exec/obidos/ASIN/0756700922/icongroupinterna
Books 487
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Increase in deer and elk tuberculosis : hearing before the Subcommittee on Livestock, Dairy, and Poultry of the Committee on Agriculture, House of Representatives, One Hundred Second Congress, second session, August 5, 1992; ISBN: 0160395046; http://www.amazon.com/exec/obidos/ASIN/0160395046/icongroupinterna
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Irresponsibility Towards Poverty: The Case of Tuberculosis by Jocelyn Kynch (1993); ISBN: 0906250250; http://www.amazon.com/exec/obidos/ASIN/0906250250/icongroupinterna
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Jornadas Sanitarias sobre Tuberculosis en Galicia, Orense, 27-28 de junio de 1980; ISBN: 8430046062; http://www.amazon.com/exec/obidos/ASIN/8430046062/icongroupinterna
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Know About Tuberculosis (Know About) by Margaret O. Hyde; ISBN: 0802783392; http://www.amazon.com/exec/obidos/ASIN/0802783392/icongroupinterna
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Light at last : triumph over tuberculosis 1900-1975, Newfoundland and Labrador by Edgar House; ISBN: 0920502326; http://www.amazon.com/exec/obidos/ASIN/0920502326/icongroupinterna
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Living in the Shadow of Death: Tuberculosis and the Social Experience of Illness in American History by Sheila M. Rothman (1995); ISBN: 0801851866; http://www.amazon.com/exec/obidos/ASIN/0801851866/icongroupinterna
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Modern drug treatment in tuberculosis by J. D. Ross; ISBN: 0901548006; http://www.amazon.com/exec/obidos/ASIN/0901548006/icongroupinterna
•
Multidrug Resistant Tuberculosis by Daniel Farb; ISBN: 1932634177; http://www.amazon.com/exec/obidos/ASIN/1932634177/icongroupinterna
•
Multidrug-Resistant Tuberculosis by Ivan Bastian (Editor), Francoise Portaels (Editor); ISBN: 0792361695; http://www.amazon.com/exec/obidos/ASIN/0792361695/icongroupinterna
•
Mycobacterium Tuberculosis Protocols (Methods in Molecular Medicine, 54) by Tanya Parish (Editor), Neil G. Stoker (Editor); ISBN: 0896037762; http://www.amazon.com/exec/obidos/ASIN/0896037762/icongroupinterna
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Mycobacterium Tuberculosis: Interactions With the Immune System (Infectious Agents and Pathogenesis) by Mauro Bendinelli, Herman Friedman (Editor) (1988); ISBN: 0306427249; http://www.amazon.com/exec/obidos/ASIN/0306427249/icongroupinterna
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National Tuberculosis Association 1904-1954: A Study of the Voluntary Health Movement in the United States (1977); ISBN: 0405098316; http://www.amazon.com/exec/obidos/ASIN/0405098316/icongroupinterna
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New Vistas in Therapeutics/Drug-Resistant Tuberculosis: From Drug Design to Gene Therapy: From Molecules to Macro-Economics (Annals of the New York Academy of Sciences, Vol 953A&B) by Paul Velletri (Editor), et al (2002); ISBN: 1573313351; http://www.amazon.com/exec/obidos/ASIN/1573313351/icongroupinterna
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Nutritional Abnormalities in Infectious Diseases: Effects on Tuberculosis and AIDS (Monograph Published Simultaneously As the Journal of Nutritional immunology , Vol 5, No 1) by Christopher E. Taylor (Editor) (1997); ISBN: 0789000199; http://www.amazon.com/exec/obidos/ASIN/0789000199/icongroupinterna
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Organization and Practice in Tuberculosis Bacteriology by J.M. Grange, et al; ISBN: 0407002960; http://www.amazon.com/exec/obidos/ASIN/0407002960/icongroupinterna
488 Tuberculosis
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Pathology of the lung, excluding pulmonary tuberculosis by Herbert Spencer; ISBN: 0080031552; http://www.amazon.com/exec/obidos/ASIN/0080031552/icongroupinterna
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Pioneers in Medicine and Their Impact on Tuberculosis by Thomas M. Daniel (2000); ISBN: 1580460674; http://www.amazon.com/exec/obidos/ASIN/1580460674/icongroupinterna
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Pointers to the Common Remedies: Dentition, Rickets, Malnutrition, Tuberculosis, Disease of Glands and Bones by M.L. Tyler (1981); ISBN: 0946717362; http://www.amazon.com/exec/obidos/ASIN/0946717362/icongroupinterna
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Prehistoric Tuberculosis in the Americas by J. E. Buikstra (Editor) (1981); ISBN: 0942118103; http://www.amazon.com/exec/obidos/ASIN/0942118103/icongroupinterna
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Present Situation of Multidrug-Resistant Tuberculosis & the Possibility of Mdr-Tb Treatment by New Quinolones: Proceedings of a Satellite Symposium for the 14th Asia Pacific Congress on Diseases of the Chest, Bali, June 1996 (Chemotherapy) by Mangunnegoro Hadiarto (Editor) (1996); ISBN: 3805564066; http://www.amazon.com/exec/obidos/ASIN/3805564066/icongroupinterna
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Protective Effect of Bcg in Exp Tuberculosis (Advances in Tuberculosis Research, 22) by Donald W. Smith (1985); ISBN: 3805540892; http://www.amazon.com/exec/obidos/ASIN/3805540892/icongroupinterna
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Pulmonary Tuberculosis: A Journey Down the Centuries by Robert Young Keers; ISBN: 0028582500; http://www.amazon.com/exec/obidos/ASIN/0028582500/icongroupinterna
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Quinolones in Pulmonary Tuberculosis Management by Len J., Jr Lascolea, Ramzan Rangoonwala; ISBN: 082479740X; http://www.amazon.com/exec/obidos/ASIN/082479740X/icongroupinterna
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Rational therapy and control of tuberculosis; a symposium; ISBN: 0813002958; http://www.amazon.com/exec/obidos/ASIN/0813002958/icongroupinterna
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Recent advances in respiratory tuberculosis by F. R. G. Heaf; ISBN: 070001330X; http://www.amazon.com/exec/obidos/ASIN/070001330X/icongroupinterna
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Reemerging Tuberculosis: Tuberculosis Genotyping Network: A Reprint from œEmerging Infectious Diseases by D. Peter Drotman (2003); ISBN: 0756728479; http://www.amazon.com/exec/obidos/ASIN/0756728479/icongroupinterna
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Report of the Working Party on Tuberculosis; ISBN: 0707637171; http://www.amazon.com/exec/obidos/ASIN/0707637171/icongroupinterna
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Reported Tuberculosis in the U.S., 1998 by Jeffrey P. Koplan (Editor) (1999); ISBN: 0756700949; http://www.amazon.com/exec/obidos/ASIN/0756700949/icongroupinterna
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Requiem for a great killer; the story of tuberculosis by Harley Williams; ISBN: 0901548324; http://www.amazon.com/exec/obidos/ASIN/0901548324/icongroupinterna
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Resistance to Tuberculosis: Experimental Studies in Native and Acquired Defensive Mechanisms by Max B. Lurie (1965); ISBN: 0674765168; http://www.amazon.com/exec/obidos/ASIN/0674765168/icongroupinterna
Books 489
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Robert-Koch-Symposium 1993 on "Progress in Tuberculosis Research by Martin E.A. Mielke (Editor), Stefan Ehlers (Editor) (1994); ISBN: 3437116444; http://www.amazon.com/exec/obidos/ASIN/3437116444/icongroupinterna
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Serology of Tuberculosis and Bcg Vaccination (Advances in Tuberculosis Research, 21) by W. Fox (Editor) (1985); ISBN: 3805538553; http://www.amazon.com/exec/obidos/ASIN/3805538553/icongroupinterna
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Short History of Tuberculosis by George N. Meachen (1978); ISBN: 0404132952; http://www.amazon.com/exec/obidos/ASIN/0404132952/icongroupinterna
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Stop Tb at the Source: Who Report on the Tuberculosis Epidemic, 1995 (1995); ISBN: 0614080541; http://www.amazon.com/exec/obidos/ASIN/0614080541/icongroupinterna
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Tb Groups at Risk: Who Report on the Tuberculosis Epidemic, 1996 by Who Staff (1996); ISBN: 0614176735; http://www.amazon.com/exec/obidos/ASIN/0614176735/icongroupinterna
•
Textbook of Tuberculosis by M. Monir Madkour (Editor) (2003); ISBN: 3540014411; http://www.amazon.com/exec/obidos/ASIN/3540014411/icongroupinterna
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Textbook of Tuberculosis by K.N. Rao (1981); ISBN: 9998033063; http://www.amazon.com/exec/obidos/ASIN/9998033063/icongroupinterna
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The 2002 Official Patient's Sourcebook on Tuberculosis: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2002); ISBN: 0597833117; http://www.amazon.com/exec/obidos/ASIN/0597833117/icongroupinterna
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The Architectural Drawings of Alvar Aalto 1917-1939: Paimio Tuberculosis Sanatorium, City of Turku 700th Anniversary Exhibition, Standard Furniture, (Garland Architectural Archives) by Alvar Aalto, et al (1994); ISBN: 0815305931; http://www.amazon.com/exec/obidos/ASIN/0815305931/icongroupinterna
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The Bioarchaeology of Tuberculosis: A Global View on a Reemerging Disease by Charlotte A. Roberts, Jane E. Buikstra (2003); ISBN: 0813026431; http://www.amazon.com/exec/obidos/ASIN/0813026431/icongroupinterna
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The Brucellosis and Tuberculosis (England and Wales) Compensation (Amendment) Order 1996: Animals (Statutory Instruments: 1996: 1352) by Great Britain (1996); ISBN: 0110626737; http://www.amazon.com/exec/obidos/ASIN/0110626737/icongroupinterna
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The Brucellosis and Tuberculosis (England and Wales) Compensation (Amendment) Order 1998: Animals (Statutory Instruments: 1998: 2073) (1998); ISBN: 0110795490; http://www.amazon.com/exec/obidos/ASIN/0110795490/icongroupinterna
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The Brucellosis and Tuberculosis (Scotland) Compensation Amendment Order 1998: Animals (Statutory Instruments: 1998: 2181) (1998); ISBN: 0110558324; http://www.amazon.com/exec/obidos/ASIN/0110558324/icongroupinterna
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The Brucellosis and Tuberculosis Compensation (Scotland) Amendment Order 1996: Animals (Statutory Instruments: 1996: 1358 (S. 126)) by Great Britain (1996); ISBN: 0110553756; http://www.amazon.com/exec/obidos/ASIN/0110553756/icongroupinterna
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The conquest of tuberculosis by Selman Abraham Waksman (Author); ISBN: B00005VON6; http://www.amazon.com/exec/obidos/ASIN/B00005VON6/icongroupinterna
490 Tuberculosis
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The Continuing Challenge of Tuberculosis (1996); ISBN: 0788129910; http://www.amazon.com/exec/obidos/ASIN/0788129910/icongroupinterna
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The Forgotten Plague: How the Battle Against Tuberculosis Was Won and Lost by Frank Ryan; ISBN: 0316763802; http://www.amazon.com/exec/obidos/ASIN/0316763802/icongroupinterna
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The Imaging of Tuberculosis: With Epidemiological, Pathological, and Clinical Correlation by Philip E. S. Palmer, et al (2002); ISBN: 3540418210; http://www.amazon.com/exec/obidos/ASIN/3540418210/icongroupinterna
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The Making of a Social Disease: Tuberculosis in Nineteenth-Century France by David S. Barnes (1995); ISBN: 0520087720; http://www.amazon.com/exec/obidos/ASIN/0520087720/icongroupinterna
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The miracle of the empty beds : a history of tuberculosis in Canada by George Jasper Wherrett; ISBN: 0802022693; http://www.amazon.com/exec/obidos/ASIN/0802022693/icongroupinterna
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The Modern Epidemic: A History of Tuberculosis in Japan (Harvard East Asian Monographs, No 162) by William Johnston (1996); ISBN: 0674579127; http://www.amazon.com/exec/obidos/ASIN/0674579127/icongroupinterna
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The Radiology of tuberculosis; ISBN: 0808912488; http://www.amazon.com/exec/obidos/ASIN/0808912488/icongroupinterna
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The Retreat of Tuberculosis, 1850-1950 by F.B. Smith; ISBN: 0709933835; http://www.amazon.com/exec/obidos/ASIN/0709933835/icongroupinterna
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The Return of the White Plague: Global Poverty and the New Tuberculosis by Matthew Gandy (Editor), Alimuddin Zumla (Editor); ISBN: 1859846696; http://www.amazon.com/exec/obidos/ASIN/1859846696/icongroupinterna
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The South African tuberculosis control programme : practical guidelines; ISBN: 0621141569; http://www.amazon.com/exec/obidos/ASIN/0621141569/icongroupinterna
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The Tuberculosis (Deer) (Amendment) Order 1993: Animals (Statutory Instruments: 1993: 2010) (1993); ISBN: 0110350103; http://www.amazon.com/exec/obidos/ASIN/0110350103/icongroupinterna
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The Tuberculosis (Deer) Order 1989: Animals: Animal Health (Statutory Instrument: 1989: 878) (1989); ISBN: 0110968786; http://www.amazon.com/exec/obidos/ASIN/0110968786/icongroupinterna
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The Tuberculosis (Scotland) Amendment Order 1990: Animals (Statutory Instruments: 1990: 1908 (S. 175)) (1990); ISBN: 011004908X; http://www.amazon.com/exec/obidos/ASIN/011004908X/icongroupinterna
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The tuberculosis epidemic : hearing before the Subcommittee on Health and the Environment of the Committee on Energy and Commerce, House of Representatives, One Hundred Third Congress, first session, March 29, 1993; ISBN: 0160416167; http://www.amazon.com/exec/obidos/ASIN/0160416167/icongroupinterna
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The Tuberculosis Movement: A Public Health Campaign in the Progressive Era (Contributions in Medical Studies) by Michael E. Teller (Author) (1988); ISBN: 0313257485; http://www.amazon.com/exec/obidos/ASIN/0313257485/icongroupinterna
Books 491
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The Tuberculosis Revival: Individual Rights and Societal Obligations in a Time of AIDS (A Special Report / United Hospital Fund of New York) (1992); ISBN: 1881277127; http://www.amazon.com/exec/obidos/ASIN/1881277127/icongroupinterna
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The Tuberculosis Survival Handbook by Paul Mayho, et al; ISBN: 0953513904; http://www.amazon.com/exec/obidos/ASIN/0953513904/icongroupinterna
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The Weariness, the Fever, and the Fret: The Campaign Against Tuberculosis in Canada, 1900-1950 (McGill-Queen'S/Hannah Institute Studies in the History of Medicine, Health, And Society, 8.) by Katherine McCuaig (1999); ISBN: 0773518754; http://www.amazon.com/exec/obidos/ASIN/0773518754/icongroupinterna
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The White Death: A History of Tuberculosis by Thomas Dormandy (2002); ISBN: 1852856629; http://www.amazon.com/exec/obidos/ASIN/1852856629/icongroupinterna
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The White Plague: Tuberculosis, Man, and Society by Rene J. Dubos, et al (1987); ISBN: 0813512247; http://www.amazon.com/exec/obidos/ASIN/0813512247/icongroupinterna
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Timebomb:The Global Epidemic of Multi-Drug Resistant Tuberculosis by Lee B. Reichman, Janice Hopkins Tanne (Contributor); ISBN: 0071359249; http://www.amazon.com/exec/obidos/ASIN/0071359249/icongroupinterna
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Treatment of Tuberculosis: Guidelines for National Programmes (1993); ISBN: 9241544511; http://www.amazon.com/exec/obidos/ASIN/9241544511/icongroupinterna
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Tuberculosis; ISBN: 0030612594; http://www.amazon.com/exec/obidos/ASIN/0030612594/icongroupinterna
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Tuberculosis by David Schlossberg (Editor); ISBN: 038794026X; http://www.amazon.com/exec/obidos/ASIN/038794026X/icongroupinterna
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Tuberculosis by Anthony Lowell, et al; ISBN: 0674911350; http://www.amazon.com/exec/obidos/ASIN/0674911350/icongroupinterna
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Tuberculosis by Guy P. Youmans; ISBN: 0721696414; http://www.amazon.com/exec/obidos/ASIN/0721696414/icongroupinterna
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Tuberculosis by William N., Md. Rom (Editor), et al; ISBN: 0781736781; http://www.amazon.com/exec/obidos/ASIN/0781736781/icongroupinterna
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Tuberculosis by William H. Hay (1996); ISBN: 0787310204; http://www.amazon.com/exec/obidos/ASIN/0787310204/icongroupinterna
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Tuberculosis by Douglas R. Gracey; ISBN: 0874888751; http://www.amazon.com/exec/obidos/ASIN/0874888751/icongroupinterna
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Tuberculosis by Jay A. Meyers, Jay A. Myers (1970); ISBN: 087527059X; http://www.amazon.com/exec/obidos/ASIN/087527059X/icongroupinterna
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Tuberculosis by T. M. Shinnick (Editor); ISBN: 3540609857; http://www.amazon.com/exec/obidos/ASIN/3540609857/icongroupinterna
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Tuberculosis; ISBN: 354094026X; http://www.amazon.com/exec/obidos/ASIN/354094026X/icongroupinterna
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Tuberculosis (A Venture Book) by Elaine Landau; ISBN: 0531125556; http://www.amazon.com/exec/obidos/ASIN/0531125556/icongroupinterna
492 Tuberculosis
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Tuberculosis (Clio Media No 16) by Gerald Webb; ISBN: 0404589162; http://www.amazon.com/exec/obidos/ASIN/0404589162/icongroupinterna
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Tuberculosis (Deadly Diseases and Epidemics) by Kim Renee Finer, et al; ISBN: 0791073092; http://www.amazon.com/exec/obidos/ASIN/0791073092/icongroupinterna
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Tuberculosis (Diseases and People) by Alvin Silverstein, et al; ISBN: 0894904620; http://www.amazon.com/exec/obidos/ASIN/0894904620/icongroupinterna
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Tuberculosis (Epidemics) by Fred Ramen (2001); ISBN: 0823933490; http://www.amazon.com/exec/obidos/ASIN/0823933490/icongroupinterna
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Tuberculosis (Examination and Testing) Scheme Order (Northern Ireland) 1999: Animals (Statutory Rule: 1999: 264) by Great Britain (1999); ISBN: 0337934975; http://www.amazon.com/exec/obidos/ASIN/0337934975/icongroupinterna
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Tuberculosis (Great Medical Discoveries) by Gail B. Stewart, Joel Cohen (2002); ISBN: 1560069317; http://www.amazon.com/exec/obidos/ASIN/1560069317/icongroupinterna
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Tuberculosis (States-Of-The-Art Series) (1999); ISBN: 3805570007; http://www.amazon.com/exec/obidos/ASIN/3805570007/icongroupinterna
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Tuberculosis (Twenty-First Century Books Medical Library) by Diane Yancey; ISBN: 0761316248; http://www.amazon.com/exec/obidos/ASIN/0761316248/icongroupinterna
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Tuberculosis : como evitarla y como curarla Andrián Vander by Adrián Vander; ISBN: 8471500205; http://www.amazon.com/exec/obidos/ASIN/8471500205/icongroupinterna
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Tuberculosis Among Certain Indian Tribes Of The United States (Bureau of American Ethnology Bulletins) by Ales Hrdlicka; ISBN: 0781240425; http://www.amazon.com/exec/obidos/ASIN/0781240425/icongroupinterna
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Tuberculosis and AIDS: The Relationship Between Mycobacterium Tb and the HIV Type 1 by Lawrence L., Md Scharer, John M., MD McAdam (1995); ISBN: 0826190006; http://www.amazon.com/exec/obidos/ASIN/0826190006/icongroupinterna
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Tuberculosis and Its Prevention by Stefan Grzybowski (Author); ISBN: 8752719871; http://www.amazon.com/exec/obidos/ASIN/8752719871/icongroupinterna
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Tuberculosis and Leprosy (British Medical Bulletin) by R.J.W. Rees (Editor); ISBN: 0443039771; http://www.amazon.com/exec/obidos/ASIN/0443039771/icongroupinterna
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Tuberculosis and Nontuberculous Mycobacterial Infections by David Schlossberg (Editor), Richard Zorab (Editor); ISBN: 0721673082; http://www.amazon.com/exec/obidos/ASIN/0721673082/icongroupinterna
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Tuberculosis and the aged : the epidemoligical implications of tuberculosis for the social structure in South Africa : a socio-anthropological case study of the black elderly in the Durban Functional Region by Sayo Skweyiya; ISBN: 0958316910; http://www.amazon.com/exec/obidos/ASIN/0958316910/icongroupinterna
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Tuberculosis As a Disease of the Masses & How to Combat It (Public Health in America) by S. Adolphus Knopf, Adolphus S. Knopf (1977); ISBN: 0405098243; http://www.amazon.com/exec/obidos/ASIN/0405098243/icongroupinterna
Books 493
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Tuberculosis Bacteriology: Organization and Practice by C. H. Collins, et al; ISBN: 0750624582; http://www.amazon.com/exec/obidos/ASIN/0750624582/icongroupinterna
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Tuberculosis case-finding and chemotherapy : questions and answers by K. Toman; ISBN: 9241541369; http://www.amazon.com/exec/obidos/ASIN/9241541369/icongroupinterna
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Tuberculosis Chemotherapy: Evaluation and Treatment by Sumitra Kalappa (Editor); ISBN: 8175251573; http://www.amazon.com/exec/obidos/ASIN/8175251573/icongroupinterna
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Tuberculosis Control (Amendment) Order (Northern Ireland) 1994: Animals (Statutory Rule: 1994: 216); ISBN: 0337912165; http://www.amazon.com/exec/obidos/ASIN/0337912165/icongroupinterna
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Tuberculosis Control (Amendment) Order (Northern Ireland) 1996: Animals (Statutory Rule: 1996: 240); ISBN: 0337922004; http://www.amazon.com/exec/obidos/ASIN/0337922004/icongroupinterna
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Tuberculosis Control (Amendment) Order (Northern Ireland) 1998: Animals (Statutory Rule: 1998: 293) by Great Britain (1998); ISBN: 0337932107; http://www.amazon.com/exec/obidos/ASIN/0337932107/icongroupinterna
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Tuberculosis control as an integral part of primary health care; ISBN: 9241542446; http://www.amazon.com/exec/obidos/ASIN/9241542446/icongroupinterna
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Tuberculosis control in developing countries by Douglas Hoseason Shennan; ISBN: 0443005753; http://www.amazon.com/exec/obidos/ASIN/0443005753/icongroupinterna
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Tuberculosis control measures : a manual by Theodore Francis Barnabus Collins; ISBN: 0621031747; http://www.amazon.com/exec/obidos/ASIN/0621031747/icongroupinterna
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Tuberculosis Control Order (Northern Ireland) 1999: Animals (Statutory Rule: 1999: 263) by Great Britain (1999); ISBN: 0337935009; http://www.amazon.com/exec/obidos/ASIN/0337935009/icongroupinterna
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Tuberculosis Control Programs in Developing Countries by Paul Shears (1988); ISBN: 0855980966; http://www.amazon.com/exec/obidos/ASIN/0855980966/icongroupinterna
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Tuberculosis Control: A Manual on Methods and Procedures for Integrated Programs (Scientific Publication, 498) (1986); ISBN: 9275114986; http://www.amazon.com/exec/obidos/ASIN/9275114986/icongroupinterna
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Tuberculosis for First Responders by Marcom Group Ltd (1996); ISBN: 0766830586; http://www.amazon.com/exec/obidos/ASIN/0766830586/icongroupinterna
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Tuberculosis in Childhood by P.R. Donald, et al; ISBN: 0627024084; http://www.amazon.com/exec/obidos/ASIN/0627024084/icongroupinterna
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Tuberculosis in Healthcare by Marcom Group Ltd (1996); ISBN: 0766830594; http://www.amazon.com/exec/obidos/ASIN/0766830594/icongroupinterna
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Tuberculosis in Institutions by Marcom Group Ltd (1996); ISBN: 0766830608; http://www.amazon.com/exec/obidos/ASIN/0766830608/icongroupinterna
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Tuberculosis in New York City : an epidemic returns : hearing before the Human Resources and Intergovernmental Relations Subcommittee of the Committee on
494 Tuberculosis
Government Operations, House of Representatives, One Hundred Second Congress, first session, December 18, 1991; ISBN: 0160409594; http://www.amazon.com/exec/obidos/ASIN/0160409594/icongroupinterna •
Tuberculosis in the Workplace by Marilyn J. Field (Editor), Institute of Medicine; ISBN: 0309073308; http://www.amazon.com/exec/obidos/ASIN/0309073308/icongroupinterna
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Tuberculosis Nurse (History of American Nursing Series) by Ellen N. Lamotte, Susan Reverby (Editor); ISBN: 0824065174; http://www.amazon.com/exec/obidos/ASIN/0824065174/icongroupinterna
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Tuberculosis of the Bones and Joints by Michel Martini (Editor); ISBN: 0387181660; http://www.amazon.com/exec/obidos/ASIN/0387181660/icongroupinterna
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Tuberculosis of the skeleton : focus on radiology by Cornelis Jacob Pieter Thijn; ISBN: 3540510176; http://www.amazon.com/exec/obidos/ASIN/3540510176/icongroupinterna
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Tuberculosis Pearls by Steven A. Sahn (Editor), et al; ISBN: 1560531568; http://www.amazon.com/exec/obidos/ASIN/1560531568/icongroupinterna
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Tuberculosis Resurgent by Richard Westlund (Editor), et al (1995); ISBN: 1879772027; http://www.amazon.com/exec/obidos/ASIN/1879772027/icongroupinterna
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Tuberculosis Training and Education Resource Guide by Barry Leonard (Editor) (2000); ISBN: 0756701902; http://www.amazon.com/exec/obidos/ASIN/0756701902/icongroupinterna
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Tuberculosis, a resurgence in Newark : hearing before the Human Resources and Intergovernmental Relations Subcommittee of the Committee on Government Operatons, House of Representatives, One Hundred Second Congress, second session, October 20, 1992; ISBN: 0160413974; http://www.amazon.com/exec/obidos/ASIN/0160413974/icongroupinterna
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Tuberculosis, the federal failure : hearing before the Human Resources and Intergovernmental Relations Subcommittee of the Committee on Government Operations, House of Representatives, One Hundred Second Congress, second session, April 2, 1992; ISBN: 0160409322; http://www.amazon.com/exec/obidos/ASIN/0160409322/icongroupinterna
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Tuberculosis: A Clinical Handbook by Larry I. Lutwick (Editor); ISBN: 0412607409; http://www.amazon.com/exec/obidos/ASIN/0412607409/icongroupinterna
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Tuberculosis: A Clinical Timebomb [DOWNLOAD: PDF] by Datamonitor (Author); ISBN: B00008R3N0; http://www.amazon.com/exec/obidos/ASIN/B00008R3N0/icongroupinterna
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Tuberculosis: A Comprehensive International Approach (Lung Biology in Health and Disease, V. 144) by Lee B. Reichman (Editor), Earl S. Hershfield (Editor) (2000); ISBN: 082478121X; http://www.amazon.com/exec/obidos/ASIN/082478121X/icongroupinterna
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Tuberculosis: A Sourcebook for Nursing Practice by Felissa R. Lashley (Editor), et al (1995); ISBN: 082618720X; http://www.amazon.com/exec/obidos/ASIN/082618720X/icongroupinterna
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Tuberculosis: An Interdisciplinary Perspective by John D. H. Porter (Editor), et al; ISBN: 1860941435; http://www.amazon.com/exec/obidos/ASIN/1860941435/icongroupinterna
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Tuberculosis: Arresting Everyone's Enemy (1995); ISBN: 0866884165; http://www.amazon.com/exec/obidos/ASIN/0866884165/icongroupinterna
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Tuberculosis: Back to the Future (The London School of Hygiene and Tropical Medicine Annual Public Health Forum) by K.M. McAdam (Editor), J.P. Porter (Editor); ISBN: 0471943460; http://www.amazon.com/exec/obidos/ASIN/0471943460/icongroupinterna
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Tuberculosis: Clinical Management and New Challenges by Milton D., M.D. Rossman, Rob Roy, M.D. MacGregor; ISBN: 0070539502; http://www.amazon.com/exec/obidos/ASIN/0070539502/icongroupinterna
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Tuberculosis: Costly & Preventable Cases Continue in Five Cities (1995); ISBN: 0788120484; http://www.amazon.com/exec/obidos/ASIN/0788120484/icongroupinterna
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Tuberculosis: Current Concepts and Treatment, Second Edition by Lloyd N. Friedman (Editor); ISBN: 0849315654; http://www.amazon.com/exec/obidos/ASIN/0849315654/icongroupinterna
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Tuberculosis: Current Topics and Reviews by a Louise Sugden (Editor), et al (1997); ISBN: 0853694036; http://www.amazon.com/exec/obidos/ASIN/0853694036/icongroupinterna
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Tuberculosis: Extracting Value From a Stagnant Market [DOWNLOAD: PDF] by Datamonitor (Author); ISBN: B00008R3XV; http://www.amazon.com/exec/obidos/ASIN/B00008R3XV/icongroupinterna
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Tuberculosis: Pathogenesis, Protection, and Control by Barry R., Ph.D. Bloom (Editor) (1994); ISBN: 1555810721; http://www.amazon.com/exec/obidos/ASIN/1555810721/icongroupinterna
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Tuberculosis: Praeger Monographs in Infectious Disease by David Schlossberg (Editor); ISBN: 0275914127; http://www.amazon.com/exec/obidos/ASIN/0275914127/icongroupinterna
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Tuberculosis: The Global Cost of Diagnosis 2000 [DOWNLOAD: PDF] by Apex Group The (Author); ISBN: B00005RA6C; http://www.amazon.com/exec/obidos/ASIN/B00005RA6C/icongroupinterna
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Tuberculosis: the Greatest Story Never Told: The Human Story of the Search for the Cure for Tuberculosis and the New Global Threat by Frank Ryan; ISBN: 1874082006; http://www.amazon.com/exec/obidos/ASIN/1874082006/icongroupinterna
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Tuberculosis: the Illustrated History of a Disease: Propos by Jacques Chretien; ISBN: 2911432002; http://www.amazon.com/exec/obidos/ASIN/2911432002/icongroupinterna
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Tuberculosis: Whole Blood Bacterial Activity and Prediction of Response to Treatment (AZREFI Special Publications) by Robert S. Wallis; ISBN: 8190123823; http://www.amazon.com/exec/obidos/ASIN/8190123823/icongroupinterna
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Tuberculous Meningitis: Tuberculomas and Spinal Tuberculosis: A Handbook for Clinicians (Oxford Medical Publications) by Malcolm Parsons; ISBN: 0192617214; http://www.amazon.com/exec/obidos/ASIN/0192617214/icongroupinterna
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Update Treatment of Multidrug-Resistant Tuberculosis: Proceedings of a Sponsored Symposium to the 29th World Conference of the International Union Against Tuberculosis and Lung Diseases (Iuatld/Uictmr) B (Chemotherapy) by Michael D.
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Iseman (Editor), Praparn Youngchaiyud (Editor) (1999); ISBN: 3805569246; http://www.amazon.com/exec/obidos/ASIN/3805569246/icongroupinterna •
Use DOTS More Widely!: WHO Report on the Tuberculosis Epidemic 1997; ISBN: 011951530X; http://www.amazon.com/exec/obidos/ASIN/011951530X/icongroupinterna
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Use DOTS More Widely: WHO Report on the Tuberculosis Epidemic 1997; ISBN: 0119517531; http://www.amazon.com/exec/obidos/ASIN/0119517531/icongroupinterna
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Va Health Care: Tuberculosis Controls Receiving Greater Emphasis at Va Medical Centers (1993); ISBN: 0788106597; http://www.amazon.com/exec/obidos/ASIN/0788106597/icongroupinterna
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White Plague Black Labour: Tuberculosis and the Political Economy of Health and Disease in South Africa (Comparative Studies of Health Systems and M) by Randall M. Packard; ISBN: 0520065743; http://www.amazon.com/exec/obidos/ASIN/0520065743/icongroupinterna
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White Plague, Black Labor: Tuberculosis and the Political Economy of Health and Disease in South Africa by R.T. Jones; ISBN: 0869807331; http://www.amazon.com/exec/obidos/ASIN/0869807331/icongroupinterna
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White Plague, Black Labor: Tuberculosis and the Political Economy of Health and Disease in South Africa (Comparative Studies of Health Systems and M) by Randall M. Packard (1990); ISBN: 0520065751; http://www.amazon.com/exec/obidos/ASIN/0520065751/icongroupinterna
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Whole Little City by Itself : Tranquille and Tuberculosis by Wayne Norton; ISBN: 0969884249; http://www.amazon.com/exec/obidos/ASIN/0969884249/icongroupinterna
The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “tuberculosis” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •
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A program for the eradication of tuberculosis in California. Author: California Interagency Council on Tuberculosis.; Year: 2003; [Sacramento] 1964
In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
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Alkaline proteins in the treatment of tuberculosis and other diseases of the respiratory tract: abstract Author: Cherry, Louis Bond.; Year: 1901; Kansas City, Mo.: Cherry Laboratories, c1925
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An experimental investigation of methods for the cultivation of mycobacterium tuberculosis from sputum. Author: Saxholm, Rolf.; Year: 1908; Copenhagen, Munksgaard, 1958
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An investigation into a yeast-like fungus isolated from patients suffering from, or suspected of, pulmonary tuberculosis, by Einar Hollström. Author: Hollström, Einar Filip,; Year: 1963; Stockholm [Almqvist; Wiksells boktryckeri a.-b.] 1943
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Areawide planning of facilities for tuberculosis services: report of the Joint Committee of the National Tuberculosis Association, Public Health Service. Author: Joint Committee of the National Tuberculosis Association and the Public Health Service on Areawide Planning of Facilities for Tuberculosis Services; Year: 1905; Washington, D.C.: U.S. Dept. of health, Education, and Welfare, Public Health Service, [1963 i.e. 1964]
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Bovine tuberculosis in man, a clinical study of bovine tuberculosis, especially pulmonary tuberculosis, in the southernmost part of Sweden, by Erik Hedvall. The relation between bovine and human tuberculosis from the veterinary point of view, by Hilding Magnusson. Author: Hedvall, Erik,; Year: 1963; Helsingfors, Mercators tryckeri, 1942
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Diagnosis and treament of incipient pulmonary tuberculosis Author: English, W. T.; Year: 1856; [Pittsburgh?: s.n., 1901?]
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First fifteen (15) years of the anti-tuberculosis crusade 1873-1888: first two hospitals in this country for the care of tuberculous, 1876-1877 Author: Hutt, W. H.; Year: 1901; Philadelphia, 1909
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I. On the surgical treatment of pulmonary tuberculosis, by Johan Holst, Carl Semb and J. Frimann-Dahl. II. Thoracoplasty with extra-fascial apicolysis, by Carl Semb. Author: Holst, Johan Martin,; Year: 1962; Oslo, Nationaltrykkeriet, 1935
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Iathergic immunity in experimental tuberculosis (a lecture delivered at the Chr. Michelsen Institute's annual meeting, March 14, 1940). Author: Birkhaug, Konrad,; Year: 1958; Bergen, J. Griegs boktrykkeri, 1940
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Incidence and coincidence of diabetes mellitus and pulmonary tuberculosis in a Swedish county, by Hans Silwer and Per Nanne Oscarsson. [Tr. from Swedish]. Author: Silwer, Hans,; Year: 1895; Kristianstad, 1958
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On the collapse treatment of pulmonary tuberculosis; a clinical adaptation and follow-up examination of the material from Vejlefjord sanatorium 1906-1932, by Chr. M. F. Sinding-Larsen. Author: Sinding-Larsen, Christian Magnus Falsen,; Year: 1964; Oslo, Nationaltrykkeriet, 1937
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On the occurrence of lymphogranulomatosis (Sternberg) in Sweden, 1915-1931, and some considerations as to its relation to tuberculosis. Author: Uddströmer, Martin,; Year: 1900; Lund, Aktiebolaget Skånska centraltryckeriet, 1934
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Pregnancy and tuberculosis. Author: Hedvall, Erik,; Year: 1943; Stockholm [Norstedt] 1953
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TB: tuberculosis = TB: tuberculose Author: World Health Organization.; Year: 1964; Geneva: World Health Organization, c2003; ISBN: 9242590703
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The electrocardiogram in pulmonary tuberculosis. Author: Björkman, Allan.; Year: 1942; Stockholm, 1951
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The prognosis of open pulmonary tuberculosis; a clinical-statistical analysis. Author: Berg, Gunnar,; Year: 1964; Lund, Ohlsson, 1939
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The statistics of pulmonary tuberculosis in Denmark, 1925-1934; a statistical investigation on the occurrence of pulmonary tuberculosis in the period 1925-1934, worked out on the basis of the Danish National Health Service file of notifiedcases and of deaths. Author: Lindhardt, Marie,; Year: 1965; Copenhagen, E. Munksgaard, 1939
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The Von Ruck treatment for tuberculosis: remarks of Hon. Luke Lea, of Tennessee, in the Senate of the United States, Friday, September 8, 1916 Author: Lea, Luke.; Year: 2003; Washington, 1916
Chapters on Tuberculosis In order to find chapters that specifically relate to tuberculosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and tuberculosis using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “tuberculosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on tuberculosis: •
Mycobacterial Diseases: Tuberculosis and Leprosy Source: in Maddison, P.J. et al., Eds. Oxford Textbook of Rheumatology. Volume 2. NewYork, NY: Oxford University Press, Inc. 1993. p. 574-581. Contact: Available from Oxford University Press, Inc., New York, NY. Summary: This chapter for health professionals presents an overview of tuberculosis and leprosy. They are infectious diseases characterized by inflammation. The epidemiology, pathogenesis, immunology, pathology, clinical manifestations, diagnosis, and treatment of these diseases are discussed. Tuberculosis can affect bones or joints. It is diagnosed through microbiological cultures and radiographs, and it is treated with anti tuberculous drugs. Surgical intervention may also be used in selected cases. Leprosy affects the skin and nerves. Progressive degenerative joint changes may occur because of lesions of the peripheral nerve. Leprosy is diagnosed through microbiological, serological, and radiographic tests, and it is treated with multi drug therapy. 58 references, 3 figures, and 1 table.
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Genitourinary Tuberculosis Source: in Suki, W.N. Massry, S.G., eds. Therapy of Renal Diseases and Related Disorders, 2nd ed. Hingham, MA: Kluwer Academic Publishers. 1991. p. 387-393. Contact: Available from Kluwer Academic Publishers. P.O. Box 358, Accord Station, Hingham, MA 02018. (617) 871-6600. PRICE: $315. ISBN: 0792306767. Summary: This chapter, from a medical text on the therapy of renal disease and related disorders, discusses genitourinary tuberculosis. The author reviews the diagnostic tests used in investigating genitourinary tuberculosis; the management of the disease; the use of chemotherapy with antituberculous drugs; the use of steroids; hypersensitivity reactions to drug therapy; and the role of surgery, including reconstructive surgery, in the management of genitourinary tuberculosis. 2 figures. 4 tables. 7 references.
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Reemergence of Mycobacterium Tuberculosis Infection as a Major Occupational Risk for Health Professionals Source: in Greenspan, J.S. Greenspan, D., eds. Oral Manifestations of HIV Infection: Proceedings of the Second International Workshop on the Oral Manifestations of HIV Infection. Carol Stream, IL: Quintessence Publishing Company, Inc. 1995. p. 296-308. Contact: Available from Quintessence Publishing Company, Inc. 551 North Kimberly Drive, Carol Stream, IL 60188-1881. (800) 621-0387 or (630) 682-3223; Fax (630) 682-3288; E-mail:
[email protected]; http://www.quintpub.com. PRICE: $64.00 plus shipping and handling. ISBN: 0867152869. Summary: This chapter on the reemergence of Mycobacterium tuberculosis (TB) infections as a major occupational risk is from the proceedings of the Second International Workshop on the Oral Manifestations of HIV Infection, held in February 1993 in San Francisco, California. The authors discuss the etiology, transmission, and progression of this infectious disease, current risk factors, management of infected patients, and effectiveness of established infection control guidelines. The authors conclude with a discussion of the implications of TB for dentistry, including infection control concerns and guidelines. 2 figures. 5 tables. 38 references.
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CHAPTER 8. MULTIMEDIA ON TUBERCULOSIS Overview In this chapter, we show you how to keep current on multimedia sources of information on tuberculosis. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.
Video Recordings An excellent source of multimedia information on tuberculosis is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “tuberculosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “tuberculosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on tuberculosis: •
Tuberculosis : DOTS Contact: Pan American Health Organization, 525 23rd St NW, Washington, DC, 20037, (202) 974-3000, http://www.paho.org. Summary: This video, for health professionals, government agencies, and organizations, provides information about the use and success of directly observed therapy, shortcourse (DOTS) in helping to treat and prevent the spread of tuberculosis (TB) and in lowering TB morbidity and mortality rates. It reviews the global epidemiology of TB and the factors contributing to its resurgence around the world.
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[Bridging Hmong America : Tuberculosis] Contact: Appleton City Health Department, Nursing Section, 100 N Appleton St, Appleton, WI, 54911-4702, (920) 832-6429, http://www.appleton.org/health. Summary: This video provides information about tuberculosis (TB). Topics include methods of transmission, the effect of TB on the body, latent TB infection (LTBI) and
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active TB, and the TB skin test. It discusses how someone with LTBI can avoid developing active TB and how individuals with active TB can avoid transmitting it. •
Tuberculosis Challenge: An Update Contact: Quality Line Enterprises, 1424 Fourth St, Ste 800, Santa Monica, CA, 90401, (310) 451-5994. Summary: This video provides information about tuberculosis (TB) and the prevention of occupational transmission of TB using administrative and engineering controls, personal protective equipment, and universal precautions. It explains how TB is transmitted, the difference between latent TB infection (LTBI) and active TB, how to administer and read a TB skin test, and TB treatment.
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Tuberculosis 2000: Fundamentals of Clinical Tuberculosis and Tuberculosis Control: Part II Contact: Francis J Curry National Tuberculosis Center, 3180 18th St Ste 101, San Francisco, CA, 94110-2042, (415) 502-4600, http://www.nationaltbcenter.edu. Summary: This video provides health professionals with information on the prevention and control of tuberculosis (TB). It discusses using directly observed therapy, shortcourse (DOTS) and public education campaigns to help prevent TB and outlines the elements of an effective DOTS program and DOTS role in maintaining patient adherence to drug regimens and in the prevention of TB. The video explains various components of institutional engineering controls to help fight against the nosocomial spread of TB including the use of air filters and ventilation protocols and discusses different types of personal respiratory protective equipment and the proper use of them.
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Creating a Plan to Control Tuberculosis Contact: Texas Department of Health, Tuberculosis Elimination Division, 1100 W 49th St, Austin, TX, 78756-3199, (512) 458-7447, http://www.tdh.state.tx.us/tb/default.htm. Summary: This video, for health professionals and administrators, discusses the establishment of a tuberculosis (TB) control plan in correctional facilities. It provides guidelines about how to conduct a risk assessment for a TB control plan; it recommends that all facility health staff be trained in TB and tuberculin skin testing, and that facilities identify key people and their functions in infection control; it examines establishing TB screening procedures and schedules; it provides information about the isolation of prisoners with active TB in rooms with engineering controls or local hospitals if no such rooms are available; and it suggests how to maintain and transfer (if necessary) prisoner medical records, and how to create a TB training program for staff.
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Tuberculosis Screening and Diagnosis in Correctional Facilities Contact: Texas Department of Health, Tuberculosis Elimination Division, 1100 W 49th St, Austin, TX, 78756-3199, (512) 458-7447, http://www.tdh.state.tx.us/tb/default.htm. Summary: This video, for health professionals, discusses tuberculosis (TB) screening and diagnosis in correctional facilities. It identifies and describes the two types of TB screening; it lists the elements of a TB screening program for correctional facilities and outlines the steps of the complete diagnostic process; it examines special circumstances that may require further testing (e.g., in persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and in persons who have received the BCG vaccine); it discusses how and when to use two-step TB skin testing
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and makes recommendations regarding medical record maintenance and transferals; and it explains how to treat and monitor patients with TB and stresses the importance of maintaining patient confidentiality. •
Preventing Tuberculosis in Correctional Facilities Contact: Texas Department of Health, Tuberculosis Elimination Division, 1100 W 49th St, Austin, TX, 78756-3199, (512) 458-7447, http://www.tdh.state.tx.us/tb/default.htm. Summary: This video, for health professionals, provides information about tuberculosis (TB) prevention and control in correctional facilities. It discusses TB transmission; the difference between active TB and latent TB infection (LTBI); active TB symptoms and symptoms for groups at risk for contracting LTBI or developing active TB; and TB control measures by category: engineering controls, administrative controls, and universal precautions. The video demonstrates how to use respirators to prevent TB.
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Safely Transporting Inmates With Tuberculosis Contact: Texas Department of Health, Tuberculosis Elimination Division, 1100 W 49th St, Austin, TX, 78756-3199, (512) 458-7447, http://www.tdh.state.tx.us/tb/default.htm. Summary: This video, for correctional facility personnel, discusses policies regarding the transfer or deportation of incarcerated persons with active tuberculosis (TB). It outlines the possible reasons for prisoner transports, the procedures for how to deal with suspected cases of active TB in incarcerated individuals, and how to decline transport on medical grounds. It reviews specific procedures for clearing prisoners for transport and makes recommendations regarding the timely transfer of the medical records of individuals with TB, informing transport personnel of the risks on a case by case basis, and training all personnel on TB prevention. The video examines what universal precautions should be taken when moving prisoners with active TB and how to ensure continued treatment of incarcerated individuals upon their release to the public or their deportation.
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You Can Prevent TB: A Video for People with Tuberculosis Infection Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This video, for individuals with tuberculosis (TB), provides information on preventive therapy. It features the story of a man, Trevor, who discovers that he has been infected by the organism that causes TB. During a counseling session with his healthcare provider, Trevor learns about TB infection and how it affects the body, particularly the lungs. The video provides information on TB treatment, it discusses preventive treatment and how it works, it distinguishes between TB infection and active TB, and it stresses the importance of adhering to TB treatments to avoid multidrugresistant TB and to ensure proper treatment.
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You Can Prevent TB: A Video for People with Tuberculosis Infection (With BCG Explanation) Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html.
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Summary: This video, for individuals with tuberculosis (TB), provides information on preventive therapy. It features the story of a man, Trevor, who discovers that he has been infected by the organism that causes TB despite having been given the BCG vaccine during his childhood. During a counseling session with his healthcare provider, Trevor learns about TB infection and how it affects the body, particularly the lungs. The video provides information on TB treatment, it discusses preventive treatment and how it works, it distinguishes between TB infection and active TB, and it stresses the importance of adhering to TB treatments to avoid multidrug-resistant TB and to ensure proper treatment. •
Puedes Prevenir la Tuberculosis Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This video, for individuals with tuberculosis (TB), provides information on preventive therapy. It features the story of a woman, Ana, who discovers that she has been infected by the organism that causes TB. During a counseling session with her healthcare provider, Ana learns about TB infection and how it affects the body, particularly the lungs. The video provides information on TB treatment, it discusses preventive treatment and how it works, it distinguishes between TB infection and active TB, and it stresses the importance of adhering to TB treatments to avoid multidrugresistant TB and to ensure proper treatment.
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Tuberculosis 2000: Fundamentals of Clinical Tuberculosis and Tuberculosis Control: Part III Contact: Francis J Curry National Tuberculosis Center, 3180 18th St Ste 101, San Francisco, CA, 94110-2042, (415) 502-4600, http://www.nationaltbcenter.edu. Summary: This video, for health professionals, examines issues related to the medical treatment of tuberculosis (TB) in children and persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), as well as topics related to general TB prevention. It examines the challenges involved in treating adults and children with HIV/AIDS and TB and what to consider when treating children (i.e., dosage procedures and patient adherence); and it identifies current public health measures, including public education and the screening of high-risk groups in order to control the spread of TB. It provides information about and makes recommendations for current and future healthcare policies and policy development for TB control.
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Tuberculosis (Correctional Officers) Contact: Texas Department of Health, Tuberculosis Elimination Division, 1100 W 49th St, Austin, TX, 78756-3199, (512) 458-7447, http://www.tdh.state.tx.us/tb/default.htm. Summary: This video, for correctional facilities and their staff, provides information about tuberculosis and occupational transmission prevention. It discusses the prevalence of TB among incarcerated populations and prison populations; ways for correctional personnel to protect themselves and other incarcerated individuals from contracting TB through the use of universal precautions, isolation in cells, and hospital wards; and the role of the correctional officer in helping to maintain adherence to antiTB regimens among incarcerated individuals.
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Tuberculosis 2000: Fundamentals of Clinical Tuberculosis and Tuberculosis Control: Part I Contact: Francis J Curry National Tuberculosis Center, 3180 18th St Ste 101, San Francisco, CA, 94110-2042, (415) 502-4600, http://www.nationaltbcenter.edu. Summary: This video, for health professionals, provides information about diagnosing, treating, and screening for tuberculosis (TB). It identifies the different tests used in the TB diagnostic process and how to administer each test, and it examines how to treat TB including how to determine drug regimens and dosages. The video identifies which demographic populations are at risk for TB and how to conduct screening on these populations.
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Lo Que Sabe de Tuberculosis Puede Ser su Meuerte Contact: Texas Department of Health, Tuberculosis Elimination Division, 1100 W 49th St, Austin, TX, 78756-3199, (512) 458-7447, http://www.tdh.state.tx.us/tb/default.htm. Summary: This video, for incarcerated person, discusses tuberculosis (TB). It identifies those populations at risk for TB, methods of transmission, and the symptoms of active TB. It differentiates between active TB and latent TB infection (LTBI); it lists the factors that increase the chances of developing active TB; it demonstrates the tuberculin skin test; and it stresses the importance of patient adherence to TB medicines. The video discusses some of the treatments available for tuberculosis, the possible side effects, and how to treat individuals with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and TB.
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What You Don't Know About Tuberculosis. Could Kill You Contact: Texas Department of Health, Tuberculosis Elimination Division, 1100 W 49th St, Austin, TX, 78756-3199, (512) 458-7447, http://www.tdh.state.tx.us/tb/default.htm. Summary: This video, for incarcerated person, discusses tuberculosis (TB). It identifies populations at risk for TB, methods of transmission, the tuberculin skin test, and the symptoms of active TB. It differentiates between active TB and latent TB infection (LTBI). The video discusses available treatments for tuberculosis and their possible side effects; it reviews how individuals with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and TB are treated; and stresses the importance of patient adherence to TB medicines.
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Tuberculosis: Return of An Ancient Killer Contact: GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, (888) 8255249, http://corp.gsk.com/. Summary: This video provides in-depth information on the resurgence of tuberculosis (TB) in the United States. Particular attention is given to multidrug-resistant strains. TB infects one-third of the world's population and is the largest single cause of death worldwide. The video explains that prevention programs and funding for TB education dwindled in the 1980s. Since that time, there has been an increase of between 15 and 20 percent due to immigration, the HIV epidemic, homelessness, and incarceration. Treatment recommendations and public health care strategies, including directly observed therapy, are presented.
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Tuberculosis -- TB Guide Contact: American Lung Association of Brooklyn, 175 Remsen St Ste 1020, Brooklyn, NY, 11201-4300, (718) 624-8531, http://www.lungusa.org/brooklyn. Summary: This video, for the general public, presents information about TB and its treatment. Information on TB transmission, its symptoms, and the difference between latent TB infection (LTBI) and active TB is provided. The video reviews the basic facts about TB treatment and stresses the importance of patient adherence to the anti-TB regimen.
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A Satellite Primer on Tuberculosis (Modules 1-5) Contact: Alabama Department of Public Health, Bureau of Health Promotion and Chronic Diseases, Video Communications Division, PO Box 303017 Ste 940, Montgomery, AL, (334) 206-5618, http://www.alpubhealth.org/alphtn. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 4585231, http://www.cdcnpin.org. Summary: These five videotapes make up an instructional package that provides detailed information about tuberculosis (TB) for health care workers. The videotapes include information on the transmission and pathogenesis of TB, the epidemiology of TB, diagnosis and treatment of TB infection and disease, and infectiousness and infection control.
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Tuberculosis Challenge : An Update Contact: Quality Line Enterprises, 1424 Fourth St, Ste 800, Santa Monica, CA, 90401, (310) 451-5994. Summary: This video explains the treatment of persons with tuberculosis (TB) and the protection of health care workers from occupational exposure to the virus. The video examines the reasons for the re-emergence of TB and multidrug-resistant TB (MDRTB) in the United States (US). It explains how TB is spread and describes the TB skin test. It identifies the symptoms of active TB and makes recommendations concerning how to test patients and workers for TB. It reviews techniques designed to maintain patient adherence to TB treatments such as directly observed therapy (DOT). The video outlines a TB infection control plan for health care settings, focusing on the use of respirators and universal precautions.
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Tuberculosis: A Preventable Epidemic Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. Summary: This video examines the tuberculosis (TB) problem in the United States and discusses diagnosis and preventive therapy regimens. The video provides an overview of populations considered to be at greater risk for contracting TB, such as the elderly and the immunocompromised, and recommends the use of the tuberculin skin test and preventive therapy for high-risk patients, regardless of their Mantoux test result. The video recommends that patients diagnosed with extrapulmonary TB be tested for HIV/AIDS, lists treatment options for persons with and without HIV/AIDS, and discusses eligibility for preventive therapy or intermittent therapy. The video also discusses multidrug-resistant TB and treatment and the advantages and disadvantages
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of TB tests (Mantoux PPD, tine, and booster). Recommendations to ensure patient adherence include using current regimens and directly observed therapy (DOT). •
Tuberculosis in America: The People's Plague: Part I: The Captain of All These Men of Death Contact: Direct Cinema Limited Incorporated, PO Box 10003, Santa Monica, CA, 904101003, (310) 636-8200, http://directcinema.com/index.htm. Summary: This video provides the general public with information on the history of tuberculosis (TB) in America from the nineteenth century until the early twentieth century. It discusses past treatments for TB, focusing on the sanatorium movement that began in the late nineteenth century, and it examines the events that led to the discovery of modern drugs to prevent tuberculosis and the development of the tuberculin skin test.
•
Tuberculosis in America: The People's Plague: Part II: The Gospel of Health Contact: Direct Cinema Limited Incorporated, PO Box 10003, Santa Monica, CA, 904101003, (310) 636-8200, http://directcinema.com/index.htm. Summary: This video provides the general public with information on the re-emergence of tuberculosis (TB) in the 20th century. It chronicles efforts to discover a cure for TB and discusses factors contributing to its re-emergence, including the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic and medical complacency. The video examines medical research and developments in treatment since the re-emergence of TB in the 1980s.
•
Tuberculosis - TB Guide Contact: American Lung Association of Brooklyn, 175 Remsen St Ste 1020, Brooklyn, NY, 11201-4300, (718) 624-8531, http://www.lungusa.org/brooklyn. Summary: This videorecording explains tuberculosis (TB) symptoms, diagnosis, treatment, and how it is affected by the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS).
•
Preventing tuberculosis in children: We can all help Source: Stone Mountain, GA: Duke and Associates. ca. 1993. 1 videotape (VHS, 1/2 inch, 12 minutes). Contact: Available from Duke and Associates, 5728 Little Oak Trail, Stone Mountain, GA 30087. Telephone: (404) 921-3077. Summary: This videotape gives statistics on tuberculosis in Georgia in 1991-1992, and describes the dangers this disease poses for children, and the increased risk to children in contracting it due to the increasing use of child day care. The videotape recommends skin tests for child care providers, gives signs of tuberculosis to watch for in children, and recommends guidelines for prevention.
Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html.
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To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Sound Recordings.” Type “tuberculosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on tuberculosis: •
Pediatric Tuberculosis: An Audiotape for Clinicians Contact: Francis J Curry National Tuberculosis Center, 3180 18th St Ste 101, San Francisco, CA, 94110-2042, (415) 502-4600, http://www.nationaltbcenter.edu. Summary: This audiocassette and its accompanying study guide, for health professionals, discuss the diagnosis and treatment of tuberculosis (TB) in children. The audiocassette identifies the risk factors associated with pediatric exposure to TB and lists the procedures for evaluating a young child exposed to an adult with contagious TB. The audiocassette covers how prior vaccination with BCG impacts the placement and interpretation of the tuberculin skin test. It describes the steps for and the proper placement and interpretation of the tuberculin skin test. It outlines the current recommendations for the treatment of latent TB infection (LTBI) and active TB.
•
Diagnosis and Treatment of Latent Tuberculosis Infection in the 21st Century: An Audio Recording for Clinicians Contact: Francis J Curry National Tuberculosis Center, 3180 18th St Ste 101, San Francisco, CA, 94110-2042, (415) 502-4600, http://www.nationaltbcenter.edu. Summary: This CD and study guide, designed for health professionals, discusses the diagnosis and treatment of latent tuberculosis (TB) infection (LTBI), especially in special populations including individuals with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). It discusses the major risk factors for developing active TB once LTBI has been contracted; the tuberculin skin test process and how to evaluate the results of this diagnostic test; the medical treatment options for individuals with LTBI and HIV-infected patients; and how patients being treated for LTBI should be monitored. It provides an overview of the drugs used to treat LTBI and their possible side effects.
Bibliography: Multimedia on Tuberculosis The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in tuberculosis (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on tuberculosis (for more information, follow the hyperlink indicated): •
Diagnostic procedures in tuberculosis [motion picture] Source: [presented by] National Tuberculosis Association; produced by Motion Picture Service Corp; Year: 1938; Format: Motion picture; [United States]: The Association, [1938]
•
Pathogenesis of tuberculosis [filmstrip] Source: Trainex Corporation; Year: 1974; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1974
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•
Right pulmonary tuberculosis [motion picture]: (clinical manifestations and surgical treatment) Source: [production company unknown]; S.W. Harrington; Year: 1935; Format: Motion picture; [S.l.: s.n., 1935]
•
The Combined niacin-nitrate reduction test for M. tuberculosis [motion picture] Source: Laboratory Branch, Communicable Disease Center; produced by Public Health Service Audiovisual Facility; Year: 1965; Format: Motion picture; Atlanta: The Center: [for loan by National Medical Audiovisual Center, 1965]
•
The diagnosis of tuberculosis with an improved culture medium [motion picture] Source: a Communicable Disease Center production in cooperation with the Tuberculosis Control Division, U.S.P.H.S; Year: 1942; Format: Motion picture; [United States]: The Center, [1942]
•
The Modern management of tuberculosis [motion picture] Source: American Lung Association; Year: 1973; Format: Motion picture; [New York]: The Association; [Indianapolis, Ind.: Dow Pharmaceuticals; Atlanta: for loan by National Medical Audiovisual Center], 1973
•
Therapeutic use of total lung rest in pulmonary tuberculosis [motion picture]: the principle and operation of the equalizing pressure chamber Source: [production company unknown]; Alvan L. Barach; Year: 1949; Format: Motion picture; [S.l.: s.n., 1949]
•
Thoracic surgery. Lobectomy, right upper and middle lobes, in the treatment of pulmonary tuberculosis [motion picture] Source: United States Army; Year: 1951; Format: Motion picture; United States: War Office, 1951
•
Tuberculosis: laboratory aids to diagnosis and treatment [motion picture] Source: U. S. Public Health Service, Audiovisual Facility; Year: 1964; Format: Motion picture; Atlanta: National Medical Audiovisual Center, 1964
•
Tuberculosis [motion picture]: its diagnosis, treatment, and control: an instructional sound film Source: produced by Erpi Classroom Films Inc., in collaboration with Esmond R. Long, C. Howard Marcy, Charles R. Reynolds; Year: 1940; Format: Motion picture; [United States]: Encyclopaedia Britannica Films, c1940
•
Tuberculosis [slide] Source: McMaster University Health Sciences; Year: 1974; Format: Slide; [Hamilton, Ont.: Health Sciences McMaster Univ.], 1974
•
Tuberculosis skin test [filmstrip] Source: Trainex Corporation; Year: 1974; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1974
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CHAPTER 9. PERIODICALS AND NEWS ON TUBERCULOSIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover tuberculosis.
News Services and Press Releases One of the simplest ways of tracking press releases on tuberculosis is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “tuberculosis” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to tuberculosis. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “tuberculosis” (or synonyms). The following was recently listed in this archive for tuberculosis: •
Tuberculosis blocks export of Zambia lions to U.S. Source: Reuters Health eLine Date: July 25, 2003 http://www.reutershealth.com/archive/2003/07/25/eline/links/20030725elin003.htm l
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•
Fourfold increased risk of tuberculosis seen with rheumatoid arthritis Source: Reuters Medical News Date: July 21, 2003
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Tuberculosis risk depends on duration of HIV infection Source: Reuters Medical News Date: June 10, 2003
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Simple urine test can monitor compliance with tuberculosis drug Source: Reuters Medical News Date: April 01, 2003
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India makes steady progress towards tuberculosis control Source: Reuters Medical News Date: March 24, 2003
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Thioridazine can kill drug-resistant M. tuberculosis at clinically relevant levels Source: Reuters Industry Breifing Date: March 12, 2003
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Nutrient in peanuts may aid tuberculosis treatment Source: Reuters Health eLine Date: March 12, 2003
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Arginine supplementation may offer adjuvant therapy for tuberculosis Source: Reuters Industry Breifing Date: March 12, 2003
•
Tuberculosis a risk for some lab workers Source: Reuters Health eLine Date: February 14, 2003 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name.
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Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “tuberculosis” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “tuberculosis” (or synonyms). If you know the name of a company that is relevant to tuberculosis, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “tuberculosis” (or synonyms).
Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “tuberculosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on tuberculosis: •
Etanercept: A New Drug for the Treatment of Psoriatic Arthritis Source: Psoriasis Forum. 8(1): 1,4,5. Spring 2002. Contact: National Psoriasis Foundation. P.O. Box 9009, Portland, OR 97207-9009. (800) 723-9166 ext. 12 or (503) 244-7404. Fax: (503) 245-0626. Email:
[email protected]. Website: www.psoriasis.org. Summary: This newsletter article discusses etanercept, the first FDA-approved drug for treating psoriatic arthritis. This drug was approved by the FDA for treating patients with RA in 1998 and has also been used to treat juvenile rheumatoid arthritis. Both topical and systemic therapies are used to treat psoriatic arthritis. Systemic therapies
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which include UVB and PUVA can cause organ toxicity. Etarnercept works by inhibiting the tumor necrosis factor-alpha (TNF-alpha)that is found in elevated levels in the skin and synovium of patients with psoriatic arthritis. The drug is administered subcutaneously by the patient. The most common side effect of etanercept is injectionsite reactions. Ninety percent of these were resolved without treatment. Other side effects include infections, sepsis, and rarely, This newslet, neurologic events, and pancytopenia. Overall, etanercept is well tolerated with an excellent safety profile and provides patients with psoriasis a new treatment option.
Academic Periodicals covering Tuberculosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to tuberculosis. In addition to these sources, you can search for articles covering tuberculosis that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for tuberculosis. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with tuberculosis. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to tuberculosis: Aminoglycosides •
Systemic - U.S. Brands: Amikin; Garamycin; G-Mycin; Jenamicin; Kantrex; Nebcin; Netromycin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202027.html
Aminosalicylate Sodium •
Systemic - U.S. Brands: Tubasal http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202028.html
Ascorbic Acid (Vitamin C) •
Systemic - U.S. Brands: Ascorbicap; Cecon; Cee-500; Cemill; Cenolate; Cetane; Cevi-Bid; Flavorcee; Ortho/CS; Sunkist http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202071.html
Cycloserine •
Systemic - U.S. Brands: Seromycin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202175.html
Ethambutol •
Systemic - U.S. Brands: Myambutol http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202229.html
Isoniazid •
Systemic - U.S. Brands: Laniazid; Nydrazid http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202307.html
Pyrazinamide •
Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202307.html
Rifabutin •
Systemic - U.S. Brands: Mycobutin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202683.html
Rifampin •
Systemic - U.S. Brands: Rifadin; Rimactane http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202511.html
Rifampin and Isoniazid •
Systemic - U.S. Brands: Rifamate http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202512.html
Rifampin, Isoniazid, and Pyrazinamide •
Systemic - U.S. Brands: Rifater http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202775.html
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Rifapentine •
Systemic - U.S. Brands: Priftin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203609.html
Tuberculin, Purified Protein Derivative (Ppd) •
Injection - U.S. Brands: Aplisol; Aplitest; Tubersol http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202761.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.
Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to tuberculosis by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “tuberculosis” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact
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information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for tuberculosis: •
Thalidomide http://www.rarediseases.org/nord/search/nodd_full?code=23
•
Rifampin (trade name: Rifadin I.V.) http://www.rarediseases.org/nord/search/nodd_full?code=14
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Rifampin, isoniazid, pyrazinamide (trade name: Rifater) http://www.rarediseases.org/nord/search/nodd_full?code=15
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Rifapentine (trade name: Priftin) http://www.rarediseases.org/nord/search/nodd_full?code=16
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Aconiazide http://www.rarediseases.org/nord/search/nodd_full?code=512
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Aminosalicylic acid (trade name: Paser Granules) http://www.rarediseases.org/nord/search/nodd_full?code=538
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Aminosidine (trade name: Gabbromicina) http://www.rarediseases.org/nord/search/nodd_full?code=539
•
Rifalazil http://www.rarediseases.org/nord/search/nodd_full?code=979
If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDICES
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute12: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
•
National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
12
These publications are typically written by one or more of the various NIH Institutes.
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•
National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
•
National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.13 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:14 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
•
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
•
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
13
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 14 See http://www.nlm.nih.gov/databases/databases.html.
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•
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
•
Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html The Combined Health Information Database
A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “tuberculosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “tuberculosis” (or synonyms) into the “For these words:” box. The following is a sample result: •
Prevention and Control of Tuberculosis in U.S. Communities with At-Risk Minority Populations and Prevention and Control of Tuberculosis Among Homeless Persons : Recommendations of the Advisory Council for the Source: MMWR Morbidity and Mortality Weekly Report Recommendations and Reports April 17 1992;41(RR-5):1-21. Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, Office of the Morbidity and Mortality Weekly Report Series, 1600 Clifton Rd NE M/S C-08, Atlanta, GA, 30333, (404) 332-4555, http://www.cdc.gov. US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report discusses the management and prevention of tuberculosis (TB) among minorities and homeless persons in the United States (US). The report provides a brief history of the epidemiology of TB in the US among minority groups and homeless persons and describes the problems associated with finding, tracking, and managing TB cases and contacts among homeless populations. The report discusses TB training and education for public and private health care providers and encourages local, state, or national coalitions to fight TB, and to reach as many people involved in the prevention and control of TB as possible. It advises screening of at-risk populations for TB and TB infection and emphasizes the importance of reporting cases to the local health department early. Recommendations for appropriate diagnosis, preventive therapy, treatment, and methods to ensure patient compliance for the duration of their treatment are included. The report recommends the use of directly observed therapy (DOT) in the treatment of homeless persons and discusses how to treat persons who are also infected with the human immunodeficiency virus (HIV). Recommendations are made for national, state, and local public awareness campaigns, targeting minorities and homeless persons for prevention, case management, and treatment of cases.
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Kentucky's Tuberculosis Control Law: A Manual for Local Health Departments and Health-Care Providers Contact: Kentucky Department for Public Health, Division of Epidemiology and Health Planning, Communicable Disease Branch, 275 E Main St 1st Fl-HS, Frankfort, KY, 40621, (502) 564-3261, http://publichealth.state.ky.us/index.htm. Summary: This report outlines the state of Kentucky's tuberculosis (TB) control laws. The report explains the need for and the benefits of the Kentucky TB control law. It discusses features and definitions of the law including progressive authority given to the local health department to issue a notice for required examination to individuals with active TB for failure to take prescribed medicine, a notice to complete treatment, a notice for directly observed therapy (DOT), and an emergency quarantine order. It provides a number of examples of various forms used to comply or demonstrate compliance with state law.
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Tuberculosis Morbidity Among US-Born and Foreign-Born Populations--United States, 2000 Source: Morbidity and Mortality Weekly Report Weekly Feb 8 2002;51(5):101-104. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report summarizes data from the national tuberculosis (TB) surveillance for the year 2000 and compares them with the data from 1992-1999. During 2000, there was a seven percent decrease in TB cases from 1999 and a 39 percent decrease from 1992. The number of cases among foreign-born persons remains high, about seven times that of US-born persons.
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An Expanded DOTS Framework for Effective Tuberculosis Control Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This report discusses the expanded strategic framework of the Directly Observed Therapy Short Course (DOTS) for control of tuberculosis (TB). The report explains the reasons for expanding the DOTS framework and making it a comprehensive support strategy for all providers, patients, and people to tackle the problem of TB and defines the goals, targets, and guiding principles of the framework. The expanded framework reinforces the five essential elements of the DOTS strategy: (1) sustained political commitment, (2) access to quality-assured TB sputum microscopy, (3) standardized short-course chemotherapy to all cases of TB under proper casemanagement conditions including direct observation of treatment, (4) uninterrupted supply of quality-assured drugs, and (5) recording and reporting system enabling outcome assessment. The report also describes key operations that need to be established and sustained until TB is no longer a public health threat.
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Tuberculosis in the Workplace Contact: National Academy Press, 2101 Constitution Ave NW, Box 285, Washington, DC, 20055, (202) 334-3313.
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Summary: This report, which was requested by the United States Congress in 1999, provides findings of a short-term study to examine the risk of tuberculosis (TB) among health care workers and the possible effects of federal guidelines and regulations intended to protect workers from this risk. It discusses responses to resurgent TB and proposed strategies for the elimination of TB in the Unites States and worldwide; TB transmission, infection, and disease; the Occupational Safety and Health Act of 1970 (OSHA) and its administration; a comparison of the Centers for Disease Control and Prevention's guidelines on preventing TB transmission in health care facilities with the proposed OSHA rule; occupational risk of TB; implementation and effects of CDC guidelines; and regulation and the future of TB in the workplace. •
Tuberculosis: Compliance Guide and Trainer's Kit Contact: Safety Priority Consultants LLC, 120 Ledyard St, Hartford, CT, 06114, (860) 2961654, http://www.safetypriority.com. Summary: This manual, for settings where formal compliance with worker protection from tuberculosis (TB) is required or where worker awareness is desired, contains the latest information available from the Centers for Disease Control (CDC) and the Occupational Safety and Health Administration (OSHA) on tuberculosis compliance. It covers enforcement procedures and scheduling for occupational exposure to TB; a TB infection control plan and support documents including information on TB infection and TB disease, how to do a risk assessment, the role of emergency service agencies, and universal precautions; respiratory protection program and support documents; trainer's presentation notes; instructional media, handouts, quiz, evaluation, and other forms for copying; and the 1994 CDC Guidelines for Preventing the Transmission of Tuberculosis in Health-Care Facilities.
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NIAID Global Health Research Plan for HIV/AIDS, Malaria, and Tuberculosis Contact: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Instiute of Allergy and Infectious Diseases, Division of AIDS, 505 E King St, Room 304, Carson City, NV, 89710, (702) 687-4804. Summary: This report discusses the National Institute of Allergy and Infectious Diseases (NIAD) long term strategy for supporting research that will lead to effective human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), tuberculosis (TB), and malaria prevention and treatment for individual countries struggling with these diseases. The report outlines NIAID's short-term, intermediate, and long-term goals for addressing the challenges put forth by the G8 nations in July 2000 for strengthening the Institute's role in collaborative international research. It discusses NIAID international projects in HIV/AIDS including epidemiological data related to the worldwide incidence of AIDS; HIV vaccine research; non-vaccine HIV prevention research; HIV therapeutics research; and capacity building, training, communications, and outreach, and the NIAID global research plan for malaria and TB including vaccine development, drug development, diagnostics tools, and strengthening of infrastructure and research capability.
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Designing a Tuberculosis Standardized Patient Program for Medical Students Contact: University of Medicine and Dentistry of New Jersey, New Jersey Medical School, National Tuberculosis Center, Second Fl E Wing, 225 Warren St, Newark, NJ, 07103-3620, (973) 972-3270, http://www.umdnj.edu/ntbc.
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Summary: This manual is designed for medical school faculty who are interested in implementing a tuberculosis (TB) standardized patient (SP) program for medical schools. An SP is a person trained to consistently portray one type of patient for teaching purposes. The manual discusses recruiting and training the SPs, the role of the SP program coordinator, and modifying the SP scenarios. The appendices include the TB SP Orientation Manual, a sample confirmation letter to the SP, patient role descriptions, a sample student study packet, patient intake information, facilitator verbal instructions, a program evaluation form for students, an student evaluation checklist for SPs, and a video review appointment reminder sheet and checklist. •
A Human Rights Approach to Tuberculosis Contact: World Health Organization, Communicable Diseases, Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This report provides health professionals, government agencies, and organizations with information on human rights issues affecting people's vulnerability to contracting tuberculosis (TB) and their access to TB treatment. It discusses the socioeconomic factors that make people vulnerable to TB, ways to change these factors, discrimination issues that individuals face when trying to access quality TB treatment, and strategies to make quality health care delivery accessible to persons with low income, children, women, migrants and refugees, incarcerated persons, substance abusers, and individuals with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), among others.
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Keep Your Family and Friends Safe From Tuberculosis : Join in the TB Awareness Campaign Contact: American Lung Association of Los Angeles County, 5858 Wilshire Blvd Ste 300, Los Angeles, CA, 90036, (323) 935-5864. Summary: This brochure discusses tuberculosis (TB), its transmission, symptoms, the tuberculin skin test, and how to prevent TB.
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[Keep Your Family and Friends Safe From Tuberculosis : Be a TB Buster! : Join the TB Awareness Campaign] Contact: American Lung Association of Los Angeles County, 5858 Wilshire Blvd Ste 300, Los Angeles, CA, 90036, (323) 935-5864. University of Utah, Health Sciences Center, Spencer S Eccles Health Sciences Library, 10 North 1900 East, Salt Lake City, UT, 841125890, (801) 581-8771, http://medstat.med.utah.edu/index.html. Summary: This brochure discusses tuberculosis (TB), how it develops, its transmission, symptoms, the tuberculin skin test, and how TB can be prevented.
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Tuberculosis Awareness Contact: Coastal Video Communications Corporation, 3083 Brickhouse Ct, Virginia Beach, VA, 23452-6854, (800) 767-7703, http://www.coastal.com. Summary: This information kit was developed to alert healthcare workers to the risk of contracting tuberculosis (TB) and to provide guidelines for protection against the spread of TB. The video (1) discusses the reasons for the resurgence of mycobacterium TB, (2) defines TB and describes how infection occurs, (3) explains how TB is transmitted and identifies the places where persons are more at risk of contracting TB, (4) describes the
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difference between latent TB infection and active TB, (5) discusses the methods for detecting and treating TB, (6) discusses the problem of multi-drug-resistant TB, and (7) identifies the five groups of people who are more susceptible to TB and discusses the heightened risks of immunocompromised persons. The leader's guide outlines the information on the video and provides tips for preparing for and conducting training sessions. It also provides discussion topics for the training session. •
Update: Fatal and Severe Liver Injuries Associated With Rifampin and Pyrazinamide for Latent Tuberculosis Infection, and Revisions in American Thoracic Society/CDC Recommendations--United States, 2001 Source: Morbidity and Mortality Weekly Report Weekly Aug 31 2001;50(34):733-735. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report provides preliminary information about 21 cases of liver injury associated with a two-month rifampin-pyrazinamide (RIF-PZA) regimen for the treatment of latent tuberculosis infection (LTBI). The report also includes the revised recommendations on selecting appropriate LTBI therapy for patients and monitoring the use of RIF-PZA to treat LTBI. Of the 21 patients with RIF-PZA liver injury, 16 recovered and five died of liver failure. In most instances, the nine-month isoniazid regimen is preferred for the treatmemt of patients with LTBI. RIF-PZA may be used in selected cases and requires more intensive clinical and laboratory monitoring than previously recommended. To reduce the risks associated with RIF-PZA therapy, the American Thoracic Society and the Centers for Disease Control and Prevention (CDC) with the endorsement of the Infectious Diseases Society of America have prepared recommendations that supersede previous guidelines.
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Fatal and Severe Hepatitis Associated with Rifampin and Pyrazinamide for the Treatment of Latent Tuberculosis Infection--New York and Georgia, 2000 Source: Morbidity and Mortality Weekly Report Weekly Apr 20 2001;50(15):289-291. Summary: This report presents two case reports to illustrate that the two-month regimen of rifampin (RIF) and pyrazinamide (PZA) for the treatment of latent tuberculosis infection (LBTI) can cause severe hepatitis in some people. The first case is that of a 53-year-old incarcerated man who was treated with 600 mg RIF and 1750 mg PZA daily while receiving treatment for hypertension. The patient died of liver necrosis and failure as a result of hepatitis following LTBI treatment. The second case is that of a 59-year-old woman who received 600 mg RIF and 2000 mg PZA for LTBI. She was also receiving treatment for nasal allergies and asthma and had a history of anaphylactic reactions to penicillin and an estrogen sulfates blend. On the 49th and last day of treatment this patient was admitted to a hospital because of jaundice and altered mental states. After treatment with 40 mg prednisone daily, the patient recovered. In these cases biochemical monitoring did not help avoid liver injury. The report advises that patients with LTBI and risk factors for active TB should be offered treatment and should receive instruction and reminders about the symptoms of hepatitis and of stopping medication if symptoms develop. Cases of severe hepatitis that develop in patients being treated for LTBI should be reported to the CDC.
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Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection Source: MMWR Morbidity and Mortality Weekly Report Recommendations and ReportsJune 9 2000;49(RR-6):1-54.
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Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This joint statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC) provides new recommendations for targeted tuberculin testing and treatment regimens for persons with latent tuberculosis infection (LTBI) and updates previously published guidelines. During the past decade, a series of studies of 'short-course' treatment of LTBI in persons with human immunodeficiency virus (HIV) infection has been undertaken. The results of these trials have recently become available, and the in-depth analyses of these and prior studies of isoniazid form the scientific basis of the treatment guidelines presented in this report. In addition, many changes to previous recommendations regarding testing for and treatment of LTBI are presented. The report states that targeted tuberculin testing programs should be conducted only among groups at high risk and discouraged in those at low risk and that infected persons who are considered to be at high risk for developing active TB should be offered treatment of LTBI irrespective of age. The report also identifies priorities for future research. •
Global Tuberculosis Control: WHO Report 2000 Contact: World Health Organization, Communicable Diseases, Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This report discusses the global epidemiology of tuberculosis (TB) based on the results of a study performed by the World Health Organization (WHO). The report explains the methodology of data collection for this study. It examines and analyzes the results of the study in the areas of directly observed therapy short-term (DOTS) and provides the numbers of new and cured cases and deaths. A discussion on the progress of tuberculosis prevention on the global and regional/country level and developments in TB monitoring and evaluation is included. Statistical information is broken down in several appendices into regional and demographic categories including age, race, gender, country, and region.
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Supplement to the Tuberculosis Training and Education Resource Guide Contact: CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This resource guide supplement lists educational materials from the Centers for Disease Control and Prevention's (CDC) National Prevention Information Network's (NPIN) Educational Materials Database and includes fact sheets, guides, reports, and videos on tuberculosis (TB). Materials are listed alphabetically and grouped into two categories: (1) patient and public education and (2) professional education. Since materials target multiple audiences, overlap exists between the sections.
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The Economic Impacts of Tuberculosis Contact: World Health Organization, Communicable Diseases, Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm.
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Summary: This report discusses the economic impacts of tuberculosis (TB) on global populations. Section topics include (1) the morbidity and mortality burden of TB; (2) the economic and social burden of TB (treatment and non-treatment costs borne by patients and their families, costs from estimates of simulation studies, and psychological and social costs); (3) household coping strategies; and (4) benefits and costs of new strategies of dealing with TB (intervention strategies for TB control, simulation studies of alternative TB treatment regimes, and obstacles to the adoption of directly observed treatment, short-course [DOTS]). •
Updated Guidelines for the Use of Rifabutin or Rifampin for the Treatment and Prevention of Tuberculosis Among HIV-Infected Patients Taking Protease Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors Source: Morbidity and Mortality Weekly Report Weekly Mar 10 2000;49(9):185-190. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report presents updated data pertaining to drug-drug-interactions between protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for treatment of the human immunodeficiency virus (HIV) and rifamycins for the treatment of TB. The notice also presents recommendations for the use of these drugs. New data indicate that rifampin can be used for the treatment of active TB in three situations. Also, the updated guidelines recommend substantially reducing the dose of rifabutin when it is administered to patients taking ritonavir and increasing the dose of rifabutin when rifabutin is used concurrently with efavirenz. For patients undergoing therapy with complex combinations of protease inhibitors or NNRTIs, the use of antituberculosis regimens containing no rifamycins can be considered (e.g., isoniazid, which does not have an interactive effect with either the protease inhibitors or NNRTIs). Management of HIV-infected patients taking protease inhibitors or NNRTIs and undergoing treatment for active TB with rifabutin or rifampin should be directed by, or conducted in consultation with, a physician with experience in the care of patients with these two diseases.
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Update: Nucleic Acid Amplification Tests for Tuberculosis Source: Morbidity and Mortality Weekly Report Weekly Jul 7 2000;49(26):593-594, 603. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report udates the original summary published in 1996 on the use of nucleic acid amplification (NAA) tests including the Amplified Mycobacterium Tuberculosis Direct Test (MTD) and the Amplicor Mycobacterium Tuberculosis Test for detecting tuberculosis (TB) in respiratory specimens that have positive acid-fast bacilli (AFB) smears. The report makes suggestions for using and interpreting NAA test results for managing patients suspected of having TB. The report also provides an algorithm as a reasonable approach to NAA testing of respiratory specimens for patients with signs or symptoms of active pulmonary TB for whom a presumed diagnosis has not been established.
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Diagnostic Standards and Classification of Tuberculosis in Adults and Children Source: American Journal of Respiratory and Critical Care Medicine 2000;161:1376-1395.
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Contact: American Thoracic Society, 1740 Broadway, New York, NY, 10019-4374, (212) 315-8700, http://www.thoracic.org. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: A joint statement of the American Thoracic Society and the CDC, this article provides a framework for and an understanding of the diagnostic approaches to tuberculosis (TB) infection/disease and to present a classification scheme that facilitates management of all persons to whom diagnostic tests have been applied. The specific objectives of this revision of the Diagnostic Standards are to define diagnostic strategies for high- and low-risk patient populations based on current knowledge of TB epidemiology and information on newer technology and to provide a classification scheme for TB that is based on pathogenesis. Definitions of TB disease and latent infection have been selected that (1) aid in an accurate diagnosis; (2) coincide with the appropriate response of the health care team, whether it be no response, treatment of latent infection, or treatment of disease; (3) provide the most useful information that correlates with the prognosis; (4) provide the necessary information of appropriate public health action; and (5) provide a uniform, functional, and practical means of reporting. Because TB, even after it has been treated adequately, remains a pertinent and lifelong part of a person's medical history, previous as well as current disease is included in the classification. This edition of the Diagnostic Standards has been prepared as a practical guide and statement of principles for all persons involved in the care of patients with TB. References have been included to guide the reader to texts and journal articles for more detailed information on each topic. Section headings are (I) Epidemiology, (II) Transmission of Mycobacterium Tuberculosis, (III) Pathogenesis of Tuberculosis, (IV) Clinical Manifestations of Tuberculosis, (V) Diagnostic Microbiology, (VI) Tuberculin Skin Test, (VII) Classification of Persons Exposed to and/or Infected with Mycobacterium Tuberculosis, and (VIII) Reporting of Tuberculosis. •
Tuberculosis Exposure Control Plan : Template for the Clinic Setting Contact: Francis J Curry National Tuberculosis Center, 3180 18th St Ste 101, San Francisco, CA, 94110-2042, (415) 502-4600, http://www.nationaltbcenter.edu. Summary: This guideline provides a clinic exposure control plan (ECP) template designed to assist clinic management in developing and documenting effective tuberculosis (TB) ECP. The template focuses on exposure control of staff who work primarily in the clinic and addresses facility risk assessment, employee categories at risk for TB exposure, administrative and engineering controls, respiratory protection, and program evaluation. The guideline was produced in a template format, which can be customized by each facility to reflect facility characteristics, needs, and preferences. The template is issued in disk and written form to provide broad access and ease of use.
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Policy and Procedures for Tuberculosis Screening of Health-Care Workers Contact: Francis J Curry National Tuberculosis Center, 3180 18th St Ste 101, San Francisco, CA, 94110-2042, (415) 502-4600, http://www.nationaltbcenter.edu. Summary: This guideline provides healthcare facility administrators with a template for policy and procedures for tuberculosis (TB) screening of healthcare workers (HCWs) and for designing, implementing, and documenting an effective TB screening program for HCWs. Part 1 contains a complete model TB screening policy divided into seventeen sub-sections outlining components of the TB screening program. Part 2, the 'how-to' section, includes fourteen detailed, step-by-step procedures and nine corresponding flowcharts. Each of these procedures is designed to stand alone, if desired. Topics
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include general policy, compliance with guidelines and regulations, authority and responsibility for policy and procedures, transmission and pathogenesis, epidemiology of TB in the United States, TB screening and skin testing, HCW education and training, counseling of HCWs about risk, workers' compensation, contract personnel, physicians, volunteers, compliance with the TB screening program, confidentiality, and record keeping and reporting. •
Tuberculosis at a Glance Contact: Center for Pulmonary and Infectious Disease Control, University of Texas Health Center at Tyler, 11937 US Hwy 271, Tyler, TX, 75708-3154, (903) 877-7790, http://research.uthct.edu/cpidc/. Summary: This guideline provides health professionals with quick references concerning the screening, diagnosis, and treatment of tuberculosis (TB). The guideline describes the Mantoux skin test and explains when to use two-step testing and anergy testing. It covers preventive therapy and current disease therapy, as well as who is eligible to receive them. The guideline comments on the risks involved in administering preventive therapy to a pregnant woman. The guideline discusses the issue of the Bacillus Calmette-Guerin (BCG) vaccine and how it can affect the skin test results. Isolation of patients with or who have developed TB is addressed in relation to a hospital setting. The guideline includes segments on childhood and geriatric TB, and how they can be treated effectively.
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Social Support Services for Tuberculosis Clients Contact: Charles P Felton National Tuberculosis Center at Harlem Hospital, 2238 5th Ave, New York, NY, 10037-2127, (212) 939-8254. Summary: Because tuberculosis (TB) treatment is inextricably involved in a host of psychological, social, and economic problems, this manual was developed to help providers establish and enhance social support services in a TB clinic. The purpose of the manual is to help the worker establish social services, develop a therapeutic alliance with clients, create an intake form to identify barriers to TB treatment and formulate goals to reduce those barriers and to increase client functioning, counsel and help clients achieve their goals, form support groups, and lead or participate in case management.
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Tuberculosis Training for the International Medical Graduate Contact: Charles P Felton National Tuberculosis Center at Harlem Hospital, 2238 5th Ave, New York, NY, 10037-2127, (212) 939-8254. Summary: This manual is for residency program directors, health administrators, and tuberculosis (TB) control programs to help them provide an educational program for international medical graduates (IMGs) that will ensure that they update their knowledge and skills in accordance with current TB control guidelines. The manual discusses the need for such training, program planning, training program components, and program evaluation. The appendices include citations for readings about TB management in selected countries, sources of TB educational materials appropriate for IMG training, need assessment and program evaluation questionnaires, and information on recent TB-related satellite teleconferences.
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Improving Treatment Completion for Latent Tuberculosis Infection Among Healthcare Workers Contact: Charles P Felton National Tuberculosis Center at Harlem Hospital, 2238 5th Ave, New York, NY, 10037-2127, (212) 939-8254. Summary: This manual describe the procedures used in the Fast Track program, a program of the Charles P. Felton National Tuberculosis Center of Harlem Hospital that provides treatment for health care workers (HCWs) with latent TB infection, and delineates methods that may be useful for other institutions to develop a similar program. It discusses (1) baseline documentation and preparatory steps; (2) program development, including barriers to treatment adherence (i.e., scheduling and structural issues and informational and attitudinal issues), potential solutions to barriers, program initiation, and the role of the program coordinator; and (3) the evaluation of program outcomes.
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Tuberculosis Elimination Revisited: Obstacles, Opportunities, and a Renewed Commitment Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report discusses current considerations in and recommendations for the elimination of tuberculosis (TB). In 1989, the Centers for Disease Control and Prevention (CDC) and the Advisory Council for the Elimination of Tuberculosis (ACET) issued 'A Strategic Plan for the Elimination of Tuberculosis in the United States.' Since then, the United States (US) has experienced a resurgence of TB followed by a successful mobilization against the epidemic. Because the nature of this disease has changed during the past decade, as has health care organization and delivery, ACET has reassessed its 1989 plan. Recent progress against TB should reinforce the nation's confidence that the disease can be controlled and ultimately eliminated. However, existing TB-control efforts must be sustained and enhanced, and new and improved diagnostic, treatment, and prevention methods, including a new vaccine, must be developed and applied. Support for these efforts should be broad-based and include the establishment of new partnerships. Because eliminating TB in the US will have widespread economic, public health, and social benefits, committing to this action will also fulfill an obligation to persons throughout the world who have this preventable and curable disease. With this reassessment, ACET reaffirms its call for the elimination of TB in the US.
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Tuberculosis Programs : Review : Planning : Technical Support : A Manual of Methods and Procedures Contact: International Union Against Tuberculosis and Lung Disease, 68 Boulevard Saint-Michel, Paris, (011) 33144320360, http://www.iuatld.org. Summary: This manual provides information about tuberculosis (TB) program reviews, TB program planning, and technical support to TB programs and provides a view of international partnership towards the goal of eliminating TB. Specific TB program review topics include steps in preparing and executing a program review, methods used in site visits, and information collection. The manual discusses why program planning is important, who plans TB control, when planning takes place, what should be planned, and how a long-term plan should be written. Finally, the manual discusses the
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usefulness and evaluation of technical support, the provision of technical support, and the activities of a technical consultant. •
Tuberculosis Commentary: Tuberculosis Control in a Changing Health Care System: Model Contract Specifications for Managed Care Organizations Source: Clinical Infectious Diseases June 16 1998;27;677-686. Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. Summary: This report discusses the recent changes in healthcare from individual to managed care for persons with tuberculosis (TB) and the challenges facing this new method of health services delivery. It provides and explains the purpose of a model contract for patients with TB and managed care organizations. The report discusses the ten sections of the model managed care contract and makes recommendations about how to design each section of the model contract to meet the needs of the provider and the TB patient. It summarizes the guiding principles for the management of persons with TB or TB infections and defines a number of terms related to managed care.
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Development of New Vaccines for Tuberculosis: Recommendations of the Advisory Council for the Elimination of Tuberculosis (ACET) Source: MMWR Morbidity and Mortality Weekly Report Aug 21 1998;47(RR-13):1-15. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report summarizes the efforts currently being made to develop a vaccine to eliminate tuberculosis (TB). The report provides an overview of current control measures used to prevent the spread of TB and examines current treatment methods used on patients with TB. The report discusses the progress of vaccine development for TB and reviews the needs of TB vaccine research.
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Recommendations for the Prevention and Control of Tuberculosis Among ForeignBorn Persons: Report of the Working Group on Tuberculosis Among Foreign-Born Persons Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, Office of the Morbidity and Mortality Weekly Report Series, 1600 Clifton Rd NE M/S C-08, Atlanta, GA, 30333, (404) 332-4555, http://www.cdc.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report supersedes any previous report about recommendations for the prevention and control of tuberculosis (TB) among foreign-born persons. It reviews the new Centers for Disease Control and Prevention (CDC) guidelines about TB screening for immigrants and the medical treatment of infected persons. Recent immigration trends and the epidemiology of TB among immigrants is examined. The report discusses the prioritization of TB case finding, screening, and preventive therapy for immigrants in the overall elimination of TB in the United States (US). It includes recommendations
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to improve epidemiologic reporting on the federal, state, and local levels for foreignborn persons in the US. The issues concerning barriers hindering case finding and contact investigations among immigrants with TB are discussed, with suggestions for improvement. There is a section about obstacles facing health professionals; problems with attempts to screen and provide preventive therapy for immigrants who have TB, and the difficulty of diagnosis and TB case management among immigrants. It also includes recommendations to improve treatment adherence among immigrants, and explains how to improve training programs for health professionals who work with immigrants who have TB. •
Prevention and Treatment of Tuberculosis Among Patients Infected With Human Immunodeficiency Virus : Principles of Therapy and Revised Recommendations Source: MMWR Morbidity and Mortality Weekly Report Recommendations and Reports October 30 1998;47(20):1-51. Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, Office of the Morbidity and Mortality Weekly Report Series, 1600 Clifton Rd NE M/S C-08, Atlanta, GA, 30333, (404) 332-4555, http://www.cdc.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report updates previous Centers for Disease Control and Prevention (CDC) recommendations for the diagnosis, treatment, and prevention of tuberculosis (TB) among adults and children co-infected with human immunodeficiency virus (HIV). It discusses the methodology and effectiveness of therapies used to prevent and treat persons with TB and HIV. The report examines the epidemiology of TB and multi-drugresistant TB among persons with HIV and discusses the adverse reactions that sometimes occur in persons who are taking both anti-TB and antiretroviral therapeutic drugs. It identifies factors that should be considered when treating patients who concurrently have TB and HIV and are taking antiretroviral drugs.
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Tuberculosis: School Nurse Handbook Contact: University of Medicine and Dentistry of New Jersey, New Jersey Medical School, National Tuberculosis Center, Second Fl E Wing, 225 Warren St, Newark, NJ, 07103-3620, (973) 972-3270, http://www.umdnj.edu/ntbc. Summary: This guideline provides information concerning the role of school nurses in the prevention, testing, and medical treatment of students with tuberculosis (TB). The guideline explains the transmission and pathogenesis of TB and makes recommendations for school-wide TB testing. It advises the readers how to administer and read a tuberculin skin test using the Mantoux (PPD) skin test method. The guideline describes the treatments available for active TB and preventive therapy for those with TB infection. It discusses the process of safely and correctly administering medications to students and monitoring them for any changes. The guideline explains how to keep a tuberculin skin test record, the side effects of TB medications, and how to maintain an accurate directly observed therapy (DOT) log.
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Notice to Readers: Use of Short-Course Tuberculosis Preventive Therapy Regimens in HIV-Seronegative Persons Source: Morbidity and Mortality Weekly Report Weekly Oct 30 1998;47(42):911-912.
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Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report in the form of a notice to readers states that the Centers for Disease Control and Prevention (CDC) in conjunction with the American Thoracic Society expects to issue new guidelines on screening and preventive therapy for tuberculosis (TB) that will include a recommendation on the use of the two-month regimen of daily rifampin and pyrazinamide (2RZ) as an alternative to 12-month isoniazid for prevention of TB in human immunodeficiency virus (HIV)-negative persons for whom preventive therapy is indicated. A comparative trial of the 2RZ regimen in HIV-negative persons has not been conducted. However, until the new guidelines are issued the regimen for HIV-positive persons can be used for HIVnegative persons, following the same guidelines as for HIV-positive persons. •
Tuberculosis Nursing : A Comprehensive Guide to Patient Care Contact: National Tuberculosis Controllers Association Incorporated, 2951 Flowers Rd S Ste 102, Atlanta, GA, 30341-5533, (770) 455-0801, http://www.yp.bellsouth.com/sites/ntca. Summary: This manual provides healthcare workers with information about the management of tuberculosis (TB). It discusses transmission, pathogenesis, diagnosis of TB infection and disease, patient adherence, contact investigation, TB containment, nontuberculous mycobacteria, quality assurance in TB control, and treatment with therapeutic drugs. This manual is based on and should be used in conjunction with three joint statements of the Centers for Disease Control and Prevention: Diagnostic Standards and Classification of TB, Treatment of TB and TB Infection in Adults and Children, and Control of TB.
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Examining Relationships Between HIV/AIDS and Tuberculosis Programs in Title I Eligible Metropolitan Areas Contact: US Department of Health and Human Services, Public Health Service, Health Resources and Services Administration, Bureau of Health Resources Development, Division of HIV Services, Parklawn Bldg Rm 7A-55, 5600 Fishers Ln, Rockville, MD, 20857, (301) 443-9091. Summary: This report provides information on an evaluation study by the Health Resources and Services Administration (HRSA) that addresses the lack of knowledge regarding the relationship between human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and tuberculosis (TB) programs in Title I cities experiencing a high prevalence of both diseases. The study discusses the (1) factors that affect the delivery of TB-related services in HIV care settings, (2) successful models of collaboration between HIV/AIDS and TB prevention and control programs, (3) the provision of TB services in HIV care settings to control the spread of TB, and (4) the effect of separate funding streams and programming on program collaboration at the provider/client level. It provides information on the methodology used in the study; findings; recommendations to Federal, State, and local HIV and TB programs; and study participants.
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Linguistic and Cultural Aspects of Tuberculosis Screening and Management for Refugees and Immigrants Contact: University of Washington, AIDS Clinical Trials Unit, Harborview Medical Center, (206) 731-3184, http://www.depts.washington.edu/~actu/.
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Summary: This is the transcript of a presentation made at the International Union Against Tuberculosis (TB) and Lung Disease Conference held in Chicago, Illinois in March 1996. The presentation focuses on TB screening and management of active cases in the context of communication issues across linguistic and cultural differences between biomedicine and non-western cultures. The speaker offers strategies for managing chronic problems in TB treatment and prophylaxis in the multicultural setting, explains why translation and patient education is a complex process, and outlines a system for negotiating cultural differences. •
Tuberculosis Control : The DOTS Strategy (Directly Observed Treatment ShortCourse) : An Annotated Bibliography Contact: World Health Organization, Communicable Diseases, Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This bibliography provides a number of citations about topics related to tuberculosis (TB) control and directly-observed therapy, short-course (DOTS). The bibliography provides a listing of sources concerning TB-related and DOTS topics such as case finding, intermittent treatment, and treatment for persons with TB and the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). For each of these sources, the bibliography provides information such as title, author, journal of origin or publisher, date published, pages of reference, and a brief abstract.
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Tuberculosis Control and Prevention in a Changing Managed Care Environment : Challenges and Opportunities for Local Health Departments, Managed Care Organizations, and Others Contact: National Association of County and City Health Officials, 1100 17th St 2nd Fl, Washington, DC, 20036, (202) 783-5550, http://www.naccho.org. Summary: This report supplies the readers with case studies concerning the prevention and control of tuberculosis (TB) in managed care settings. The report examines five case studies in three locations: Nashville, Tennessee (TN); St. Louis, Missouri (MO); and Palm Beach County, Florida (FL). Each of the case studies includes information about how the study was conducted in the locale, the epidemiology of TB in the area, available TB services and managed care options, funds granted for TB control, a description of the the local TB control authority, TB control training in the area, social services supplied to area residents, and demographic and epidemiological data concerning special populations including persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and immigrants. The report analyzes the information from each of these case studies and combines the strengths of each locale in its recommendations for controlling TB in managed care settings.
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Tuberculosis and AIDS: The Dual Epidemic Contact: World Health Organization, Joint United Nations Programme on HIV/AIDS, 20 Avenue Appia, CH-1211 Geneva, http://www.unaids.org. Summary: This report addresses the problems associated with the combined tuberculosis (TB) and HIV epidemics, particularly in developing nations. The sheet explains that HIV spurs the spread of TB and increases the TB risk for the entire population. As HIV weakens the immune system, the individual gradually becomes unable to combat opportunistic infections such as TB. The fact sheet outlines several components of a dual strategy to combat and prevent both HIV and TB.
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The Role of BCG Vaccine in the Prevention and Control of Tuberculosis in the United States: A Joint Statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Source: MMWR Morbidity and Mortality Weekly Report Recommendations and Reports April 26 1996;45(RR-4);1-18. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report updates and replaces previous recommendations regarding the use of Bacillus of Calmette and Guerin (BCG) vaccine for controlling tuberculosis (TB) in the United States (MMWR 1988;37:663-4, 669-75). It discusses the spread, pathogenesis, and epidemiology of TB in the US and the basic plans for managing TB in the US. The report defines and examines the use of BCG and the vaccine's safety and potency and discusses tuberculin skin testing and interpretation of results after BCG vaccination. It includes recommendations for the use of the vaccine among children, health care workers in settings associated with high and low risk for TB transmission, and persons with the human immunodeficiency virus (HIV). The report provides information on contraindications, BCG vaccination during pregnancy, implementation of BCG vaccination, and surveillance.
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Prevention and Control of Tuberculosis in Correctional Facilities: Recommendations of the Advisory Council for the Elimination of Tuberculosis Source: MMWR Morbidity and Mortality Weekly Report Recommendations and Report June 7 1996;45 (RR-8):1-27. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: The Advisory Council for the Elimination of Tuberculosis (ACET) has prepared this report to assist officials of federal, state, and local correctional facilities in controlling tuberculosis (TB) among inmates and employees of both short- and longterm correctional facilities, such as prisons, jails, and juvenile detention centers. TB is a problem in correctional facilities in the United States, and effective TB prevention and control in such facilities is necessary to reduce TB rates and, eventually, to eliminate TB in the United States. This report provides an overview of this problem and general guidelines for preventing and controlling TB in correctional facilities. In addition, this report describes the three essential activities necessary for a successful TB prevention and control program, which are TB screening, containment, and assessment, and the roles of the correctional facility and the public health department in achieving the goals of such programs.
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Clinical Update: Impact of HIV Protease Inhibitors on the Treatment of HIV Infected Tuberculosis Patients With Rifampin Source: MMWR Morbidity and Mortality Weekly Report, October 25, 1996:45(42);921925. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov.
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Summary: This report describes approaches for managing patients with tuberculosis (TB) who are candidates for or who are undergoing protease inhibitor therapy and presents interim recommendations for managing these patients until additional data are available and formal guidelines are issued. Protease inhibitors interact with rifamycin derivatives, which are used to treat and prevent the mycobacterial infections commonly observed in patients with the human immunodeficiency virus (HIV). The report provides background information on the management of TB and the three treatment options currently available for these patients. The concurrent use of protease inhibitors with rifampin might be possible by modifying the doses of both to compensate for the drug interaction. •
Nucleic Acid Amplification Tests for Tuberculosis Source: Morbidity and Mortality Weekly Report Weekly Nov 1 1996;45(43):950-952. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: This report summarizes potential uses of nucleic acid amplification (NAA) tests such as the Amplified Mycobacterium Tuberculosis Direct Test (MTD) for tuberculosis (TB) diagnosis and provides interim guidelines for the use of such tests. The report lists the current NAA tests, their FDA approved uses, their non-approved indications also known as off-label uses, limitations, and cautions.
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Controlling Tuberculosis in Community Corrections Contact: US Department of Justice, National Institute of Justice, AIDS Program, 810 7th St NW, Washington, DC, 20531, (202) 514-6210, http://www.ojp.usdoj.gov/nij. Summary: This report considers the increasing incidence and prevalence of tuberculosis (TB) infection in the United States. Persons with TB are often also infected with HIV. Unless inmates with TB are identified and treated while incarcerated, the disease can continue to spread. It outlines the challenges and opportunities that face the correctional community regarding the screening and control of TB. An examination of six community corrections departments' initiatives are briefly summarized. An explanation of the detection and transmission process is also included, along with a glossary of commonly used terms.
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The Tuberculosis Epidemic : Legal and Ethical Issues for Alcohol and Other Drug Abuse Treatment Providers Contact: US Department of Health and Human Services, Public Health Service, Substance Abuse and Mental Health Services Administration, Office for Treatment Improvement, 5600 Fishers Ln Ste 740, Rockville, MD, 20852, (301) 443-6533. Summary: This guideline for substance abuse treatment personnel explains the legal and ethical issues surrounding the management and treatment of patients with tuberculosis (TB). The guideline discusses TB, the difference between active TB and TB infection, methods of transmission, diagnosis, as well as treatment options for both types. It examines federal and State laws concerning alcohol and other drug (AOD) programs, and the protection of the confidentiality of TB infected patients. It describes how AOD programs can provide services for persons with TB that are within federal and State laws/regulations, while keeping employees of the program safe from transmission of TB.
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Forging Partnerships to Eliminate Tuberculosis Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, 1600 Clifton Rd NE MS E06, Atlanta, GA, 30333, (404) 639-8063, http://www.cdc.gov/nchstp/od/nchstp.html. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report provides a framework for tuberculosis (TB) prevention and control programs to use in planning new intervention strategies and strengthening existing ones through partnership formation. It discusses how to forge partnerships, why partnership formation is important, and how the formation benefits the partners and the community. The report covers each step in partnership building (preparation, groundwork, organization, maintenance, and evaluation). It discusses types of partnerships, such as task forces and advisory committees, and their purposes. By working in partnerships, people have a stake in the prevention and control of TB, which can foster support and participation in activities, lead to new resources, and help develop community-building skills. The report includes a resource section that provides further information on coalition building, marketing and media relations, and resource acquisitions.
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Multidrug-Resistant Tuberculosis Contact: CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report reviews the causes, treatment, and control of drug-resistant tuberculosis, and describes recent outbreaks of multidrug-resistant tuberculosis. Drugresistant tuberculosis is not a new phenomenon. However, recent outbreaks have differed considerably from previous ones; recent outbreaks involve large numbers of patients and the disease is transmitted not only from patient to patient, but also from patient to health care worker. Most cases of drug-resistant tuberculosis in the United States can be prevented by using drug-susceptibility surveillance to monitor trends, directly observed therapy to ensure adherence to and completion of therapy, and initial regimens that include four drugs. Most of the transmission of drug-resistant tuberculosis in health care settings can be prevented by fully implementing Centers for Disease Control and Prevention (CDC) guidelines.
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Screening for Tuberculosis and Tuberculosis Infection in High-Risk Populations : Recommendations of the Advisory Council for the Elimination of Tuberculosis Source: MMWR Morbidity and Mortality Weekly Report Recommendations and Reports September 8 1995;44(RR-11):1-17. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report from the Advisory Council for the Elimination of Tuberculosis (ACET) updates and replaces previous recommendations for screening for tuberculosis (TB) and TB infection among high-risk populations. These recommendations emphasize that screening for TB infection should not be given preference over higher priority TB prevention and control activities, especially identifying and completely treating all
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persons who have active TB and conducting prompt, effective contact investigations. This report provides additional important information to health professionals, including recommendations for screening specific high-risk groups; detailed descriptions of the tuberculin skin test; and the revision of CDC's previous recommendations regarding anergy testing. •
Tuberculin Skin Testing of Inpatients in Connecticut Hospitals : Recommendations of the Connecticut Tuberculosis Elimination Advisory Committee Summary: This report discusses the epidemiology of tuberculosis (TB) in Connecticut and state control of TB through screening and medical treatment. It states that Connecticut has witnessed an increase in the number of TB cases since the mid-1980s, and defines the demographic populations which have had the most notable increases of TB cases. The report defines TB, TB infection, human immunodeficiency virus (HIV) and TB/HIV co-infection. It provides specific information about the state reporting requirements for TB cases. It discusses the state board of health's recommendations for when screening should be done and explains the screening process. The report lists characteristic groups for whom preventive therapy is recommended and outlines management techniques for the care of TB-infected people.
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Tuberculosis Statistics in the United States Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. Summary: This report presents tuberculosis morbidity and mortality data for states, cities, and the nation as a whole. It is intended for use by federal, state, and local health officials, and for persons in other areas of public and private industry interested in tuberculosis. Statistics presented in these reports are discussed and interpreted. Information is presented by state and city, and organized by age, race, sex, and form of disease.
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Tuberculosis in Correctional Facilities Contact: US Department of Justice, National Institute of Justice, National Criminal Justice Reference Service, Electronic Bulletin Board, PO Box 6000, Rockville, MD, 208496000, (301) 519-5500, http://www.ncjrs.org. Summary: This report summarizes the results of a survey conducted to determine the extent of tuberculosis (TB) and tuberculosis control in correctional facilities. The questionnaire was mailed to 88 correctional systems, the Federal Bureau of Prisons, all 50 state correctional systems, and 37 large city and county jail systems. In addition to presenting survey data on the prevalence of TB in correctional facilities the report provides basic clinical background on TB, its resurgence in the United States beginning in the mid- and late-1980s, and the increase in multidrug-resistant tuberculosis (MDRTB). The report also describes correctional systems' policies and procedures regarding Centers for Disease Control and Prevention (CDC) guidelines for TB control, screening and diagnosis of TB infection, diagnosis of TB disease, management and treatment of inmates with TB disease, containment of TB, discharge issues, and training and education. A summary of legal issues and relevant case law is also provided. In general, the TB control policies in place in most correctional systems appear to follow most of the CDC recommendations.
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The HIV/AIDS and Tuberculosis Epidemics, Implications for TB Control Contact: World Health Organization, Joint United Nations Programme on HIV/AIDS, 20 Avenue Appia, CH-1211 Geneva, http://www.unaids.org. Summary: This paper summarizes the state of knowledge about how best to deal with tuberculosis (TB) in circumstances where HIV is prevalent or emerging. It examines the background and trends of the TB and HIV epidemics (covering epidemiology, demographics, underlying causes and drug-resistant TB) and synopsizes the recommended approach to TB control. This paper discusses the interaction of HIV and TB and their impact; increased TB incidence, increased TB mortality, and the effect on health services. The main programmatic issues for TB treatment in HIV- prevalent settings is outlined (including advocacy, training, screening, education and transmission issues) and an agenda is proposed for collaboration of nation TB programs with national AIDS programs.
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Developing Tuberculosis Policy for Your Community Based Organization Contact: North Jersey Community Research Initiative, North Jersey AIDS Alliance, 393 Central Ave Ste 301, Newark, NJ, 07103-2842, (973) 483-3444, http://www.njcri.org. Summary: This statement is part of a conference workshop focusing on the development of a tuberculosis (TB) policy for community-based organizations. The package contains the outline for the workshop, a true/false pre-test and post-test of TB-related knowledge for participants, and a fact sheet listing elements of a comprehensive TB education program. Also included is a draft summary of recommended guidelines on TB and HIV for community-based HIV service providers, an organizational survey for participants to use in their small-group work, a scenario with accompanying questions for analysis and discussion, and an article on TB symptoms and treatment.
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Stopping the Spread of Tuberculosis in Your Workplace Contact: Hunter College, Center on AIDS Drugs and Community Health, 425 E 25th St, New York, NY, 10010-2590, (212) 481-7672. Summary: This manual on tuberculosis (TB) prevention in the workplace consists of two parts. First, it presents a survey on how to assess air flow, which plays a large role in TB transmission within the workplace. The reader is told how to examine the workplace with regard to air movement, air conditioning system, and ease in opening windows. Second, it examines cost effective ways of improving air flow, such as adding fans, opening windows, and improving the heating system. A guide to purchasing fans is included.
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Tuberculosis and HIV: Guidelines for Community-Based HIV Service Providers Contact: North Jersey Community Research Initiative, North Jersey AIDS Alliance, 393 Central Ave Ste 301, Newark, NJ, 07103-2842, (973) 483-3444, http://www.njcri.org. Summary: This report provides guidelines for the prevention and treatment of tuberculosis (TB) among persons with the human immunodeficiency syndrome (HIV)/acquired immunodeficiency syndrome (AIDS). The report outlines a plan for TB prevention/intervention and medical treatment strategies for persons with HIV/AIDS using TB screening, staff training, TB prevention education and practices, and policy development.
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Estimates of Future Global Tuberculosis Morbidity and Mortality Source: Morbidity and Mortality Weekly Report; Vol. 42, No. 49, December 17, 1993. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: Tuberculosis (TB) is the leading cause of death associated with infectious diseases globally. The incidence of TB is expected to increase substantially worldwide during the next 10 years because of the interaction between the TB and HIV epidemics. This report uses TB notification data (i.e., cases reported to the ministries of health and collected by the World Health Organization [WHO]) to estimate the future global public health impact of TB. It also assesses the present and future contribution of HIV infection to TB.
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Probable Transmission of Multidrug-Resistant Tuberculosis in a Correctional Facility - California Source: Morbidity and Mortality Weekly Report; Vol. 42, No. 3; January 29, 1993. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Summary: During 1990-1991, an inmate in a California prison spent a total of 6 months in the prison infirmary with multidrug-resistant tuberculosis (MDR-TB). As a result, from November 1990 through March 1991, 11 of the 21 prison infirmary physicians and nurses underwent tuberculin skin testing; two persons could be documented as newly positive. In addition, two correctional officers (from an unknown number tested) also had newly positive tuberculin skin tests. State and local departments of health, industrial relations, and corrections investigated the possibility of nosocomial TB transmission from inmates to staff. This report presents the findings from their investigation.
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Position Statement on Tuberculosis and HIV Contact: American Nurses Association, 600 Maryland Ave SW Ste 100W, Washington, DC, 20024-2571, (202) 651-7000, http://www.nursingworld.org. Summary: The American Nurses Association (ANA) supports access to essential tuberculosis (TB) testing, treatment, education, counseling, and follow up services for the public and for health care providers. All nurses must be informed and aware of the etiology, treatment, and risk factors of TB, and the variance in the course of TB if the person is HIV-positive. The ANA recommends that the HIV-positive nurse follow Centers for Disease Control and Prevention (CDC) guidelines for ongoing assessment, self-limit nursing practice based on a positive TB status, self-restrict contact with others to decrease potential for exposure to the disease, and adhere to the prescribed medication regime for TB.
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Asociacion de VIH y Tuberculosis: Guia Tecnica. [HIV and Tuberculosis: Technical Guide] Contact: Pan American Health Organization, 525 23rd St NW, Washington, DC, 20037, (202) 974-3000, http://www.paho.org. Summary: This report examines the relationships between HIV and tuberculosis (TB) and compares infection rates in Latin America and the Caribbean. The report explores the problems that HIV and TB present in diagnosis, prophylaxis, and treatment.
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Treatment regimens for dually diagnosed individuals are given. The report concludes with additional recommendations for future directions in HIV and TB treatment. •
Control of Tuberculosis in the United States Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, 1600 Clifton Rd NE MS E06, Atlanta, GA, 30333, (404) 639-8063, http://www.cdc.gov/nchstp/od/nchstp.html. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This statement was adopted by the American Thoracic Society Board of Directors, March 1992. This statement discusses the control of tuberculosis (TB) in the United States (US). It examines the current epidemiology of TB in the US, and then discusses how to identify people with clinically active TB, using diagnostic methods, case finding, and performing contact investigations. The statement provides a regimen of treatment for persons with clinically active TB, and what to do if the treatment is not successful. The section on environmental aspects of infection control for tuberculosis discusses the concentration of droplet nuclei and risk of infection, source control, ventilation, supplemental approaches, and decontamination. The section about the identification and treatment of persons with TB infection discusses tuberculin skin testing of high-risk groups, testing frequency, isoniazid preventive therapy, and the use of the Bacille Calmette-Guerin vaccination. Patient compliance with treatment, promoting compliance, and the ramifications of noncompliance are discussed.
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Tuberculosis and HIV Public Health Policy: A Dual Challenge Contact: AIDS Action Foundation, 1875 Connecticut Ave NW, Ste 700, Washington, DC, 20009, (202) 986-1300. Summary: This policy paper, derived from a day-long roundtable discussion held by the AIDS Action Foundation in Washington, D.C., on Jan. 28, 1992, looks at the challenge the recent rise in the incidence of tuberculosis (TB) has presented to the public-health system. It says some of this increase is due to the increased susceptibility of persons with HIV infection to TB. The paper gives background information on public-health funding for TB before recommending several strategies for protecting HIV-infected people. These recommendations include the following: insuring that all health services respect the confidentiality of HIV-infected persons; assuring that HIV-infected people work and receive services in environments that protect them from TB to the greatest extent possible; assessing people with TB for HIV infection; assessing people with HIV infection for TB; and providing effective TB diagnosis, treatment, and monitoring for vulnerable populations. Other policy initiatives listed in the paper say that state and local public health TB programs need adequate funding; research needs adequate funding; the Centers for Disease Control and Prevention (CDC) is to be commended for creating the Coalition for the Elimination of Tuberculosis; steps outlined in the CDC's 1989 Strategic Plan for the Elimination of Tuberculosis in the United States should be funded and implemented; TB and HIV programs should be coordinated, and services integrated; and universal access to health care must become a national priority. The paper also outlines several issues that it says merit further consideration.
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Tuberculosis and AIDS Contact: Minnesota AIDS Project, 1400 Park Ave, Minneapolis, MN, 55404-1550, (612) 341-2060, http://www.mnaidsproject.org. Summary: This policy statement argues that aggressive public health programs are necessary to control the growing number of drug-resistant tuberculosis (TB) cases among HIV-positive persons. Following background information on TB, it examines the connection between HIV and the reemergence of the TB epidemic. Applicable laws are examined and recommendations at both the Minnesota state and national levels are given. State recommendations include meeting the housing, nutritional, and medical needs of people at risk for TB; implementing TB education programs for the general public and HIV-infected persons; applying privacy standards to TB patients' records; and coordinating efforts among AIDS organizations and TB programs. National recommendations cover increasing TB surveillance activity and making TB testing available, making TB treatment available, providing a continuum of intervention for those with active TB who do not comply with treatment, following infection control procedures, and re-establishing TB as an active specialty area in medical schools.
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Prevention and Control of Tuberculosis in US Communities With At-Risk Minority Populations and Prevention and Control of Tuberculosis Among Homeless Persons: Recommendations of the Advisory Council for the Source: MMWR Morbidity and Mortality Weekly Report Recommendations and Reports April 17 1992;41(RR-5):1-23. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Massachusetts Medical Society, Medical Publishing Group, CSPO Box 9121, Waltham, MA, 02254, (800) 843-6356. US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, 1600 Clifton Rd NE MS E06, Atlanta, GA, 30333, (404) 639-8063, http://www.cdc.gov/nchstp/od/nchstp.html. Summary: This report discusses the management and prevention of tuberculosis (TB) among minorities and homeless persons in the United States (US). The report provides a brief history of the epidemiology of TB in the US among minority groups and homeless persons and describes the problems associated with finding, tracking, and managing TB cases and contacts among homeless populations. The report discusses TB training and education for public and private health care providers and encourages local, state, or national coalitions to fight TB, and to reach as many people involved in the prevention and control of TB as possible. It advises screening of at-risk populations for TB and TB infection and emphasizes the importance of reporting cases to the local health department early. Recommendations for appropriate diagnosis, preventive therapy, treatment, and methods to ensure patient compliance for the duration of their treatment are included. The report recommends the use of directly observed therapy (DOT) in the treatment of homeless persons and discusses how to treat persons who are also infected with the human immunodeficiency virus (HIV). Recommendations are made for national, state, and local public awareness campaigns, targeting minorities and homeless persons for prevention, case management, and treatment of cases.
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Tuberculosis and HIV Disease: A Report of the Special Initiative on AIDS of the American Public Health Association Contact: American Public Health Association, 800 I St NW, Washington, DC, 20001, (301) 893-1894, http://www.apha.org.
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Summary: This report summarizes the connection between tuberculosis (TB) and HIV infection. It starts out with background information on TB and the incidence of TB infection worldwide. It then turns to clinical symptoms of TB, symptoms of HIV disease, and the connection between the two. Diagnosis of TB infection through chest X-rays and sputum sample testing, TB treatment, and TB prevention are examined. The report concludes with policy issues involving discrimination, availability of medications, access to treatment, and occupational safety. •
Assessment of the Need of Drugs for Tuberculosis, Candidiasis and Antiretrovirals in Selected Developing Countries; Identification of Obstacles to Their Access Including Requirements for Safe and Contact: World Health Organization, Joint United Nations Programme on HIV/AIDS, 20 Avenue Appia, CH-1211 Geneva, http://www.unaids.org. Summary: This report describes the increasing need for drugs to treat HIV infection and HIV-related diseases such as candidiasis, tuberculosis (TB), toxoplasmosis, and pneumocystis carinii pneumonia and identifies several obstacles which affect access to those drugs in certain developing countries in Africa. Using tables, this report indicates incidence of AIDS-related infections in Africa, yearly costs of full course therapy for AIDS, TB, and certain opportunistic infections in four selected African countries, prevalence of HIV infection, AIDS, TB, and certain opportunistic infections in four selected African countries, and percentage of National AIDS Control Programme (NACP) budget allocated for full course therapies for 1 year. It discusses the distance from a fixed health facility, drug availability, import taxes on foreign manufactured products, and improper planning of national drug needs as major obstacles to drug access. The report continues listing barriers, emphasizing the weak infrastructure for drug distribution, improper prescribing and use of drugs, and lack of skill in monitoring safe and effective use.
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National Action Plan to Combat Multidrug - Resistant Tuberculosis Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This manual outlines planned steps to be taken in the United States government's plan to control multi-drug resistant tuberculosis (MDR-TB). It starts out with background information on the illness (which has been tied to HIV infection), then examines epidemiology to determine the magnitude of the problem. It goes on to consider the need for improved laboratory diagnosis, patient management techniques, and screening and preventive therapy. Infection-control procedures to minimize the risk of transmission in institutional settings are outlined, along with methods to control outbreaks of MDR-TB. It evaluates TB control programs and looks at the need for information dissemination and research.
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Control of Tuberculosis in Correctional Facilities: A Guide for Health Care Workers Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov.
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Summary: This manual provides information on the prevention and control of tuberculosis (TB) in correctional facilities; it can be used in developing educational programs or as a reference manual. It starts out by looking at national TB trends, then considers whether or not TB is a problem in correctional facilities. Questions cover how TB spreads, what TB infection is, what TB disease is, and what is the connection between TB and HIV. The manual then looks at TB control procedures. It starts off by looking at guidelines for screening, diagnosis, case reporting, and contact investigation. It then turns to issues surrounding containment, isolation, TB prevention, and TB treatment. •
The Tuberculosis Revival: Individual Rights and Societal Obligations in a Time of AIDS Contact: United Hospital Fund of New York, Empire State Bldg, 350 5th Ave 23rd Fl, New York, NY, 10118-2399, (212) 494-0700, http://www.uhfnyc.org. Summary: This report publishes the texts of five papers related to tuberculosis (TB) and AIDS. The first and longest consists of a report from The Working Group on Tuberculosis and HIV, and examines ethical, legal, and public policy issues connected with screening, treatment, and protection of those in congregate facilities. It includes an executive summary and recommendations. The remaining papers look at recommendations on the facilities needed to care for patients with TB, developing a system for TB prevention and care in New York City, TB in correctional facilities, and an historical analysis of sanitorium treatment.
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Tuberculosis and HIV: Challenges in Policy and Practice Contact: AIDS Action, 1906 Sunderland Pl NW, Washington, DC, 20036, (202) 530-8030, http://www.aidsaction.org. Summary: This paper looks at the connection between tuberculosis (TB) and HIV infection, and its implication for future health-care policies. It opens with background information on TB, how it is treated, and the development of multi-drug resistant (MDR) strains of the illness. The paper outlines the current status of the TB epidemic in the United States, and the need to allocate funds to respond to the epidemic. It also suggests changes needed in health-care policy and practice to fight TB.
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Management of Persons Exposed to Multidrug-Resistant Tuberculosis Source: MMWR Morbidity and Mortality Weekly Report 1992 (June);41(RR-11):1-8. Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, Office of the Morbidity and Mortality Weekly Report Series, 1600 Clifton Rd NE M/S C-08, Atlanta, GA, 30333, (404) 332-4555, http://www.cdc.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report offers suggestions for evaluating and managing persons who have been exposed to patients with infectious multidrug-resistant TB (MDRTB). It provides background information on alternative preventive therapy regimens with drugs other than isoniazid or rifampin, and presents considerations relevant to making a decision to offer one of these alternative regimens. This document explains the general pathogenesis and prevention of tuberculosis (TB). It defines MDRTB, persons who are at greater risk for infection with MDRTB, persons at greater risk of developing TB once infected, and preventive treatment. The report discusses calculating the likelihood of
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new infection with MDRTB, and the likelihood of developing active MDRTB. The document examines preventive therapy regimens and treatment duration available for persons likely to be infected with MDRTB. •
Prevention and Control of Tuberculosis in Migrant Farm Workers: Recommendations of the Advisory Council for the Elimination of Tuberculosis Source: Morbidity and Mortality Weekly Report (MMWR) Recommendations and Reports June 5 1992;41(RR-10):1-11. Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, Office of the Morbidity and Mortality Weekly Report Series, 1600 Clifton Rd NE M/S C-08, Atlanta, GA, 30333, (404) 332-4555, http://www.cdc.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report analyzes and makes recommendations for the treatment and management of tuberculosis (TB) among migrant farm workers in the United States (US). It provides a brief overview of migratory patterns and rates of TB cases for farm workers in eastern, midwestern, and western regions of the US. The report lists the services of highest priority to be available to all farm workers and their families that include detection, diagnosis, and treatment of persons with active TB; contact investigation and appropriate preventive therapy for those exposed to infectious cases; and screening and appropriate preventive therapy for workers who may be immunosuppressed. Other priorities are also listed. Recommendations are given for diagnosis, types of treatment, monitoring response to therapy, and compliance with treatment.Directly observed therapy (DOT) is recommended to ensure patient compliance. Suggestions are made for conducting a contact investigation and providing preventive therapy. Tuberculin skin testing/screening and preventive therapy are discussed. Recommendations are made for follow-up of persons requiring treatment, preventive therapy, or diagnostic services as they move. The report closes with information about the roles of the public health departments and public health services in relation to the prevention and treatment of TB in this population.
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Transmission of Multidrug - Resistant Tuberculosis From an HIV - Positive Client in a Residential Substance - Abuse Treatment Facility - Michigan Source: Morbidity and Mortality Weekly Report, Vol. 40, No. 8. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Massachusetts Medical Society, Medical Publishing Group, CSPO Box 9121, Waltham, MA, 02254, (800) 843-6356. Summary: This report examines an incident in which a newly relocated resident of a drug-abuse treatment facility apparently infected between 15 and 31 persons with tuberculosis (TB). The report says that even before the advent of Human immunodeficiency virus (HIV) infection, Injecting drug users (IDU's) were perceived to be at high risk for contracting TB. The findings from the report underscore the need to immediately isolate and treat institutionalized persons suspected of having infectious TB, and to quickly start a contact investigation when the possibility of TB infection is first considered. Rapid diagnostic tests to identify M. tuberculosis need to be developed, and drug-susceptibilty studies should be initiated. Also, medical information about a patient under a health department's care should be sent to the patient's new jurisdiction if the person moves.
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Purified Protein Derivative (PPD) - Tuberculin Anergy and HIV Infection: Guidelines for Anergy Testing and Management of Anergic Persons at Risk of Tuberculosis Source: Morbidity and Mortality Weekly Report; Vol. 40, no. RR-5. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. Massachusetts Medical Society, Medical Publishing Group, CSPO Box 9121, Waltham, MA, 02254, (800) 843-6356. Summary: This report says that the occurrence of tuberculosis (TB) among persons with Human immunodeficiency virus (HIV) infection has led to the development of guidelines for the management of patients who have both infections. It recommends that all HIV-infected persons receive a tuberculin skin test, and that those who react should be considered for preventive therapy. The report looks at assessment of Delayedtype hypersensitivity (DTH) skin test responsiveness, DTH response in HIV infection, studies of PPD testing in HIV infection, recommendations for evaluation for anergy of HIV-infected persons, management of anergic, HIV-infected persons, and research priorities.
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Management of Tuberculosis and CNS Toxoplasmosis Source: Aspects of HIV Management in Injecting Drug Users. Contact: Wellcome Foundation, Group Marketing, Langley Court, Beckenham. Summary: This paper, presented at an international seminar on managing Human immunodeficiency virus (HIV) among Injecting drug users (IDU's), says that tuberculosis is seen in approximately one-third of all IDU's with Acquired immunodeficiency syndrome (AIDS), and that it presents a different clinical picture than it does in other subjects. The paper, which presents the results of clinical trials in Spain to treat TB and CNS toxoplasmosis, looks at maintenance therapy for tuberculosis. It also addresses primary prophylaxis for TB and treatment for toxoplasmosis.
The NLM Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “tuberculosis” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category.
15 16
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH).
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Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 75034 7711 285 2993 30 86053
HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.19 Simply search by “tuberculosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
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Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html.
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The HSTAT URL is http://hstat.nlm.nih.gov/.
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Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 20 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 21
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 22 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Tuberculosis In the following section, we will discuss databases and references which relate to the Genome Project and tuberculosis. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).23 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “tuberculosis” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for tuberculosis: •
Mycobacterium Tuberculosis, Susceptibility to Infection by Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300259 Genes and Disease (NCBI - Map)
The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: 23
Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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•
Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html
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Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
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Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
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Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html
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Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html
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Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez
Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •
3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books
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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “tuberculosis” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database24 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html.
24
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html.
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The Genome Database25 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “tuberculosis” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).
25
Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on tuberculosis can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to tuberculosis. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to tuberculosis. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “tuberculosis”:
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Guides on tuberculosis Tuberculosis http://www.nlm.nih.gov/medlineplus/tuberculosis.html
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Other guides AIDS and Infections http://www.nlm.nih.gov/medlineplus/aidsandinfections.html Laboratory Tests http://www.nlm.nih.gov/medlineplus/laboratorytests.html Preventing Disease and Staying Healthy http://www.nlm.nih.gov/medlineplus/preventingdiseaseandstayinghealthy.html Respiratory Diseases http://www.nlm.nih.gov/medlineplus/respiratorydiseases.html
Within the health topic page dedicated to tuberculosis, the following was listed: •
General/Overviews Questions and Answers about TB Source: Centers for Disease Control and Prevention http://www.cdc.gov/nchstp/tb/faqs/qa.htm
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Diagnosis/Symptoms Cough: Self-Care Flowcharts Source: American Academy of Family Physicians http://familydoctor.org/flowcharts/516.html QuantiFERON-TB http://www.fda.gov/cdrh/mda/docs/P010033.pdf Radiography -- Chest (Chest X-ray) Source: American College of Radiology, Radiological Society of North America http://www.radiologyinfo.org/content/chest_radiography.htm Tuberculin Skin Test Source: New York City Dept. of Health, Bureau of Tuberculosis Control http://www.ci.nyc.ny.us/html/doh/html/tb/tbskin.html Tuberculosis: The Meaning of a Positive Test Source: American Academy of Family Physicians http://familydoctor.org/handouts/120.html
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Treatment Directly Observed Therapy Source: New York City Dept. of Health, Bureau of Tuberculosis Control http://www.ci.nyc.ny.us/html/doh/html/tb/tbdot.html I.T. (Intermittent Therapy) Source: New York City Dept. of Health, Bureau of Tuberculosis Control
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http://www.ci.nyc.ny.us/html/doh/html/tb/tbit.html Multidrug-Resistant Tuberculosis Source: American Lung Association http://www.lungusa.org/diseases/mdrtbfac.html Tuberculosis: Treatment of Active Tuberculosis Source: American Academy of Family Physicians http://familydoctor.org/handouts/184.html Tuberculosis: Treatment of Tuberculosis Infection Source: American Academy of Family Physicians http://familydoctor.org/handouts/185.html •
Specific Conditions/Aspects Connection between TB and HIV (the AIDS Virus) Source: Centers for Disease Control and Prevention http://www.cdc.gov/nchstp/tb/pubs/pamphlets/tbandhiv_eng.htm Tuberculosis Risk on Aircraft Source: National Center for Infectious Diseases http://www.cdc.gov/travel/tb_risk.htm
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Children Pediatric Tuberculosis Source: American Lung Association http://www.lungusa.org/diseases/pedtbfac.html
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From the National Institutes of Health Learn about Tuberculosis http://www.niaid.nih.gov/publications/pubTB/TBEnglish06.pdf Learn about Tuberculosis Infection http://www.niaid.nih.gov/publications/pubTB/TBInfEng06.pdf Tuberculosis Overview Source: National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/factsheets/tb.htm
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Organizations American Lung Association http://www.lungusa.org/ CDC National Prevention Information Network (NPIN) Source: National Center for HIV, STD, and TB Prevention http://www.cdcnpin.org/ National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/
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Prevention/Screening BCG (Bacille Calmette-Guérin) Vaccine Source: New York City Dept. of Health, Bureau of Tuberculosis Control http://www.ci.nyc.ny.us/html/doh/html/tb/tbbcg.html Prevent TB Source: New York City Dept. of Health, Bureau of Tuberculosis Control http://www.ci.nyc.ny.us/html/doh/html/tb/tbprev.html
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Research End of a 30-Year Wait for 1.9 Billion People Source: Global Alliance for Tuberculosis Drug Development http://www.tballiance.org/7_6_1%2520BigHomepageFeatureStory.asp Focus on Tuberculosis: Ancient Enemy, Present Threat Source: National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/newsroom/focuson/tb02/tb.htm No R&D in 30 Years Source: Global Alliance for Tuberculosis Drug Development http://www.tballiance.org/2_3_C_NoRandDin30Years.asp Short-Course Treatment for Latent Tuberculosis Is Associated with More Frequent Liver Injury Than Long-Course Treatment Is Source: American College of Physicians http://www.annals.org/cgi/content/full/137/8/I-32 Sloppy Repair Helps TB Bug Resist Drugs Source: National Institute of Allergy and Infectious Diseases http://www.nih.gov/news/pr/apr2003/niaid-17.htm
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Statistics CDC Telebriefing Transcript, World TB Day 2002: New Data on TB Epidemics Worldwide Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/transcripts/t020321.htm FASTATS: Tuberculosis Source: National Center for Health Statistics http://www.cdc.gov/nchs/fastats/tb.htm TB Elimination: Now Is the Time Source: National Center for HIV, STD, and TB Prevention http://www.cdc.gov/nchstp/tb/worldtb2002/NIT.htm Trends toward Tuberculosis Elimination Source: National Center for HIV, STD, and TB Prevention http://www.cdc.gov/nchstp/tb/worldtb2002/trends.htm
You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating
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unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on tuberculosis. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •
[Tuberculosis Infection and Disease] Contact: County of Los Angeles, Department of Health Services, Public Health Programs and Services, Tuberculosis Program, 2615 S Grand Ave Rm 507, Los Angeles, CA, 90007, (213) 744-6160, http://phps.dhs.co.la.ca.us/tb/index.htm. Summary: This pamphlet provides information about tuberculosis (TB). The pamphlet discusses TB transmission, the TB skin test, additional TB diagnostic tests, and adherence to anti-TB medications.
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[Contact With Tuberculosis] Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This pamphlet provides information about tuberculosis (TB). It explains how TB is transmitted and the difference between latent TB infection (LTBI) and active TB. The pamphlet discusses how the former develops into the latter, the need for treatment of both types of TB, and overall TB prevention.
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[What You Need to Know About Tuberculosis] Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This pamphlet provides information about tuberculosis (TB), including how TB is transmitted and the difference between latent TB infection (LTBI) and active TB. The pamphlet discusses how the former develops into the latter, the need for treatment of both types of TB, and overall TB prevention.
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[Stop Tuberculosis] Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This pamphlet provides information about tuberculosis (TB). It explains how TB is transmitted and the difference between latent TB infection (LTBI) and active TB. The pamphlet discusses how the former develops into the latter, the need for treatment of LTBI, and overall TB prevention.
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Tuberculosis (TB) Contact: Gay Mens Health Crisis, 119 W 24th St Tisch Bldg, New York, NY, 10011-1995, (212) 367-1205, http://www.gmhc.org. Summary: This pamphlet explains the facts about tuberculosis (TB). The pamphlet discusses TB, how it is transmitted, diagnosed, and medical treatments. It also discusses the medicines used in TB treatment and their possible adverse reactions, and what it means to have multidrug-resistant TB (MDRTB).
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Tuberculosis: A World Wide Communicable Disease Contact: Manchester Health Department, Division of Community Health, 1528 Elm St, Manchester, NH, 03101, (603) 624-6466, http://216.204.100.81/CityGov/HLT/Home.html. Summary: This pamphlet provides general information about tuberculosis (TB). It explains what TB is, what it means to have latent TB infection (LTBI) and active TB, and how TB affects the body. The pamphlet discusses transmission, symptoms, at-risk groups, and treatment. It explains the TB skin testing procedure and the meaning of its results.
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[Tuberculosis: The Connection Between TB and HIV (the AIDS Virus) ] Contact: Alameda County Public Health Department, Division of AIDS and Communicable Disease, 1000 Broadway Ste 5000, Oakland, CA, 94607-4033, (510) 2678000, http://www.co.alameda.ca.us/PublicHealth/index.htm. Summary: This pamphlet explains tuberculosis (TB) and its connection with the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). It discusses TB transmission, areas of the body commonly affected by TB, and provides general symptoms of TB and pulmonary TB. It describes TB infection, testing, how to prevent infection from developing into TB disease, and treatment. TB is presented as a preventable and curable opportunistic infection, related to HIV.
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Treatment of Latent Tuberculosis Infection (LTBI) in Pregnancy/Postpartum Contact: Charles P Felton National Tuberculosis Center at Harlem Hospital, 2238 5th Ave, New York, NY, 10037-2127, (212) 939-8254. Summary: This pamphlet provides health professionals with information on the treatment of latent tuberculosis infection (LTBI) in pregnant and postpartum women. The pamphlet discusses recommended treatments for LTBI in pregnancy/postpartum, candidates for treatment, the monitoring of patients on treatment for LTBI in pregnancy/postpartum, and drug regimen information.
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Treatment of Latent Tuberculosis Infection (LTBI) in Children and Adolescents Contact: Charles P Felton National Tuberculosis Center at Harlem Hospital, 2238 5th Ave, New York, NY, 10037-2127, (212) 939-8254. Summary: This pamphlet provides health professionals with information on the treatment of latent tuberculosis infection (LBTI) in children and adolescents. Tables provide information on the recommended drug regimens for the treatment of LTBI in children and adolescents and candidates for treatment of LTBI based on the category of child/adolescent tested and their tuberculin skin test results. The brochure also provides information on the monitoring of children and adolescents on treatment for LTBI. Drug
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regimen information includes the interval and duration, pediatric dosages, and criteria for completion of isoniazid, rifampin, and rifampin with pyrazinamide. •
[HIV and TB (Tuberculosis)] Contact: Canadian Public Health Association, Canadian HIV/AIDS Clearinghouse, 4001565 Carling Ave Ste 400, Ottawa, (613) 725-3434, http://www.cpha.ca. Summary: This pamphlet discusses tuberculosis (TB) and its relationship to persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). The pamphlet describes how TB enters the body, how it is transmitted, the difference between TB infection and active TB, the symptoms of active TB, and how latent TB infection (LTBI) and active TB affect a person with HIV/AIDS. It discusses who is at risk for TB, the TB skin testing process, TB treatments, and the effects of TB on pregnant women and their unborn children.
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Tuberculosis (TB): Class 3 and 5 Contact: County of Los Angeles Department of Health Services, Public Health Programs and Services, Tuberculosis Program, 2615 S Grand Ave Rm 507, Los Angeles, CA, 90007, (213) 744-6160, http://lapublichealth.org/tb/. Summary: This pamphlet presents information about tuberculosis (TB). The pamphlet explains TB, the symptoms of active TB, and how TB is transmitted. It also discusses the treatments available, and possible adverse reactions individuals may experience while taking anti-TB medications.
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Tuberculosis (TB): Preventive Therapy Contact: County of Los Angeles Department of Health Services, Public Health Programs and Services, Tuberculosis Program, 2615 S Grand Ave Rm 507, Los Angeles, CA, 90007, (213) 744-6160, http://lapublichealth.org/tb/. Summary: This pamphlet presents information about tuberculosis (TB) preventive therapy. The pamphlet explains what TB is, the TB skin test, transmission, the treatments available to individuals with latent TB infection to prevent active TB, and possible adverse reactions to anti-TB medications.
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What You Should Know About Tuberculosis Contact: New Jersey Department of Health and Senior Services, Division of Epidemiology Environmental and Occupational Health, Tuberculosis Control Program, PO Box 369, Trenton, NJ, 08625-0369, (609) 588-7522, http://www.state.nj.us/health/cd/tbhome.htm. Summary: This pamphlet answers many frequently asked questions about tuberculosis (TB) testing, after testing, and other things an individual should know about TB. These include reasons why an individual needs to be tested for TB, the meaning of exposed to TB, the Mantoux test, whether an individual can refuse to be tested, what if the test is positive, what does it mean when the test needs to be repeated in 12 weeks, and taking medicine as a precaution. The pamphlet also explains the transmission of TB, the difference between active TB disease and TB infection, the symptoms of TB disease, and the length of time a person with active TB is able to spread the disease to others.
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Tuberculosis: It Can Happen to You Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This comic book provides general information about tuberculosis (TB), how it is treated, and side effects of TB medications. It discusses the Bacillus Calmette and Guerin (BCG) vaccine, why and where it is used, and why it should not be viewed as an effective preventive measure against TB. Diagnostic tests used to determine if a person has TB are discussed, and active TB and its treatment are explained. It explains how TB is spread and dispels myths about TB. The comic book addresses TB infection and preventive therapy.
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CureTB: Binational Tuberculosis Referral Program: What Do You Do When Your TB Patients Move to Mexico? Contact: Bi-National AIDS Advocacy Project, 2440 3rd Ave, San Diego, CA, 91101, (619) 281-6068, http://www.baap.org. Summary: This pamphlet describes CureTB, a referral program for tuberculosis (TB) patients and their contacts moving between the US and Mexico. The pamphlet discusses the primary goal of CureTB, the types of services US providers can request from the program, who can access CureTB services, and how. The pamphlet also lists telephone numbers, including a toll-free number, and fax numbers for CureTB to give providers and patients easy access to services.
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Adolescent Tuberculosis: Tools for Prevention: Tuberculosis Control in an Adolescent Population: Part A Contact: University of California Los Angeles, School of Public Health, Department of Community Health Sciences, Box 951772, 26-070C CHS, Los Angeles, CA, 90095-1772, (310) 825-8508, http://www.ph.ucla.edu/chs. Summary: This pamphlet discusses a study, conducted at two health centers, to examine the effects of Educational Peer Counseling and Parent-Participant Contingency Contracting on treatment adherence of adolescents undergoing preventive tuberculosis (TB) treatment. Adolescents were randomly divided into a peer counseling group, contingency contract group, a group that combined both peer counseling and contingency contracting, and a fourth group that received the usual clinic care. A slightly higher number of participants in the combined interventions group completed treatment. Results are reported with reference to ethnicity, person with whom the patient lived, responsibility and support in treatment, site satisfaction with care, and access to the clinic. Based on the results of this study, the pamphlet gives suggestions for TB control programs and for implementing these interventions at a clinic.
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Adolescent Tuberculosis: Tools for Prevention: Guidelines for Implementing the Peer Counseling Component and the Contingency Contract Component: Part B Contact: California State University Long Beach, Student Health Services, 1250 Bellflower Blvd, Long Beach, CA, 90840-0201, (562) 985-4771. Summary: This pamphlet presents guidelines for a peer counseling intervention and a contingency contract intervention to achieve treatment adherence of adolescents undergoing preventive tuberculosis (TB) treatment. The pamphlet discusses the advantages of peer counseling and describes the peer counselor component,
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recruitment, criteria and training for counselors, patient orientation to peer counseling, and possible challenges that may arise during the intervention. The pamphlet also discusses the advantages of the contingency contract, the contingency contract, negotiation procedures, suggestions for incentives, obtaining both parent and teen agreement on the incentive, and ensuring that the incentive is given. A sample of an adolescent-adult incentive agreement is included. •
Your Tuberculosis Test and Adjustment Status : What You Should Know Contact: Massachusetts Department of Public Health/Division of Tuberculosis Prevention and Control, Massachusetts Department of Public Health, Bureau of Communicable Disease Control, Division of Tuberculosis Prevention and Control, State Laboratory Institute, 305 South St, Jamaica Plain, MA, 02130, (617) 983-6970, http://www.state.ma.us/dph/cdc/tb/INDEX.HTM. Summary: This pamphlet discusses latent tuberculosis (TB) infection LTBI and the need for follow-up TB examinations. It discusses the effectiveness of the BCG vaccination and its effects the TB skin test results. It provides contact information for TB clinics in Massachusetts.
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Treatment of Tuberculosis (TB) in Adult and Adolescent Patients Co-Infected With the Human Immunodeficiency Virus (HIV) Contact: University of Medicine and Dentistry of New Jersey, New Jersey Medical School, National Tuberculosis Center, Second Fl E Wing, 225 Warren St, Newark, NJ, 07103-3620, (973) 972-3270, http://www.umdnj.edu/ntbc. Summary: This brochure provides health professionals with information on the treatment of drug-susceptible tuberculosis (TB) in children and adolescents who have the human immunodeficiency virus (HIV). Specifically it discusses three types of antiretroviral therapy (ART) regimens: (1) Rifabutin-based regimen, high dose; (2) Rifabutin-based regimen, low dose; and (3) Streptomycin-based regimen. It also provides general TB treatment information.
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Short Course Therapy for Tuberculosis Infection Contact: Florida Department of Health Bureau of TB and Refugee Health, 4052 Bald Cypress Way Bin A10, Tallahassee, FL, 32399-1718, (850) 245-4350, http://www.doh.state.fl.us/disease_ctrl/refugee/. Summary: This brochure, for individuals with tuberculosis (TB), discusses TB infection, active TB, and the use of directly observed therapy, short-course (DOTS) to prevent the development of active TB. It identifies the drugs used in DOTS including rifampin (RIF)/rifabutin (RBT), pyrazinamide (PZA), isoniazid (INH), and their side effects. It makes suggestions for persons with the human immunodeficiency virus (HIV) and TB.
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INH: Standing Between You and Tuberculosis Contact: Florida Department of Health Bureau of TB and Refugee Health, 4052 Bald Cypress Way Bin A10, Tallahassee, FL, 32399-1718, (850) 245-4350, http://www.doh.state.fl.us/disease_ctrl/refugee/. Summary: This brochure, for persons with tuberculosis (TB), discusses the use of the drug isoniazid (INH) to treat TB. It provides details and tips on taking INH including the length of treatment and INH side effects.
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Tuberculosis : Back From the Past Contact: Coastal Training Technologies Corporation, 500 Studio Dr, Virgina Beach, VA, 23542, (800) 725-3418, http://www.coastal.com. Summary: This pamphlet, for health professionals, examines the risk of tuberculosis (TB) in health care settings and how to prevent TB transmission. It discusses TB, multiple drug-resistant TB, environmental controls to prevent the spread of TB in the workplace, respiratory protection, and TB testing. The pamphlet reviews possible work restrictions placed upon healthcare professionals who have TB.
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Information on Tuberculosis Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This pamphlet provides general tuberculosis (TB) information including transmission, diagnosis, risk factors, symptoms, treatment, and multidrug-resistant TB (MDRTB).
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Treatment of Latent Tuberculosis Infection (LTBI): Revised Guidelines for RIF-PZA Contact: Charles P Felton National Tuberculosis Center at Harlem Hospital, 2238 5th Ave, New York, NY, 10037-2127, (212) 939-8254. Summary: This pamphlet provides health professionals guidelines for the treatment of latent tuberculosis infection (LTBI) in adults with rifampin (RIF) and pyrazinamide (PZA). It provides information on the recommended drug regimens of isoniazid, RIF, and RIF plus PZA, including information on interval and duration, dosage, and criteria for completion. It also discusses the monitoring of patients on treatment for LTBI and candidates for treatment of LTBI.
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Information on Tuberculosis for Criminal Justice Workers Contact: New York Department of Health, Bureau of Tuberculosis Control, Corning Tower Rm 840, Albany, NY, 12237-0669, (518) 474-7000, http://www.ci.nyc.ny.us/html/doh/html/tb/tb.html. Summary: This brochure, for criminal justice workers, provides information about tuberculosis (TB). The brochure describes TB and the tuberculin skin test, it distinguishes between TB infection and active TB, it identifies persons at risk for contracting or developing either, it explains the symptoms and available treatments for TB, and it discusses how TB is transmitted from person to person and what criminal justice workers can do to help to control its spread in correctional facilities.
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Information on Tuberculosis for Health Care Workers Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This brochure, for healthcare workers and professionals, provides information about tuberculosis (TB). The brochure describes TB, its transmission, and symptoms; it discusses multidrug-resistant TB (MDRTB) and how it develops; it identifies individuals at risk for TB infection and active TB; it discusses the importance of testing healthcare professionals for TB; and it reviews the tuberculin skin test
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procedure and the medical treatments available for active TB and TB infection. The brochure examines what healthcare facilities and personnel can do to prevent the spread of TB in the workplace. •
Understanding Tuberculosis Contact: StayWell Company, 1100 Grundy Ln, San Bruno, CA, 94066-3030, (650) 7420400, http://www.staywell.com. Santa Clara Valley Health and Hospital System, Santa Clara County Public Health Department, Health Protection Division, 2220 Moorpark Ave, San Jose, CA, 95128, (408) 423-0764, http://www.sccphd.org/phmain/Protection.asp. Summary: This pamphlet discusses the disease tuberculosis (TB) and the importance of knowing about it, getting tested, and receiving treatment if infected. The pamphlet discusses the risk of getting TB, its transmission, active and inactive TB, the TB skin test, the meaning of negative and positive results, and medication for TB disease and TB infection. The pamphlet emphasizes the need to take all of the prescribed medication or run the risk of developing drug-resistant TB.
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Learn About Tuberculosis Contact: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, 6700-B Rockledge Dr, Bethesda, MD, 20892-7630, (301) 496-1884, http://www.niaid.nih.gov/dmid. Summary: This pamphlet for persons who have tested positive for tuberculosis (TB) provides information about the disease. TB can be determined through a skin test or a chest x-ray and is a germ usually found in the lungs. TB is spread through the air when an infected person coughs or laughs. Persons with TB should not go to school or work until they are cured of TB and should take precautions to cover their mouths when coughing or laughing. A doctor or local health department will provide antibiotics to persons with TB. All of the medication must be taken. Local health departments may offer directly observed therapy (DOT) to ensure patient adherence. While undergoing treatment, good nutrition and proper rest are recommended.
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Learn About Tuberculosis Infection Contact: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, 6700-B Rockledge Dr, Bethesda, MD, 20892-7630, (301) 496-1884, http://www.niaid.nih.gov/dmid. Summary: This pamphlet provides information for persons who have tuberculosis (TB) infection, not active TB disease. If an individual's skin test (PPD test) is positive, but the chest x-ray does not have spots or shadows, that individual is said to have TB infection or latent TB infection. This means that the germ that causes TB disease is in the body, but is not active. That individual cannot spread the germ to others. Individuals with TB infection may not look or feel sick, but the germ may become active at any time and make them sick. Then they can spread the germ to others. A doctor or local health department may give them medicines, called antibiotics, for their TB infection. However, it is important that individuals with TB take all of their medicines for the required length of time. If they stop taking the medicines, the infection will not go away, and they may become even sicker. Individuals with TB should eat well and get lots of rest while taking their medications. Their PPD tests will always be positive, so there is
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no need to take another PPD test. They will only need a chest x-ray if they have symptoms of TB disease, such as fever, cough, or night sweats. •
Tuberculosis Medication Card for Outreach Workers Contact: New York State Department of Health, Bureau of TB Control, Corning Tower Building Room 840, Empire State Plaza, Albany, NY, 12237-0669, (518) 474-4845. Summary: This pamphlet, for outreach workers, provides information about medications used to treat tuberculosis (TB). It describes various first line, second line, and combination anti-TB medications; general dosage information; and possible side effects.
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Treatment for Latent Tuberculosis Infection Contact: Washington Department of Health, Tuberculosis Control, PO Box 47837, Olympia, WA, 98504-7837, (360) 236-4501. Summary: This brochure, for individuals with latent tuberculosis (TB) infection, discusses how to diagnosis latent TB infection, how to prevent active TB disease, treatment, the length of treatment, drug side effects, and drug interactions with other medications. The brochure also discusses the importance of medicating children of infected parents.
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The Tuberculin Skin Test: Tuberculosis Contact: Florida Department of Health Bureau of TB and Refugee Health, 4052 Bald Cypress Way Bin A10, Tallahassee, FL, 32399-1718, (850) 245-4350, http://www.doh.state.fl.us/disease_ctrl/refugee/. Summary: This brochure, for the general public, discusses tuberculosis (TB) and the tuberculin skin test. It provides general information on TB including its symptoms, methods of transmission, how TB infection develops into active TB, treatment with isoniazid (INH), who is at high-risk for TB, and TB prevention. The brochure describes the tuberculin skin test process and what the results show.
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About Tuberculosis Precautions for Law Enforcement, Correctional, Parole, and Probation Personnel Contact: Channing L. Bete Company Incorporated, 200 State Rd, South Deerfield, MA, 01373-0200, (800) 477-4776, http://www.channing-bete.com. Summary: This brochure, for correctional and law enforcement personnel, discusses tuberculosis (TB) and its prevention in the workplace. It provides information on TB transmission, the difference between active TB and latent TB infection (LTBI), TB symptoms, multidrug-resistant TB (MDRTB), and the tuberculin skin test. It identifies individuals at risk for TB, and examines how TB can be controlled and prevented in the correctional facility setting through the use inmate containment, environmental measures, preventive therapy, personal protective equipment, workplace policies, and universal precautions.
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About Tuberculosis (TB) Contact: Channing L. Bete Company Incorporated, 200 State Rd, South Deerfield, MA, 01373-0200, (800) 477-4776, http://www.channing-bete.com.
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Summary: This brochure, for the general public, discusses tuberculosis (TB); its transmission; latent TB infection (LTBI) and active TB symptoms; the tuberculin skin test and how to interpret TB test results; and TB treatment. It stresses the importance of patient adherence to TB medical treatment and discusses how TB affects individuals with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). •
Understanding Tuberculosis Today : A Handbook for Patients With Notes on the Effect of HIV Infection Contact: Arkansas Department of Health, Tuberculosis Program, 4815 W Markham St Slot 45, Little Rock, AR, 72205-3867, (501) 661-2398, http://www.healthyarkansas.com. Summary: This pamphlet provides information about tuberculosis (TB). It describes the difference between latent TB infection (LTBI) and active TB, its diagnosis and treatment, the therapeutic drugs used to treat TB and possible adverse reactions. The pamphlet examines how TB affects various groups including children and persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). It provides case studies of persons with TB that shows the benefits of patient adherence to medical therapies, and the detriments of failing to take all prescribed medicines.
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Treatment of Latent Tuberculosis Infection (LTBI) Contact: Charles P Felton National Tuberculosis Center, Harlem Hospital Center, 2238 5th Ave, New York, NY, 10037, (212) 939-8254, http://www.harlemtbcenter.org. Summary: This pamphlet provides information about the treatment of latent tuberculosis infection (LTBI). The pamphlet identifies those persons who should undergo tuberculin skin testing and provides information in chart form about the recommended drug regimens (i.e., isoniazid [INH], rifampin [RIF] plus pyrazinamide [PZA], and RIF) for treatment of LTBI in adults and candidates for treatment of LBTI. The pamphlet also provides information on the monitoring of patients on treatment for LTBI.
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The Connection Between Substance Abuse and Sexually Transmitted Diseases, Hepatitis B, Tuberculosis, HIV/AIDS Contact: Massachusetts Department of Public Health, Bureau of Communicable Disease Control, Division of Tuberculosis Prevention and Control, State Laboratory Institute, 305 South St, Jamaica Plain, MA, 02130-3515, (617) 983-6970, http://www.state.ma.us/dph/cdc/tb/INDEX.HTM. Summary: This pamphlet discusses the relationship between drug and alcohol abuse and sexually transmitted diseases (STDs), hepatitis B, tuberculosis (TB), and the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). It discusses the transmission, symptoms, and prevention of these infectious diseases and how substance abuse affects individuals with HIV/AIDS.
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Tuberculosis Treatment Card for Clinicians Contact: New York State Department of Health, Bureau of TB Control, Corning Tower Building Room 840, Empire State Plaza, Albany, NY, 12237-0669, (518) 474-4845. Summary: This pamphlet, for health professionals, provides information about medications used to treat tuberculosis (TB). It identifies various first line, second line,
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and combination anti-TB medications; general dosage guidelines; TB medication's possible side effects; and possible drug interactions. •
Tuberculosis Screening of College and University Students Contact: American College Health Association, Task Force on HIV Disease and AIDS, PO Box 28937, Baltimore, MD, 21240-8937, (410) 859-1500, http://www.acha.org. Summary: This pamphlet provides information about screening of college and university students for tuberculosis (TB). It discusses the importance of screening, when and whom to screen, screening methods, interpreting the results of a TB skin test, and what to do if the TB skin test is positive. A sample TB screening form is provided.
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The Adventures of Raz : Raz Learns About Tuberculosis Contact: Manitoba Lung Association, 629 McDermot Ave, Winnipeg, MB, (204) 7745501, http://www.mb.lung.ca. Summary: This comic book provides information about tuberculosis (TB). The comic book tells the story of a grandmother who unknowingly infects her grandchildren with TB. The comic book discusses TB, its transmission, and its affect on the body. It also discusses TB testing procedures, treatment, and prevention.
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Teacher's Guide : The Adventures of Raz : Raz Learns About Tuberculosis Contact: Manitoba Lung Association, 629 McDermot Ave, Winnipeg, MB, (204) 7745501, http://www.mb.lung.ca. Summary: This teacher’s guide provides information about tuberculosis (TB). The teacher’s guide discusses TB, its transmission, and its affect on the body. It also discusses TB testing procedures, treatment, and prevention and provides activities to help to reinforce these lessons among students.
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TB : Tuberculosis Contact: Education Training and Research Associates, PO Box 1830, Santa Cruz, CA, 95061-1830, (800) 321-4407, http://www.etr.org. Summary: This pamphlet provides general information about tuberculosis (TB). It discusses TB and who is susceptible, including persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). The pamphlet outlines the symptoms for latent and active TB, TB testing procedures, medical treatment, multidrug-resistant TB (MDRTB), and various means of prevention.
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Treatment of Tuberculosis : Standard Therapy for Active Disease Summary: This brochure provides health professionals with information on the treatment of individuals with active tuberculosis (TB). It provides dosage, adverse reactions, monitoring, and general information on four first-line and twelve second-line medications. First-line medications include isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin. Second-line medications include amikacin,capreomycin, ciprofloxacin, clarithromycin, clofazimine, cycloserine, ethionamide, kanamycin, levofloxacin, ofloxacin, para-aminosalicylic acid, and rifabutin.
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Tuberculosis (TB): Take the Drugs to Kill the Bugs! Contact: Queens University, Kingston General Hospital, 76 Stuart St, Kingston, (613) 549-6666, http://www.kgh.on.ca/kgh/home.html. Summary: This brochure, for individuals with tuberculosis (TB), provides general information about TB treatment. It explains how TB is transmitted and distinguishes between active TB and TB infection, it discusses the importance of undergoing medical treatment and adhering to anti-TB drugs, and it discusses the use of directly observed therapy (DOT). It provides information about the drugs used in the treatment and their possible side effects and recommends that individuals who experience these side effects see their healthcare providers immediately. It includes a TB diary for patients to keep track of their medication.
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Treatment to Prevent Tuberculosis (TB) : Why Do I Need It? Contact: New York City Department of Health, Bureau of Tuberculosis Control, 125 Worth St Rm 216 Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This brochure provides information about tuberculosis (TB) preventive therapy to persons with TB infection. Preventive therapy helps to keep TB infection from developing into active TB, a disease that can damage the lungs or other parts of the body. Persons with TB infection do not feel sick and cannot spread TB germs to other people, whereas persons with active TB feel sick and can spread TB germs. TB can become active at any time, especially in children, persons recently exposed to TB, persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), and persons with certain medical conditions. The BCG vaccine does not always protect against TB, and those persons who test positive for TB who have had the vaccine still need to undergo preventive therapy. The medicine usually prescribed in preventive therapy is isoniazid (INH), a relatively safe drug, which causes side effects in few people. Monthly check-ups are necessary while undergoing preventive therapy so that a doctor can make sure that no side effects are occurring, perform physicals and answer patient questions, and give medication refills. Preventive therapy takes six to twelve months to complete, during which time persons with TB should adhere to their medical treatment. The brochure provides contact information for chest clinics, which provide free TB-related services, in the five boroughs of New York City, New York.
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New Jersey Medical School National Tuberculosis Center: A Founding Component of the International Center for Public Health Contact: University of Medicine and Dentistry of New Jersey, New Jersey Medical School, National Tuberculosis Center, Second Fl E Wing, 225 Warren St, Newark, NJ, 07103-3620, (973) 972-3270, http://www.umdnj.edu/ntbc. Summary: This pamphlet describes the mission, goals, and services of the Charles P. Felton National Tuberculosis (TB) Center at Harlem Hospital. It lists a number of services provided by the Charles P. Felton National TB Center including community outreach, social services, professional education and training, and a full range of TB treatments and related health services. The pamphlet includes directions to the hospital and contact phone numbers.
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Tuberculosis Is Treatable and Curable Contact: San Francisco Department of Public Health, San Francisco General Hospital, TB Control Section, 1001 Potrero Ave, San Francisco, CA, 94110, (415) 206-8524. Summary: This pamphlet provides information about tuberculosis (TB) and its transmission. It differentiates between TB infection and active TB and identifies their symptoms. The pamphlet describes treatments for TB infection and active TB and lists side effects of TB medications for which persons should seek medical attention. The pamphlet also provides a list of TB test sites in and around San Francisco.
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[TB : What You Need to Know About Tuberculosis] Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This brochure presents information to the general public about tuberculosis (TB). TB is an airborne disease that can damage the lungs, other parts of the body, or cause serious illness. It can be spread by those persons with active TB who transmit it when they sing, talk, cough, or sneeze repeatedly towards other persons who inhale the germs. TB infection means that TB germs are in the body but are inactive because of the response of the immune system. Active TB is the disease that develops when the immune system is weakened or fails to respond to the initial contact with TB germs. Multidrug-resistant TB (MDRTB) develops when a person with TB fails to adhere to their treatment regimen or is given the incorrect medicine. MDRTB is often harder to treat, but most patients can be cured. TB patients are usually not a threat for transmission within a few weeks of taking medication. The brochure discusses the symptoms of TB, diagnostic tests, persons who should get tested for TB, and ways to prevent TB transmission for persons who have active TB, persons with TB infection, and persons who are in close contact with a person who is in either of the aforementioned groups. Addresses and telephone numbers are provided for New York City Department of Health's chest clinics, which provide free TB-related services.
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Stop Tuberculosis Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm. Summary: This pamphlet, for health professionals, organizations, and government agencies, provides information about the World Health Organization's Stop Tuberculosis (TB) initiative, which includes the use of directly observed therapy, shortcourse (DOTS) to help treat TB. It reviews the epidemiology of TB worldwide, and discusses the structure, mission, and objectives of Stop TB.
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[Tuberculosis: Get the Facts] Contact: San Diego County Health and Human Services Agency, Tuberculosis Control Program, PO Box 85222, San Diego, CA, (619) 692-5565, http://www.co.sandiego.ca.us/cnty/cntydepts/health/. Summary: This pamphlet provides general information about tuberculosis (TB), including methods of transmission, risk factors, and the symptoms associated with active TB. The pamphlet differentiates between latent TB infection (LTBI) and active TB.
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Facts About. Tuberculosis Contact: American Lung Association of Maryland, 11720 Beltsville Drive 3rd FL, Beltsville, MD, 20705, (301) 572-3205. Summary: This pamphlet provides general information concerning tuberculosis (TB). The brochure describes TB and identifies the demographic groups that are at high risk for contracting it. It lists the symptoms of TB and explains how the disease develops. It examines the TB skin test, how it is performed, and who should take the test. The brochure explores the treatments options available for person with TB and discusses the possibility that an infected person can transmit the disease to another person. It advises the readers about multidrug-resistant TB and what should be done if they test positive or negative for TB.
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What Case Managers Need to Know About Tuberculosis and HIV Contact: New York Department of Health, AIDS Institute, Corning Tower Rm 729, Empire State Plz, Albany, NY, 12237-0684, (518) 474-3405. Summary: This pamphlet, for case managers and health care professionals, discusses preventive therapy and treatment for persons with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and tuberculosis (TB). The pamphlet discusses TB and its relationship to HIV/AIDS, and how to prevent TB prevention through screening and preventative therapy. It provides a prevention and treatment plan for case mangers to assist clients with and without a history of active TB disease and clients who are hospitalized for TB disease.
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Tuberculosis Can Be Eliminated: TB Can Be Prevented: TB Can Be Treated: TB Can Be Cured Contact: Massachusetts Department of Public Health/Division of Tuberculosis Prevention and Control, Massachusetts Department of Public Health, Bureau of Communicable Disease Control, Division of Tuberculosis Prevention and Control, State Laboratory Institute, 305 South St, Jamaica Plain, MA, 02130, (617) 983-6970, http://www.state.ma.us/dph/cdc/tb/INDEX.HTM. Summary: This information kit presents information about tuberculosis (TB) prevention and treatment. The information kit outlines the facts about TB, the TB skin test, the use of directly observed therapy (DOT) in TB treatment, how to conduct contact investigations, and community-wide TB prevention strategies.
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Tuberculosis Treatment Guidelines: Reporting and Discharge Regulations Contact: Santa Clara Valley Health and Hospital System, Santa Clara County Public Health Department, Health Protection Division, 2220 Moorpark Ave, San Jose, CA, 95128, (408) 423-0764, http://www.sccphd.org/phmain/Protection.asp. Summary: This information kit contains fact sheets on diagnosis of tuberculosis (TB) infection and disease, management of active TB, and Santa Clara County treatment guidelines for latent TB infection (LTBI) and TB disease in adults and children. Forms for recording report/transfer, discharge/treatment, and morbidity of TB cases for Santa Clara County are included.
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Pediatric Tuberculosis: A Video Guide to Diagnosis and Treatment Contact: Francis J Curry National Tuberculosis Center, 3180 18th St Ste 101, San Francisco, CA, 94110-2042, (415) 502-4600, http://www.nationaltbcenter.edu. Summary: This instructional package, for health professionals, provides information about the testing and treatment of tuberculosis (TB) in children. It explains how to conduct the tuberculin skin test and what demographic groups of children should be targeted for this diagnostic test. It defines the results of a TB skin test and includes additional information about diagnostic tests for TB including the chest radiograph and gastric aspirates. The instructional package discusses aspects of treating pediatric TB: drug dosing, drug regimen development, patient adherence, dosing instructions for family, monitoring of patients with active TB, and possible treatments for children with multidrug-resistant TB.
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Cure-TB: Binational Tuberculosis Referral System: California-Mexico Contact: Bi-National AIDS Advocacy Project, 2440 3rd Ave, San Diego, CA, 91101, (619) 281-6068, http://www.baap.org. Summary: This information kit provides information on the Cure TB tuberculosis (TB) binational referral program and CURE + binational HIV/AIDS referral program for human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) or HIV-TB co-infected patients and their contacts moving between Mexico and US. The kit contains pamphlets describing the Cure TB and CURE+ programs, referral forms for both, instructions for completing the forms, and a wallet card with toll-free numbers to access the programs from the US and Mexico.
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Tuberculosis : New Strategies for the Healthcare Worker Contact: Health Edco, Division of WRS Group, Inc., PO Box 21207, Waco, TX, 767021207, (254) 776-6461. Medcom Incorporated, PO Box 6003, Cypress, CA, (800) 541-0253. Summary: This continuing education instructional package for healthcare workers provides information on tuberculosis (TB) and the recommendations made by the Centers for Disease Control and Prevention that are designed to prevent TB transmission among healthcare workers and patients. After completing the course, the learner should be able to explain what causes TB, describe the Mantoux skin test, explain the difference between TB infection and TB disease, describe multi-drug resistant TB and list ways a person can acquire it, list CDC-recommended ways to prevent transmission, and describe usage of masks and respirators.
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Self-Study Modules on Tuberculosis 6-9 Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, Public Health Practice Program Office, Division of Media and Training Services, 1600 Clifton Rd M/S G21, Atlanta, GA, 30333, (404) 6393707, http://www.cdc.gov/phtn. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This instructional package provides self study guides with detailed information about tuberculosis (TB) for health care workers and includes modules on contact investigations for TB; confidentiality in TB control; TB surveillance and case management in hospitals and institutions; and patient adherence to TB treatment. The instructional package also comes with a glossary.
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Tuberculosis: Back From the Past Contact: Coastal Training Technologies Corporation, 500 Studio Dr, Virgina Beach, VA, 23542, (800) 725-3418, http://www.coastal.com. Summary: This information kit, for health professionals and administrators, provides information about the prevention of the occupational transmission of tuberculosis (TB). It covers: (1) an introduction that discusses the resurgence of TB and the new multidrug-resistant strains, (2) disease transmission, (3) environmental controls, (4) medical procedure protection, (5) personal protective equipment, and (6) work practice controls. Recommendations for the prevention of the occupational transmission of TB include early screening of TB, the use of isolation and general-use room ventilation, and the use of respirators are provided.
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Tuberculosis: Prevention and Practices for Healthcare Workers Contact: Medcom Incorporated, PO Box 6003, Cypress, CA, (800) 541-0253. Summary: This information kit, for health professionals, provides information about tuberculosis (TB) and prevention methods in healthcare settings. The video covers TB transmission and the tuberculosis epidemic, multi-drug resistant TB (MDRTB), and TB prevention. It differentiates between active TB and latent TB infection (LTBI), identifies the symptoms of active TB, and lists persons at risk for TB. It outlines steps that can be taken to help prevent the occupational transmission of TB including patient testing and screening, and reducing air contamination through engineering controls and the use of respirators.
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Tuberculosis Update: EMS (First Responders) Contact: Long Island Productions, 106 Capitola Dr, Durham, NC, 27713-4471, (919) 5446663, http://www.lip-online.com. Summary: This information kit provides the facts about preventing the spread of tuberculosis (TB) among emergency medical services (EMS) personnel. The video explains TB, how TB is transmitted, and the difference between latent TB infection and active TB. It examines the factors that place the general public and EMS workers at risk for TB, what can be done to prevent the spread of TB in the workplace, and how to develop workplace policies on TB prevention and exposure control. The leader's guide provides an introduction to the program, guidelines on preparing for the video presentation and conducting the session, and a summary of the major points of the program. The leader's guide also contains other materials, including a scheduling and attendance form, quiz, employee training log, and training certificate.
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Tuberculosis Update: Institutional Contact: Long Island Productions, 106 Capitola Dr, Durham, NC, 27713-4471, (919) 5446663, http://www.lip-online.com. Summary: This information kit provides the facts about preventing the spread of tuberculosis (TB) among institutional personnel. The video explains TB, how TB is transmitted, and the difference between latent TB infection and active TB. It examines the factors that place the general public and institutional workers at risk for TB, what can be done to prevent the spread of TB in the workplace, and how to develop workplace policies on TB prevention and exposure control. The leader's guide provides an introduction to the program, guidelines on preparing for the video presentation and conducting the session, and a summary of the major points of the program. The leader's
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guide also contains other materials, including a scheduling and attendance form, quiz, employee training log, and training certificate. •
Prevention and Control of Tuberculosis in the Health Care Setting Contact: University of Texas Health Center, Center for Pulmonary Infectious Disease Control, PO Box 2003, Tyler, TX, (903) 877-7790. Summary: This teaching aid discusses ways to prevent tuberculosis (TB) in a health care setting. The teaching aid describes TB, its methods of transmission, symptoms, and pathogenesis from infection to disease. It explains the diagnostic test and the TB skin test used to screen for the infection/disease. It describes infection control and administrative measures that can be taken to prevent the spread of TB in a health care setting. The teaching aid explains preventive therapy and the medical treatments available to care for persons with active TB and comes with information that may be made into transparencies, to reinforce the information in the text version.
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Self-Study Modules on Tuberculosis 1-5 Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, Public Health Practice Program Office, Division of Media and Training Services, 1600 Clifton Rd M/S G21, Atlanta, GA, 30333, (404) 639-3707, http://www.cdc.gov/phtn. Summary: This instructional package provides self study guides with detailed information about tuberculosis (TB) for health care workers and includes modules on the transmission and pathogenesis of TB; the epidemiology of TB; diagnosis of TB infection and disease; treatment of TB infection and disease; and infectiousness and infection control. The instructional package also comes with a glossary.
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Tuberculosis in the Healthcare Environment: Tuberculosis Update for Healthcare Contact: Long Island Productions, 106 Capitola Dr, Durham, NC, 27713-4471, (919) 5446663, http://www.lip-online.com. Summary: This information kit provides the facts about preventing the spread of tuberculosis (TB) in healthcare settings. The video explains TB, how TB is transmitted, and the difference between latent TB infection and active TB. It examines factors that place the general public and healthcare workers at risk for TB, what can be done to prevent the spread of TB in healthcare settings, and how to develop workplace policies on TB prevention and exposure control. The leader's guide provides an introduction to the program, guidelines on preparing for the video presentation and conducting the session, and a summary of the major points of the program. The leader's guide contains other materials, including a scheduling and attendance form, quiz, employee training log, and training certificate.
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Managing Tuberculosis at District Level : A Training Course Contact: WHO Stop Tuberculosis Strategy and Operations Unit, World Health Organization, Communicable Diseases, Stop Tuberculosis Department, Stop Tuberculosis Strategy and Operations Unit, 20 Avenue Appia CH-1211, Geneva, http://www.who.int/gtb/index.htm.
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Summary: This information kit serves as curriculum to educate individuals about the treatment and control of tuberculosis (TB) on a regional and local level. It examines how to identify persons with TB through screening and selective testing of high-risk groups. The curriculum discusses how to administer quality treatment to individuals with TB, how to monitor treatment, and how to maintain a supply of medicines and other necessary materials to effectively complete treatment. It covers topics related to conducting supervisory visits to patients for directly observed therapy, short-course; providing laboratory support for TB testing; case reporting; and performing quarterly evaluations of treatment and epidemiological reporting. •
Safety and Compliance Training: Guarding Against Tuberculosis Contact: SAVANT Audiovisuals, Inc., PO Box 3670, Fullerton, CA, 92634, (714) 870-7880. Summary: This information kit serves as a curriculum to educate individuals about the prevention and control of tuberculosis (TB) in health care settings. The topics covered in this program provide employees with general knowledge about how to prevent the spread of TB and include: (1) The History of Tuberculosis as a Disease, (2) Epidemiology and Symptoms of Tuberculosis, (3) Modes by which Tuberculosis is Transmitted, (4) The Centers for Disease Control and Prevention (CDC) Tuberculosis Guidelines, (5) The Exposure Control Plan, (6) Recognizing Exposure Situations, (7) Practices to Use to Prevent Exposure, (8) Administrative Controls, (9) Engineering Controls, and (10) Selection and Use of Respirators. A video reinforces TB prevention methods.
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Improving Patient Adherence to Tuberculosis Treatment Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, 1600 Clifton Rd NE MS E06, Atlanta, GA, 30333, (404) 639-8063, http://www.cdc.gov/nchstp/od/nchstp.html. Summary: This pamphlet provides information on improving patient adherence to tuberculosis (TB) treatment and follow-up care by providing information on measuring and predicting compliance. It is intended to assist health workers in providing individualized TB prevention and treatment services that are sensitive to the patient's cultural, social, health, and economic needs. It includes sections on problem-solving and treatment adherence by adolescent and children.
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World TB Day 2002 : March 24 : The Impact of Tuberculosis Worldwide Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. Summary: This information sheet provides information about tuberculosis (TB) and World TB Day 2002. It discusses TB transmission, latent TB infection (LTBI), active TB, available medical treatments, and global TB epidemiology.
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Information on Tuberculosis (2) Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/.
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Summary: This information sheet discusses the importance of taking the prescribed medication for tuberculosis (TB). In response to specific questions, the information sheet explains that (1) taking the medicine can save the patient's life and prevent spreading the disease to others in the family; (2) the patient needs to inform the doctor of other medications; (3) there are minimal side effects from the medicine, but the doctor should be informed of certain side effects; (4) stopping the medicine can cause the disease to return; and (5) there are programs to help the patient follow doctor's orders. •
Tuberculosis Facts: TB Can Be Cured Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. Summary: This information sheet presents basic information about tuberculosis (TB). The information sheet explains the difference between latent TB infection (LTBI) and active TB, TB skin testing procedures, and the medical treatments available for TB.
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How to Handle Occupational Exposure to Tuberculosis (TB) Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This pamphlet presents the steps recommended by the New York City Department of Health, Tuberculosis Control Program to help administrators work with the health department, when an employee calls in sick and says he/she is in the hospital with tuberculosis (TB), an employee reports that he/she has tested positive for TB; or the employer learns that a close relative of an employee has TB.
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Tuberculosis Patient Discharge: Hospital to Community Contact: Massachusetts Department of Public Health/Division of Tuberculosis Prevention and Control, Massachusetts Department of Public Health, Bureau of Communicable Disease Control, Division of Tuberculosis Prevention and Control, State Laboratory Institute, 305 South St, Jamaica Plain, MA, 02130, (617) 983-6970, http://www.state.ma.us/dph/cdc/tb/INDEX.HTM. Summary: This information sheet examines Massachusetts (MA) requirements for the discharge of patients with tuberculosis (TB) from hospitals. It outlines MA's legal requirements for the discharge of patients with TB, priorities for discharge planning, and discharge safety procedures.
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Tuberculosis (TB) and the BCG Vaccine Contact: San Diego County Health and Human Services Agency, Tuberculosis Control Program, PO Box 85222, San Diego, CA, (619) 692-5565, http://www.co.sandiego.ca.us/cnty/cntydepts/health/. Summary: This information sheet, for the general public, provides general information on the Bacillus Camette-Guerin (BCG) vaccine and tuberculosis (TB).
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Tuberculosis (TB) Disease and Treatment Contact: San Diego County Health and Human Services Agency, Tuberculosis Control Program, PO Box 85222, San Diego, CA, (619) 692-5565, http://www.co.sandiego.ca.us/cnty/cntydepts/health/. Summary: This information sheet, for the general public, lists the symptoms of tuberculosis (TB), tests used to identify TB, and the most common medications used to treat TB.
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Policy: Tuberculosis Testing and Treatment for Nursing Homes and Rest Homes Contact: Massachusetts Department of Public Health/Division of Tuberculosis Prevention and Control, Massachusetts Department of Public Health, Bureau of Communicable Disease Control, Division of Tuberculosis Prevention and Control, State Laboratory Institute, 305 South St, Jamaica Plain, MA, 02130, (617) 983-6970, http://www.state.ma.us/dph/cdc/tb/INDEX.HTM. Summary: This information sheet discusses Massachusetts' policy regarding tuberculosis testing and treatment in nursing and rest homes. It outlines policy regarding the screening of employees for TB, assessing and skin testing new residents, and screening short-term residents.
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Tuberculosis (TB) Infection Contact: San Diego County Health and Human Services Agency, Tuberculosis Control Program, PO Box 85222, San Diego, CA, (619) 692-5565, http://www.co.sandiego.ca.us/cnty/cntydepts/health/. Summary: This information sheet discusses latent tuberculosis (TB) infection (LTBI), its transmission, the differences between LTBI and active TB, and how LTBI can develop into active TB.
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Tuberculosis Contact: American Federation of State County and Municipal Employees, Health and Safety Department, 1625 L St NW, Washington, DC, 20036-5687, (202) 429-1000, http://www.afscme.org/health/index.html. Summary: This fact sheet discusses tuberculosis (TB) and occupational risks of infection. It provides background information on the disease, and it covers modes of transmission, TB screening, symptoms, and safe work procedures.
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Tuberculosis y VIH (Virus del SIDA) Contact: North Carolina Department of Health and Human Services, Division of Public Health, Epidemiology Section, 1902 Mail Service Center, Raleigh, NC, 27699-1902, (919) 733-3421, http://www.schs.state.nc.us/epi. Summary: This information sheet provides persons with tuberculosis (TB) with information on the connection between the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and TB, TB transmission, and the difference between latent TB infection (LTBI) and active TB.
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Prevention: Identifying and Treating 'Old Tuberculosis' Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet provides physicians with information on the treatment and evaluation of individuals with latent tuberculosis (TB) infection (LTBI) as a result of previous active TB. It outlines multidrug treatment and discusses the tests that need to be administered before a patient begins multidrug treatment. It discusses radiographic findings associated with risk for TB and other radiologic findings.
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Management: Completion of Treatment for Tuberculosis Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet provides health professionals with information about the standard duration of treatment for tuberculosis (TB) and strategies to improve patient adherence to treatment. It reviews the Center for Disease Control and Prevention's (CDC's) standard regimen and guidelines for TB treatment. It promotes the use of directly observed therapy (DOT) and the use of the drug rifamycin for optimal treatment results and discusses cases that may call for more than six months of therapy. The information sheet provides contact information for services in New York City to assist physicians with ensuring that their patients complete treatment successfully in the shortest period of time.
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Infection Control: Tuberculosis Surveillance of Health Care Workers - Tuberculin Skin Testing Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet provides health professionals with information on the control of tuberculosis (TB) infection in health care facilities through TB surveillance among health care workers (HCWs). It discusses who is most at risk for exposure to TB and how frequently tuberculin skin testing (TST) should be administered. It provides information on how to administer the TST, interpret its results, report positive TB skin test results to local and State agencies in New York, and conduct epidemiological investigations.
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Drug Resistance: Multidrug-Resistant Tuberculosis Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet provides health professionals with information on the emergence of multidrug-resistant tuberculosis (MDRTB), MDRTB treatment regimens, and the monitoring of MDRTB treatment. It examines how infection control has facilitated the emergence of MDRTB and makes recommendations about the handling of adverse reactions of second-line medications and the scheduling of post-treatment evaluations for persons with MDRTB.
Patient Resources 579
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Diagnosis: Culture-Negative Tuberculosis Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet provides health professionals with information on the diagnosis and treatment of tuberculosis (TB) in patients with culture-negative TB results from conventional TB testing practices. The information sheet presents guidelines for diagnosing TB without bacteriologic evidence (e.g., by requesting a biopsy and through pathology studies). It recommends the treatment of all non-pregnant adults with suspected TB and emphasizes the importance of reporting suspected cases to the New York City Department of Health.
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Diagnosis: Diagnostic Tests for Tuberculosis Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet provides health professionals with information on the latest rapid diagnostic tests for tuberculosis (TB). It examines recent improvements in TB testing technologies that allow for faster laboratory diagnosis of TB, explains how nucleic acid amplification (NAA) tests have helped laboratories diagnose patients more quickly than previously and provides an overview of how these tests are used and interpreted. The information sheet outlines the limitations of NAA tests and identifies two laboratories in New York City that provide these tests at no charge.
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Diagnosis: Reporting Requirements for Tuberculosis Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet provides health professionals with information on tuberculosis (TB) reporting requirements in New York City. It emphasizes the importance of epidemiological reporting and reporting cases as soon as they are discovered, especially in young children. It describes the circumstances where laboratories are required to report cases of TB and provides guidelines regarding how to report cases of TB in New York by phone and how to report TB-related evaluation and treatment information.
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Diagnosis: False-Positive Cultures for Mycobacterium Tuberculosis Contact: New York City Department of Health, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet provides health professionals with information on rapid detection methods for tuberculosis (TB) and the avoidance of diagnostic errors based on false-positive cultures. The information sheet explains how new rapid laboratory tests for TB have improved detection and treatment of TB, but have also led to higher incidence rates of false-positive cultures. It makes recommendations regarding how to determine if there has been cross-contamination during the diagnosis process to avoid diagnostic errors and reviews New York City Department of Health policies used to monitor laboratories for incidences of false-positive cultures.
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Diagnosis: Rapid Diagnostic Tests for Tuberculosis Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet discusses new rapid diagnostic tests that can detect mycobacterium tuberculosis in 3-5 hours compared to traditional methods that require 1-8 weeks. The two new tests the Gen-Probe Amplified Mycobacterium Tuberculosis Direct (MTD) test and the Roche Amplicor mycobacterium tuberculosis (MTB) test are both based on nucleic acid amplification assays. The information sheet discusses the use and interpretation of rapid diagnostic tests, their limitations, and laboratories that offer rapid diagnostic testing.
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Tuberculosis Information Contact: Multicultural Health Communication Service, GPO Box 1614, Sydney, http://www.health.nsw.gov.au/health-public-affairs/mhcs. Summary: This information sheet uses a question-and-answer format to provide the general public with information on tuberculosis (TB). It explains what TB disease and TB infection are, how TB is spread, and how TB infection becomes TB disease. Other topics include the signs of TB, the common tests for TB, the treatments for TB disease and TB infection, the testing of people exposed to the patient, and the services provided by a chest clinic.
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Tuberculosis (TB) : Targeted Testing and Treatment of Latent TB Infection (LTBI) Contact: Florida Department of Health Bureau of TB and Refugee Health, 4052 Bald Cypress Way Bin A10, Tallahassee, FL, 32399-1718, (850) 245-4350, http://www.doh.state.fl.us/disease_ctrl/refugee/. Summary: This fact sheet for health professionals discusses the targeting of tuberculosis (TB) skin testing and medical treatment for latent TB infection (LTBI). The fact sheet identifies high-risk population who should receive tuberculin skin testing. It lists groups for whom tuberculin skin testing is no longer routinely recommended, groups for whom symptom screening should be utilized, and questions to include for symptom screening. The fact sheet provides a table indicating which groups should be treated for LTBI based on tuberculin skin test results and information on four specific treatment regimens: isoniazid (INH) for nine months, INH for six months, a combination of rifampin (RIF) and pyrazinamide (PZA), or PZA monotherapy.
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How to Handle Occupational Exposure to Tuberculosis Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: This information sheet, for health professionals, employers, and administrators, provides step-by-step instructions on how to deal with the occupational exposure of tuberculosis (TB).
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Information on Tuberculosis (1) Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention,
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Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. Summary: This information sheet presents data on tuberculosis (TB). It discusses the prevalence of the disease, and answers frequently asked questions such as the cause, symptoms, testing, the difference between TB infection and TB disease, transmission, and new drug-resistant strains. The information sheet emphasizes that untreated TB is fatal, but that it is almost always possible to treat TB. •
Anergy Testing and Tuberculosis Contact: Santa Clara Valley Health and Hospital System, Santa Clara County Public Health Department, Health Protection Division, 2220 Moorpark Ave, San Jose, CA, 95128, (408) 423-0764, http://www.sccphd.org/phmain/Protection.asp. Summary: This information sheet discusses anergy testing for people with tuberculosis (TB). It defines anergy and lists disease conditions, including infection with the human immunodeficiency virus (HIV) and TB, which are common causes of anergy. Since TB skin test and anergy testing are unreliable in people with HIV, the information sheet recommends that preventive treatment should be given to them if indicated, even if the skin test is negative.
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False-Positive Cultures for Mycobaterium Tuberculosis Contact: Santa Clara Valley Health and Hospital System, Santa Clara County Public Health Department, Health Protection Division, 2220 Moorpark Ave, San Jose, CA, 95128, (408) 423-0764, http://www.sccphd.org/phmain/Protection.asp. Summary: This information sheet contends that new rapid diagnostic laboratory techniques appear to have increased the possiblity of laboratory cross contamination and explains how to avoid diagnostic errors based on false-positive cultures.
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Reporting Requirements for Tuberculosis Contact: Santa Clara Valley Health and Hospital System, Santa Clara County Public Health Department, Health Protection Division, 2220 Moorpark Ave, San Jose, CA, 95128, (408) 423-0764, http://www.sccphd.org/phmain/Protection.asp. Summary: This information sheet presents the requirements for reporting suspected and confirmed cases of tuberculosis (TB) to the Santa Clara County Public Health Department. The evaluation and treatment of people who have been in contact with an individual with active TB also has to be reported. The reporting by providers, microbiology laboratories, and pathologists can be done by telephone and on a special form.
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Timeline for the Management of Tuberculosis: Cases and Suspects Contact: Santa Clara Valley Health and Hospital System, Santa Clara County Public Health Department, Health Protection Division, 2220 Moorpark Ave, San Jose, CA, 95128, (408) 423-0764, http://www.sccphd.org/phmain/Protection.asp. Summary: This information sheet provides a chart with the case management of different treatment regimens for people with tuberculosis (TB). The chart lists the drugs being used for treatment and type of treatment, whether daily observed therapy (DOT), bi-weekly DOT, or self-administered therapy. Provider visits, sputum specimens, chest
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X-rays, and baseline and follow-up tests are recorded. The information sheet also includes notes on treatment. •
Tuberculosis Treatment: Summary Guidelines and Regimens for Adults Contact: Santa Clara Valley Health and Hospital System, Santa Clara County Public Health Department, Health Protection Division, 2220 Moorpark Ave, San Jose, CA, 95128, (408) 423-0764, http://www.sccphd.org/phmain/Protection.asp. Summary: This information sheet lists the tuberculosis (TB) treatment guidelines and regimens for adults in the initial and continuaton phases of directly observed therapy and self adminstered therapy with isoniazid, rifampin, pyrazinamide, ethambutol, and rifamate and of other regimens for patients who are reistant or sentitive to some of these drugs.
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Tuberculosis (TB): Understanding the Basics Contact: New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, PO Box 74, New York, NY, 10013-0061, (212) 788-4155, http://www.ci.nyc.ny.us/nyclink/html/doh/html/tb/tb.html. Summary: In response to a list of questions about tuberculosis (TB), this information sheet discusses, TB transmission, latent TB infection (LTBI), drug-resistant TB, symptoms, diagnostic tests, who should get tested, whether TB patients can infect others, and the best way of fighting TB. It explains that TB is a disease that can damage a person's lungs and other parts of the body and can cause serious illness. TB is spread when people who have active untreated TB cough or sneeze and germs are released in the air. Other people breathing these germs can get infected. LTBI means that the germs are in the body but are not active. A tuberculin Mantoux skin test, a chest x-ray or a sputum test can show if a person has been infected, and the only way to fight TB is to take the medication as directed.
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Tuberculosis in Pregnancy and Lactation Contact: Center for Pulmonary and Infectious Disease Control, University of Texas Health Center at Tyler, 11937 US Hwy 271, Tyler, TX, 75708-3154, (903) 877-7790, http://research.uthct.edu/cpidc/. Summary: This fact sheet presents information for pregnant women and mothers about tuberculosis (TB). Active TB must be treated immediately with prescribed to prevent its spread to children or infants. Children and infants are at a high risk for TB infection, which can cause brain damage or death. During pregnancy, a slightly different regimen of drugs is used that is not likely to affect the baby. Breastfeeding is not affected by the medications for TB, specifically, Isoniazid (INH), and it is best to continue breastfeeding when on anti-TB medicines. A positive skin test for TB infection means that the immune system recognizes a previous infection with TB. Testing during pregnancy is recommended in some cases. Treatment with INH may be postponed until a few months after delivery due to the possible effect of medication on the mother's liver. Women infected with the human immunodeficiency virus (HIV) are at special risk for TB, and infants born to mothers with HIV may be predisposed to TB. However, it is extremely rare for TB to be transferred to an infant in the womb.
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Nursing Care Management for Tuberculosis: Fact Sheet Contact: Massachusetts Department of Public Health/Division of Tuberculosis Prevention and Control, Massachusetts Department of Public Health, Bureau of Communicable Disease Control, Division of Tuberculosis Prevention and Control, State Laboratory Institute, 305 South St, Jamaica Plain, MA, 02130, (617) 983-6970, http://www.state.ma.us/dph/cdc/tb/INDEX.HTM. Summary: This information sheet provides information regarding the roles of nurses in case management for persons with tuberculosis (TB) including when it begins, and what activities it entails. It outlines the role of nurses in TB treatment, the TB treatment program at Lemuel Shattuck Hospital in Massachusetts, and collaboration between local and regional TB surveillance.
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Tuberculosis Facts: The TB Skin Test Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: Using a question and answer format, this information sheet provides general information about tuberculosis (TB) diagnosis through a skin test. It discusses TB transmission, infection, and disease. Tiny germs that can float in the air spread TB. The germs may spray into the air if a person with TB disease of the lungs or throat coughs, shouts, or sneezes. TB germs can live in the body without making the individual sick. This is called TB infection. If the germs spread, they cause TB disease. A skin test is the only way to tell if an individual has TB infection. A small needle is used to put tuberculin, the testing material, under the skin, usually on the arm. In two or three days, a healthcare worker will check to see if there is a reaction to the test. The test is positive if a bump appears on the arm. A positive test means the individual has TB infection and will need medicine. An individual who has had a positive reaction to a TB skin test or who has been treated with TB drugs in the past should tell his or her healthcare workers.
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Tuberculosis : Occupational Exposure to Tuberculosis (Police, Fire, and Medical Personnel) Contact: Oklahoma Department of Health, Acute Disease Service, Communicable Disease Division/TB Division, 1000 NE 10th St Rm 609, Oklahoma City, OK, 73117-1299, (405) 271-4060, http://www.health.state.ok.us. Summary: This fact sheet provides police, fire, and emergency medical personnel information on occupational exposure to tuberculosis (TB) and its prevention. It makes recommendations on how to reduce the risk of infection with TB bacteria, especially in relation to the transport and on-site care of suspects, victims, and patients.
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Tuberculosis (TB) Disease - What Is It? Contact: British Columbia Ministry of Health and Ministry Responsible for Seniors, PO Box 9050 STN PROV GOVT, Victoria, (250) 952-3456, http://www.gov.bc.ca/hlth/. Summary: This fact sheet, for the general public and individuals with tuberculosis (TB), provides information on active TB, its symptoms, TB testing in British Columbia, the TB
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skin test, medical treatment options, and how to prevent the transmission of active TB. It distinguishes between active TB and TB infection and it stresses the importance of patient adherence to drug regimens to avoid the development of multidrug-resistant TB (MDRTB). •
Tuberculosis (TB) Skin Test Contact: British Columbia Ministry of Health and Ministry Responsible for Seniors, PO Box 9050 STN PROV GOVT, Victoria, (250) 952-3456, http://www.gov.bc.ca/hlth/. Summary: This fact sheet, for the general public, discusses the tuberculin skin test used to diagnose tuberculosis (TB) in individuals. The fact sheet provides information on TB, the difference between active TB and TB infection, how to get a TB skin test in British Columbia, how to perform a tuberculin skin test, the meaning of positive and negative test results, and what kind of medical treatment options are available for individuals with active TB.
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[Tuberculosis Treatment] Contact: Victoria Public Health Division, GPO Box 4057, Melbourne, http://www.dhs.vic.gov.au/phd. Summary: This fact sheet discusses drugs that are available for the treatment of tuberculosis (TB). The fact sheet identifies the general side effects of anti-TB medications and the specific side effects associated with the drugs isoniazid, rifampicin, ethambutol or myambutol, and pyrazinamide. It stresses the need for individuals to take their medications regularly until their regimen is complete. The fact sheet provides contact information for TB services in Australia.
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[Tuberculosis (TB) Skin Test] Contact: British Columbia Ministry of Health and Ministry Responsible for Seniors, PO Box 9050 STN PROV GOVT, Victoria, (250) 952-3456, http://www.gov.bc.ca/hlth/. Summary: This fact sheet, for the general public, discusses the tuberculin skin test used to diagnose tuberculosis (TB), the meaning of positive and negative test results, the difference between active TB and TB infection, and the medical treatment options for individuals with active TB.
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Tuberculosis Facts: Exposure to TB Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for HIV STD and TB Prevention, Division of Tuberculosis Elimination, 1600 Clifton Rd NE MS E10, Atlanta, GA, 30333, (404) 639-8135, http://www.cdc.gov/nchstp/tb/. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: Using a question and answer format, this information sheet provides general information on exposure to tuberculosis (TB). It discusses TB transmission, infection, disease, and diagnosis through a skin test. Tiny germs that can float in the air spread TB. TB germs can live in the body without making the individual sick. This is called TB infection. If the germs spread, they cause TB disease. The germs may spray into the air if a person with TB disease of the lungs or throat coughs, shouts, or sneezes. Individuals may have been exposed to TB if they have spent time near someone with TB disease. An individual cannot get TB from someone’s clothes, drinking glass, handshake, or toilet.
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An individual who has exposed to TB germs will be given a TB skin test. If the test is positive, the individual probably has TB infection. If it is negative, the individual may be retested in a few weeks, to confirm the initial results. •
Nontuberculosis Mycobacteria Contact: Oklahoma Department of Health, Acute Disease Service, Communicable Disease Division/TB Division, 1000 NE 10th St Rm 609, Oklahoma City, OK, 73117-1299, (405) 271-4060, http://www.health.state.ok.us. Summary: Using a question and answer format, this fact sheet provides information on nontuberculosis mycobacteria (NTM) for patients who have tested positive for the bacteria. The fact sheet explains NTM, NTM transmission, the meaning of a positive test result for NTM, NTM disease, and NTM's relation to tuberculosis TB).
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[Tuberculosis : Fact Sheet] Contact: Victoria Public Health Division, GPO Box 4057, Melbourne, http://www.dhs.vic.gov.au/phd. Summary: This fact sheet provides general information about tuberculosis (TB), an infectious disease caused by inhaling the TB bacterium. The fact sheet identifies individuals at high risk for TB and those who should be tested and explains the difference between TB infection and active TB, as well as their effect on the body. The fact sheet also discusses the tuberculin skin testing process, the meaning of negative and positive tuberculin skin test results, medical treatment, and symptoms. It provides contact information for TB services in Australia.
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Guidelines for Selecting Respirators for Protection Against Tuberculosis Source: HESIS Fact Sheet 1997;1-12. Contact: State of California Department of Health Services Occupational Health Branch Department of Industrial Relations/CAL/OSHA Hazard Evaluation System and Information Service, 1515 Clay St Ste 1901, Oakland, CA, 94612, (510) 622-4328, http://www.ohb.org/hesis.htm. Summary: This fact sheet, written for health care professionals, discusses protection from occupational exposures to tuberculosis (TB) through the use of respirators. The fact sheet describes TB, TB transmission, how respirators reduce occupational transmissions of TB, when respirators should be worn, types of respirators, factors to consider when selecting a respirator, and California's and the Occupational Safety and Health Administration's (OSHA's) standards for the wearing of respirators. The fact sheet reviews the Centers for Disease Control and Prevention's (CDC's) guidelines for wearing varying levels of protective respirators, lists the components of an effective respiratory protection program against TB, and describes the respirator fit-testing and fit-checking processes. The fact sheet provides contact information for services from which individuals can learn more about respirators and California State guidelines and OSHA standards.
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[Tuberculosis: The Facts] Contact: Victoria Public Health Division, GPO Box 4057, Melbourne, http://www.dhs.vic.gov.au/phd.
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Summary: This information sheet discusses the infectious disease, tuberculosis (TB). The information sheet identifies those individuals who are at high risk for TB, explains the difference between TB infection and active TB, and discusses TB's effect on the body. It discusses the tuberculin skin testing process, medical treatment of TB, and its symptoms. Contact information for TB services in Australia is provided. •
Tuberculosis Management Clinic : INH Evaluation/Initiation Summary: This form serves as an evaluation guide for considering the use of isoniazaid (INH) for a patient with tuberculosis (TB). The form provides an area for the patient's medical history and space for evaluating current effectiveness of INH on the patient's condition. If INH therapy has not started, then this area is used to identify the reasons for implementing the use of INH. The bottom section of the form provides a checklist which must be reviewed before INH is used because it serves as an indicator as to the eligibility of the patient to take INH.
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Tuberculosis Infection in Children Contact: American Lung Association of Texas, Houston Region, 2425 W Loop S Ste 330, Houston, TX, 77027, (713) 629-1600, http://www.texaslung.org. Summary: This information sheet discusses the transmission and treatment of tuberculosis (TB) in children. The sheet describes TB disease and TB infection and the treatment of TB infection using preventive therapy with isoniazid (INH).
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Tuberculosis Disease in Children Contact: American Lung Association of Texas, Houston Region, 2425 W Loop S Ste 330, Houston, TX, 77027, (713) 629-1600, http://www.texaslung.org. Summary: This information sheet discusses the transmission and treatment of active tuberculosis (TB) in children. It provides general information about active TB and recommendations (based on age) for when children can return to normal activities.
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Tuberculosis Exposure in Children Contact: American Lung Association of Texas, Houston Region, 2425 W Loop S Ste 330, Houston, TX, 77027, (713) 629-1600, http://www.texaslung.org. Summary: This information sheet discusses ways that children are commonly exposed to tuberculosis (TB) and the tuberculin skin test and interpretation of its results.
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Public Health Fact Sheet: Tuberculosis Contact: Massachusetts Department of Public Health/Division of Tuberculosis Prevention and Control, Massachusetts Department of Public Health, Bureau of Communicable Disease Control, Division of Tuberculosis Prevention and Control, State Laboratory Institute, 305 South St, Jamaica Plain, MA, 02130, (617) 983-6970, http://www.state.ma.us/dph/cdc/tb/INDEX.HTM. Summary: This information sheet provides general information about tuberculosis (TB) in a question and answer format.
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The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “tuberculosis” (or synonyms). The following was recently posted: •
(1) Prevention and treatment of tuberculosis among patients with infected human immunodeficiency virus: Principles of therapy and revised recommendations Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 1998 October 30 (updated 2000 Mar); 59 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2157&nbr=1383&a mp;string=tuberculosis
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(1) Targeted tuberculin testing and treatment of latent tuberculosis infection Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 2000 June 9 (addendum released 2003 August 8); 54 pages http://www.guideline.gov/summary/summary.aspx?doc_id=4004&nbr=3134&a mp;string=tuberculosis
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Guidelines for using the QuantiFERON®-TB mycobacterium tuberculosis infection
test
for diagnosing latent
Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 2003 January 31; 4 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3618&nbr=2844&a mp;string=tuberculosis •
Practice guidelines for the treatment of tuberculosis Source: Infectious Diseases Society of America - Medical Specialty Society; 2000 September; 7 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2663&nbr=1889&a mp;string=tuberculosis
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Progressing toward tuberculosis elimination in low-incidence areas of the United States Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 2002 May 3; 16 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3221&nbr=2447&a mp;string=tuberculosis
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Recommendations for prevention and control of tuberculosis among foreign-born persons. Report of the Working Group on Tuberculosis Among Foreign-Born Persons. Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 1998 September 18; 35 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2155&nbr=1381&a mp;string=tuberculosis Healthfinder™
Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •
Common Antibiotics Summary: A listing of common antibiotics, including penicillins, sulfonamides, urinary antibacterial agents, and anti-tuberculosis agent, by generic name, trade name and type. Source: Alliance for the Prudent Use of Antibiotics http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2848
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Division of Tuberculosis Elimination (DTBE) Summary: The mission of the DTBE is to provide leadership in preventing, controlling, and eventually eliminating tuberculosis (TB) from the United States, in collaboration with partners at the community, Source: National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=710
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FAQ - About Tuberculosis (TB) Source: National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=617
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healthfinder® just for you: Asian Americans, Native Hawaiians, and Other Pacific Islanders Summary: This special section of healthfinder® provides reliable health information on key issues affecting these populations, including cardiovascular disease, cancer, hepatitis B, and tuberculosis. Source: U.S. Department of Health and Human Services http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7020
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Mantoux Skin Test for Tuberculosis Source: Minnesota Department of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7285
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Medicine for Tuberculosis Disease Source: Minnesota Department of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7290
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Medicine for Tuberculosis Infection Source: Minnesota Department of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7287
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Prevention News Update -- HIV/AIDS, STD & TB Summary: Synopses of key scientific articles and lay media reports on HIV/AIDS, other sexually transmitted diseases, and tuberculosis. Source: CDC National Prevention Information Network http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=4609
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Test Your Tuberculosis I.Q. Summary: Test your knowledge of tuberculosis. Answer true or false to the statements online and find out what you know about this respiratory disease. Source: American Association for Respiratory Care http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6174
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Tuberculosis Summary: Tuberculosis (TB), a chronic bacterial infection, causes more deaths worldwide than any other infectious disease. With appropriate antibiotic therapy, TB usually can be cured. Source: National Institute of Allergy and Infectious Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=222
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Tuberculosis Disease Source: Minnesota Department of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7284
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Tuberculosis Facts: Exposure to TB Summary: A brief overview of TB (tuberculosis) exposure and TB testing. This fact sheet tells how TB germs can get into a persons body. Source: Educational Institution--Follow the Resource URL for More Information http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6144 The NIH Search Utility
The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to tuberculosis. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. NORD (The National Organization of Rare Disorders, Inc.) NORD provides an invaluable service to the public by publishing short yet comprehensive guidelines on over 1,000 diseases. NORD primarily focuses on rare diseases that might not be covered by the previously listed sources. NORD’s Web address is http://www.rarediseases.org/. A complete guide on tuberculosis can be purchased from NORD for a nominal fee. Additional Web Sources
A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMDHealth: http://my.webmd.com/health_topics
Associations and Tuberculosis The following is a list of associations that provide information on and resources relating to tuberculosis:
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American Association for the Treatment of Opioid Dependence, Inc Telephone: (212) 566-5555 Fax: (212) 349-2944 Email:
[email protected] Web Site: www.aatod.org Background: The American Association for the Treatment of Opioid Dependence, Inc. was founded in 1984 to promote the growth and development of opioid treatment services. The Association currently represents 20 states and the District of Columbia, providing treatment to individuals in approximately 700 programs. Committed to enhancing the quality of patient care, the American Association for the Treatment of Opioid Dependence, in conjunction with the American Society of Addiction Medicine, developed clinical guidelines to assist individual practitioners and policy makers in the development of effective opioid treatment services. In addition, the Association focuses on federal, state, and program specific treatment policies; advocates on behalf of affected individuals and their families; engages in professional and public education; and promotes the coordination of and communication among opioid treatment programs. The Association also convenes a National Conference every 18 months for researchers, treatment personnel, and policy makers. The Association also provides a variety of materials including fact sheets and brochures, and maintains a website with information about opioid treatment for patients and practitioners, national advisories and policy statements, news from the states, and Conference/Symposium registration materials. Relevant area(s) of interest: Tuberculosis
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American Lung Association Telephone: (212) 315-8700 Toll-free: (800) 586-4872 Fax: (212) 265-5642 Email:
[email protected] Web Site: http://www.lungusa.org Background: The American Lung Association (ALA) is a national not-for-profit voluntary health organization dedicated to the prevention, cure, and control of all types of lung disease such as asthma, emphysema, tuberculosis, and lung cancer. This is accomplished through programs of community service, public health education, advocacy, and research. The ALA was established in 1904 as the National Association for the Study and Prevention of Tuberculosis. As the number of tuberculosis cases declined over the years, the association widened its focus to include other forms of lung disease and, in 1973, changed its name to the American Lung Association. The Association offers assistance through support groups, genetic counseling, patient networking, referrals, and the development and dissemination of educational materials. Such materials include reports, brochures, audiovisual aids, and Spanish language materials. Relevant area(s) of interest: Tuberculosis
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Association Paulette Ghiron-Bistagne Contre L'Amylose (Amyloidosis) Telephone: (33) 42 39 34 43 Fax: (33) 42 39 71 36
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Email:
[email protected] Web Site: None Background: Association Paulette Ghiron-Bistagne Contre L'Amylose, which translates to 'the Paulette Ghiron-Bistagne Against Amylose (Amyloidosis) Association,' is a voluntary not-for-profit self-help organization that was established in 1994 in France in memory of Paulette, who was affected by a hereditary form of amyloidosis. Amyloidosis is a chronic disorder in which an abnormal starch-like protein complex (amyloid) accumulates in certain tissues and organs of the body. Amyloidosis may occur as a primary disorder for unknown reasons (idiopathic) or may occur secondary to other underlying disorders such as rheumatoid arthritis, familial mediterranean fever, cancer of the bone marrow (i.e., multiple myeloma), or tuberculosis. In addition, some forms of amyloidosis may be inherited. The specific symptoms and findings associated with amyloidosis may vary greatly in range and severity, depending upon which areas of the body are affected. Whereas some affected individuals may have few symptoms, others may experience potentially life-threatening complications. The Association is dedicated to promoting and supporting medical research in the fight against amyloidosis; furthering the knowledge of affected individuals, family members, and health care professionals; working in association with other related organizations; and providing networking opportunities to individuals with amyloidosis and family members. It also provides appropriate referrals to genetic counseling and engages in patient advocacy. In addition, it provides a variety of educational materials including brochures in French, English, and Spanish as well as a regular newsletter entitled 'XAIPE.'.
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to tuberculosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with tuberculosis. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about tuberculosis. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine.
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To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “tuberculosis” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “tuberculosis”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “tuberculosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “tuberculosis” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.26
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
26
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)27: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
•
California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
•
California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
•
California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
•
California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
•
California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
•
California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
•
Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
•
Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
•
Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
27
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
Finding Medical Libraries 597
•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
•
Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
•
Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
•
Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
•
Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
•
Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
•
Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
•
Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
•
Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
•
Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
•
Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
•
Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
•
Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
•
Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
•
Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
•
Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
•
Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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•
Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
•
Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
•
Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
•
Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
•
Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
•
Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
•
Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
•
Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
•
Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
•
Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
•
Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
•
Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
•
Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
•
Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
•
Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
•
National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
•
National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
•
National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
Finding Medical Libraries 599
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
•
New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
•
New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
•
New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
•
New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
•
New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
•
New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
•
New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
•
New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
•
Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
•
Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
•
Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
•
Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
•
Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
•
Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
•
Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
•
Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
•
Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
•
Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
•
Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
600 Tuberculosis
•
South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
•
Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
•
Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
•
Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
601
ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
•
Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on tuberculosis: •
Basic Guidelines for Tuberculosis Pulmonary tuberculosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000077.htm TB Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000077.htm
•
Signs & Symptoms for Tuberculosis Chest pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003079.htm Cough Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Hemoptysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003073.htm
602 Tuberculosis
Hepatosplenomegaly Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003275.htm Malaise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003089.htm •
Diagnostics and Tests for Tuberculosis AMP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003368.htm Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm Chest X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm Liver biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003895.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
603
TUBERCULOSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetyltransferases: Enzymes catalyzing the transfer of an acetyl group, usually from acetyl coenzyme A, to another compound. EC 2.3.1. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Acyl Carrier Protein: Consists of a polypeptide chain and 4'-phosphopantetheine linked to a serine residue by a phosphodiester bond. Acyl groups are bound as thiol esters to the pantothenyl group. Acyl carrier protein is involved in every step of fatty acid synthesis by the cytoplasmic system. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the
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intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Deaminase: An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Since there are wide tissue and species variations in the enzyme, it has been used as a tool in the study of human and animal genetics and in medical diagnosis. EC 3.5.4.4. [NIH] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adjuvant Therapy: Treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, or hormone therapy. [NIH]
Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of
Dictionary 605
antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]
Agarose: A polysaccharide complex, free of nitrogen and prepared from agar-agar which is produced by certain seaweeds (red algae). It dissolves in warm water to form a viscid solution. [NIH] Air Sacs: Thin-walled sacs or spaces which function as a part of the respiratory system in birds, fishes, insects, and mammals. [NIH] Airways: Tubes that carry air into and out of the lungs. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehyde Dehydrogenase: An enzyme that oxidizes an aldehyde in the presence of NAD+ and water to an acid and NADH. EC 1.2.1.3. Before 1978, it was classified as EC 1.1.1.70. [NIH]
Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte
606 Tuberculosis
collagenase and elastase. [NIH] Alpha-Defensins: Defensins found in azurophilic granules of neutrophils and in the secretory granules of intestinal paneth cells. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Ambroxol: A metabolite of bromhexine that stimulates mucociliary action and clears the air passages in the respiratory tract. It is usually administered as the hydrochloride. [NIH] Ambulatory Care: Health care services provided to patients on an ambulatory basis, rather than by admission to a hospital or other health care facility. The services may be a part of a hospital, augmenting its inpatient services, or may be provided at a free-standing facility. [NIH]
Amikacin: A broad-spectrum antibiotic derived from kanamycin. It is reno- and ototoxic like the other aminoglycoside antibiotics. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [NIH]
Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Ammonium Sulfate: Sulfuric acid diammonium salt. It is used in fractionation of proteins. [NIH]
Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints,
Dictionary 607
heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [EU] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anergic: 1. Characterized by abnormal inactivity; inactive. 2. Marked by asthenia or lack of energy. 3. Pertaining to anergy. [EU] Anergy: Absence of immune response to particular substances. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anisotropy: A physical property showing different values in relation to the direction in or along which the measurement is made. The physical property may be with regard to thermal or electric conductivity or light refraction. In crystallography, it describes crystals whose index of refraction varies with the direction of the incident light. It is also called acolotropy and colotropy. The opposite of anisotropy is isotropy wherein the same values characterize the object when measured along axes in all directions. [NIH]
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Ankle: That part of the lower limb directly above the foot. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Antibody therapy: Treatment with an antibody, a substance that can directly kill specific tumor cells or stimulate the immune system to kill tumor cells. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the
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maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Antitubercular Agents: Drugs used in the treatment of tuberculosis. They are divided into two main classes: "first-line" agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and "second-line" drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy. [NIH] Antituberculosis: Refers to a drug used to treat tuberculosis. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Approximate: Approximal [EU] Aqueous: Having to do with water. [NIH] Aqueous humor: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Arenavirus: The only genus in the family Arenaviridae. It contains two groups LCM-Lassa complex viruses and Tacaribe complex viruses, which are distinguished by antigenic relationships and geographic distribution. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU]
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Arterial: Pertaining to an artery or to the arteries. [EU] Arterial embolization: The blocking of an artery by a clot of foreign material. This can be done as treatment to block the flow of blood to a tumor. [NIH] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articulation: The relationship of two bodies by means of a moveable joint. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asthenia: Clinical sign or symptom manifested as debility, or lack or loss of strength and energy. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atenolol: A cardioselective beta-adrenergic blocker possessing properties and potency similar to propranolol, but without a negative inotropic effect. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Audiovisual Aids: Auditory and visual instructional materials. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autolysis: The spontaneous disintegration of tissues or cells by the action of their own autogenous enzymes. [NIH] Autopsy: Postmortem examination of the body. [NIH] Avian: A plasmodial infection in birds. [NIH] Azithromycin: A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH]
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Back Pain: Acute or chronic pain located in the posterior regions of the trunk, including the thoracic, lumbar, sacral, or adjacent regions. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial Proteins: Proteins found in any species of bacterium. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Pair Mismatch: The presence of an uncomplementary base in double-stranded DNA caused by spontaneous deamination of cytosine or adenine, mismatching during homologous recombination, or errors in DNA replication. Multiple, sequential base pair mismatches lead to formation of heteroduplex DNA (nucleic acid heteroduplexes). [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Beta-Defensins: Defensins found mainly in epithelial cells. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH]
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Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Bioluminescence: The emission of light by living organisms such as the firefly, certain mollusks, beetles, fish, bacteria, fungi and protozoa. [NIH] Biomass: Total mass of all the organisms of a given type and/or in a given area. (From Concise Dictionary of Biology, 1990) It includes the yield of vegetative mass produced from any given crop. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH]
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Biopterin: A natural product that has been considered as a growth factor for some insects. [NIH]
Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bioterrorism: The use of biological agents in terrorism. This includes the malevolent use of bacteria, viruses, or toxins against people, animals, or plants. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Bladder: The organ that stores urine. [NIH] Blood Bactericidal Activity: Native bactericidal property of blood due to normally occurring antibacterial substances such as beta lysin, leukin, etc. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH]
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Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]
Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiectasis: Persistent abnormal dilatation of the bronchi. [NIH] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchoalveolar Lavage: Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. [NIH] Bronchoalveolar Lavage Fluid: Fluid obtained by washout of the alveolar compartment of the lung. It is used to assess biochemical and inflammatory changes in and effects of therapy on the interstitial lung tissue. [NIH] Bronchoscope: A thin, lighted tube used to examine the inside of the trachea and bronchi, the air passages that lead into the lungs. [NIH] Bronchoscopy: Endoscopic examination, therapy or surgery of the bronchi. [NIH] Brucellosis: Infection caused by bacteria of the genus Brucella mainly involving the reticuloendothelial system. This condition is characterized by fever, weakness, malaise, and weight loss. [NIH] Calcaneus: The largest of the tarsal bones and is situated at the lower and back part of the foot forming the heel. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Gluconate: The calcium salt of gluconic acid. The compound has a variety of uses, including its use as a calcium replenisher in hypocalcemic states. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and
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become pathologic when the environment is favorable and the host resistance is weakened. [NIH]
Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardioselective: Having greater activity on heart tissue than on other tissue. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caseation: A form of degeneration or necrosis in which structures or tissues are changed into a cheesy mass. [NIH] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH]
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Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cecum: The beginning of the large intestine. The cecum is connected to the lower part of the small intestine, called the ileum. [NIH] Cefoxitin: Semisynthetic cephamycin antibiotic resistant to beta-lactamase. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Communication: Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Physiology: Characteristics and physiological processes of cells from cell division to cell death. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon
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differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cerulenin: Antifungal antibiotic isolated from several species, including Acremonium (Cephalosporium), Acrocylindrum, and Helicoceras. It inhibits the biosynthesis of several lipids by interfering with enzyme function and is used as a biochemical tool. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Chaperonin 10: Members of the chaperonin heat-shock protein family. Chaperonin 10 purified from bacteria, plastids, or mitochondria occurs as an oligomer of seven identical subunits arranged in a single ring. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Check-up: A general physical examination. [NIH] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapeutics: Noun plural but singular or plural in constructions : chemotherapy. [EU]
Chemotherapy: Treatment with anticancer drugs. [NIH] Chest wall: The ribs and muscles, bones, and joints that make up the area of the body
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between the neck and the abdomen. [NIH] Child Care: Care of children in the home or institution. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholelithiasis: Presence or formation of gallstones. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary processes: The extensions or projections of the ciliary body that secrete aqueous humor. [NIH] Ciprofloxacin: A carboxyfluoroquinoline antimicrobial agent that is effective against a wide range of microorganisms. It has been successfully and safely used in the treatment of resistant respiratory, skin, bone, joint, gastrointestinal, urinary, and genital infections. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Civil Rights: Legal guarantee protecting the individual from attack on personal liberties, right to fair trial, right to vote, and freedom from discrimination on the basis of race, religion, national origin, age, or gender. [NIH] Clarithromycin: A semisynthetic macrolide antibiotic derived from erythromycin that is
Dictionary 619
active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical resistance: The failure of a cancer to shrink after treatment. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]
Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Coliphages: Viruses whose host is Escherichia coli. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is
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differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Communicable disease: A disease that can be transmitted by contact between persons. [NIH] Competency: The capacity of the bacterium to take up DNA from its surroundings. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the
Dictionary 621
standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concomitant: Accompanying; accessory; joined with another. [EU] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein
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structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contact Tracing: Identification of those persons (or animals) who have had such an association with an infected person, animal, or contaminated environment as to have had the opportunity to acquire the infection. Contact tracing is a generally accepted method for the control of sexually transmitted diseases. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]
Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cord Factors: Toxic glycolipids composed of trehalose dimycolate derivatives. They are produced by Mycobacterium tuberculosis and other species of mycobacterium. They induce cellular dysfunction in animals. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH]
Dictionary 623
Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cost Savings: Reductions in all or any portion of the costs of providing goods or services. Savings may be incurred by the provider or the consumer. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Cryptosporidiosis: Parasitic intestinal infection with severe diarrhea caused by a protozoan, Cryptosporidium. It occurs in both animals and humans. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cycloserine: Antibiotic substance produced by Streptomyces garyphalus. It may be used in the treatment of resistant tuberculosis as part of a multi-drug regimen. It has also been used in urinary tract infections. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom
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of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoplasmic Vesicles: Membrane-limited structures derived from the plasma membrane or various intracellular membranes which function in storage, transport or metabolism. [NIH] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Day Care: Institutional health care of patients during the day. The patients return home at night. [NIH] Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Defensins: Family of antimicrobial peptides that have been identified in humans, animals, and plants. They are thought to play a role in host defenses against infections, inflammation, wound repair, and acquired immunity. Based on the disulfide pairing of their characteristic six cysteine residues, they are divided into alpha-defensins and beta-defensins. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [NIH]
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Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic Errors: Incorrect diagnoses after clinical examination or technical diagnostic procedures. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diagnostic Services: Organized services for the purpose of providing diagnosis to promote and maintain health. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH]
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Diastolic: Of or pertaining to the diastole. [EU] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of Corynebacterium diphtheriae. It is characterized by the presence of a pseudomembrane at the site of infection. Diphtheria toxin, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. [NIH] Diphtheria Toxin: A 60 kD single chain protein elaborated by Corynebacterium diphtheriae that causes the sign and symptoms of diphtheria; it can be broken into two unequal fragments, the smaller (A fragment) inhibits protein synthesis and is the lethal moiety that needs the larger (B fragment) for entry into cells. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Outbreaks: Sudden increase in the incidence of a disease. The concept includes epidemics. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disease Susceptibility: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the individual more than usually susceptible to certain diseases. [NIH] Disease Transmission: The transmission of infectious disease or pathogens. When transmission is within the same species, the mode can be horizontal (disease transmission, horizontal) or vertical (disease transmission, vertical). [NIH] Disease Transmission, Horizontal: The transmission of infectious disease or pathogens from one individual to another in the same generation. [NIH] Disease Transmission, Vertical: The transmission of infectious disease or pathogens from one generation to another. It includes transmission in utero or intrapartum by exposure to blood and secretions, and postpartum exposure via breastfeeding. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dislocation: The displacement of any part, more especially of a bone. Called also luxation. [EU]
Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by
Dictionary 627
the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Disulfiram: A carbamate derivative used as an alcohol deterrent. It is a relatively nontoxic substance when administered alone, but markedly alters the intermediary metabolism of alcohol. When alcohol is ingested after administration of disulfiram, blood acetaldehyde concentrations are increased, followed by flushing, systemic vasodilation, respiratory difficulties, nausea, hypotension, and other symptoms (acetaldehyde syndrome). It acts by inhibiting aldehyde dehydrogenase. [NIH] Diuresis: Increased excretion of urine. [EU] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dormancy: The period when an organism (i. e., a virus or a bacterium) is in the body but not producing any ill effects. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is
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generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysphagia: Difficulty in swallowing. [EU] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding
Dictionary 629
ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emergency Medical Services: Services specifically designed, staffed, and equipped for the emergency care of patients. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empiric: Empirical; depending upon experience or observation alone, without using scientific method or theory. [EU] Empyema: Presence of pus in a hollow organ or body cavity. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU]
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Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enteritis: Inflammation of the intestine, applied chiefly to inflammation of the small intestine; see also enterocolitis. [EU] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized
Dictionary 631
causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epistaxis: Bleeding from the nose. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of
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energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]
External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extraction: The process or act of pulling or drawing out. [EU] Facial: Of or pertaining to the face. [EU] Facial Expression: Observable changes of expression in the face in response to emotional stimuli. [NIH] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] Factor V: Heat- and storage-labile plasma glycoprotein which accelerates the conversion of prothrombin to thrombin in blood coagulation. Factor V accomplishes this by forming a complex with factor Xa, phospholipid, and calcium (prothrombinase complex). Deficiency of factor V leads to Owren's disease. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Farnesyl: Enzyme which adds 15 carbon atoms to the Ras precursor protein. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH]
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Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluconazole: Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in AIDS. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescence Polarization: Measurement of the polarization of fluorescent light from solutions or microscopic specimens. It is used to provide information concerning molecular size, shape, and conformation, molecular anisotropy, electronic energy transfer, molecular interaction, including dye and coenzyme binding, and the antigen-antibody reaction. [NIH]
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Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Flushing: A transient reddening of the face that may be due to fever, certain drugs, exertion, stress, or a disease process. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallium: A rare, metallic element designated by the symbol, Ga, atomic number 31, and atomic weight 69.72. [NIH] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [NIH] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH]
Dictionary 635
Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gels: Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be unstable when, due to temperature or other cause, the solid phase liquifies; the resulting colloid is called a sol. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Fusion: Fusion of structural genes to analyze protein behavior or fusion of regulatory sequences with structural genes to determine mechanisms of regulation. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genitourinary system: The parts of the body that play a role in reproduction, getting rid of waste products in the form of urine, or both. [NIH]
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Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH]
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Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Government Agencies: Administrative units of government responsible for policy making and management of governmental activities in the U.S. and abroad. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]
Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Gram-Positive Rods: A large group of rod-shaped bacteria that retains the crystal violet stain when treated by Gram's method. [NIH] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC
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4.6.1.2. [NIH] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]
Gyrase: An enzyme that causes negative supercoiling of E. coli DNA during replication. [NIH]
Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [NIH] Haemopoietic: Haematopoietic; pertaining to or effecting the formation of blood cells. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Hawaii: A group of islands in Polynesia, in the north central Pacific Ocean, comprising eight major and 114 minor islands, largely volcanic and coral. Its capital is Honolulu. It was first reached by Polynesians about 500 A.D. It was discovered and named the Sandwich Islands in 1778 by Captain Cook. The islands were united under the rule of King Kamehameha 1795-1819 and requested annexation to the United States in 1893 when a provisional government was set up. Hawaii was established as a territory in 1900 and admitted as a state in 1959. The name is from the Polynesian Owhyhii, place of the gods, with reference to the two volcanoes Mauna Kea and Mauna Loa, regarded as the abode of the gods. (From Webster's New Geographical Dictionary, 1988, p493 & Room, Brewer's Dictionary of Names, 1992, p2330 [NIH] Health Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematuria: Presence of blood in the urine. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH]
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Hemiparesis: The weakness or paralysis affecting one side of the body. [NIH] Hemobilia: Hemorrhage in or through the biliary tract, due to trauma, inflammation, cholelithiasis, vascular disease, or neoplasms. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemoptysis: Bronchial hemorrhage manifested with spitting of blood. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heteroduplex Analysis: A method of detecting gene mutation by mixing PCR-amplified mutant and wild-type DNA followed by denaturation and reannealing. The resultant products are resolved by gel electrophoresis, with single base substitutions detectable under optimal electrophoretic conditions and gel formulations. Large base pair mismatches may also be analyzed by using electron microscopy to visualize heteroduplex regions. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous
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chromosomes. [NIH] Hip Prosthesis: Replacement for a hip joint. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeless Persons: Persons who have no permanent residence. The concept excludes nomadic peoples. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]
Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Hospices: Facilities or services which are especially devoted to providing palliative and supportive care to the patient with a terminal illness and to the patient's family. [NIH] Hospitals, Community: Institutions with permanent facilities and organized medical staff which provide the full range of hospital services primarily to a neighborhood area. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridoma: A hybrid cell resulting from the fusion of a specific antibody-producing spleen cell with a myeloma cell. [NIH] Hydrochloric Acid: A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. Gastric acid is the hydrochloric acid component of gastric juice. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1
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isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]
Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrogenation: Specific method of reduction in which hydrogen is added to a substance by the direct use of gaseous hydrogen. [NIH] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hyperreflexia: Exaggeration of reflexes. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypotension: Abnormally low blood pressure. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Ileum: The lower end of the small intestine. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immaturity: The state or quality of being unripe or not fully developed. [EU] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH]
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Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunocompromised Host: A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]
Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction. [NIH]
Immunodominant Epitopes: Subunits of the antigenic determinant that are most easily recognized by the immune system and thus most influence the specificity of the induced antibody. [NIH] Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunomodulator: New type of drugs mainly using biotechnological methods. Treatment of cancer. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of
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psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Induration: 1. The quality of being hard; the process of hardening. 2. An abnormally hard spot or place. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infection Control: Programs of disease surveillance, generally within health care facilities, designed to investigate, prevent, and control the spread of infections and their causative microorganisms. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Ingestion: Taking into the body by mouth [NIH]
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Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] In-line: A sexually-reproducing population derived from a common parentage. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inoculum: The spores or tissues of a pathogen that serve to initiate disease in a plant. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [NIH] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Instillation: . [EU] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are
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distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-10: Factor that is a coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [NIH] Interleukin-12: A heterodimeric cytokine that stimulates the production of interferon gamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper cells. It is an initiator of cell-mediated immunity. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-4: Soluble factor produced by activated T-lymphocytes that causes proliferation and differentiation of B-cells. Interleukin-4 induces the expression of class II major histocompatibility complex and Fc receptors on B-cells. It also acts on T-lymphocytes, mast cell lines, and several other hematopoietic lineage cells including granulocyte, megakaryocyte, and erythroid precursors, as well as macrophages. [NIH] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] International Agencies: International organizations which provide health-related or other cooperative services. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective
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properties and is used topically. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isocitrate Lyase: A key enzyme in the glyoxylate cycle. It catalyzes the conversion of isocitrate to succinate and glyoxylate. EC 4.1.3.1. [NIH] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isoniazid: Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. [NIH] Isonicotinic: A drug used in the treatment of tuberculosis. [NIH] Isoprenoid: Molecule that might anchor G protein to the cell membrane as it is hydrophobic. [NIH]
Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]
Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Joint Capsule: The sac enclosing a joint. It is composed of an outer fibrous articular capsule and an inner synovial membrane. [NIH] Kanamycin: Antibiotic complex produced by Streptomyces kanamyceticus from Japanese soil. Comprises 3 components: kanamycin A, the major component, and kanamycins B and C, the minor components. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Keyhole: A carrier molecule. [NIH]
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Keyhole limpet hemocyanin: KLH. One of a group of drugs called immune modulators, given as a vaccine to help the body respond to cancer. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Transplantation: The transference of a kidney from one human or animal to another. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lacrimal: Pertaining to the tears. [EU] Lacrimal gland: The small almond-shaped structure that produces tears; located just above the outer corner of the eye. [NIH] Laparoscopy: Examination, therapy or surgery of the abdomen's interior by means of a laparoscope. [NIH] Laparotomy: A surgical incision made in the wall of the abdomen. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Laryngeal: Having to do with the larynx. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Laser therapy: The use of an intensely powerful beam of light to kill cancer cells. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lavage: A cleaning of the stomach and colon. Uses a special drink and enemas. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]
Least-Squares Analysis: A principle of estimation in which the estimates of a set of parameters in a statistical model are those quantities minimizing the sum of squared differences between the observed values of a dependent variable and the values predicted by the model. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and
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plants. [NIH] Leishmaniasis: A disease caused by any of a number of species of protozoa in the genus Leishmania. There are four major clinical types of this infection: cutaneous (Old and New World), diffuse cutaneous, mucocutaneous, and visceral leishmaniasis. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Levofloxacin: A substance used to treat bacterial infections. It belongs to the family of drugs called quinolone antibiotics. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]
Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Life Cycle Stages: The continuous sequence of changes undergone by metamorphosing insects and other animals during the post-embryonic development process. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligase Chain Reaction: A DNA amplification technique based upon the ligation of oligonucleotide probes. The probes are designed to exactly match two adjacent sequences of a specific target DNA. The chain reaction is repeated in three steps in the presence of excess probe: (1) heat denaturation of double-stranded DNA, (2) annealing of probes to target DNA, and (3) joining of the probes by thermostable DNA ligase. After the reaction is repeated for 20-30 cycles the production of ligated probe is measured. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Likelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together
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from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lip: Either of the two fleshy, full-blooded margins of the mouth. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipid Peroxides: Peroxides produced in the presence of a free radical by the oxidation of unsaturated fatty acids in the cell in the presence of molecular oxygen. The formation of lipid peroxides results in the destruction of the original lipid leading to the loss of integrity of the membranes. They therefore cause a variety of toxic effects in vivo and their formation is considered a pathological process in biological systems. Their formation can be inhibited by antioxidants, such as vitamin E, structural separation or low oxygen tension. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposarcoma: A rare cancer of the fat cells. [NIH] Liposomes: Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes and membrane proteins. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Local Government: Smallest political subdivisions within a country at which general governmental functions are carried-out. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Logistic Models: Statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. A common application is in epidemiology for estimating an individual's risk (probability of a disease) as a function of a given risk factor. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability,
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requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Luminescence: The property of giving off light without emitting a corresponding degree of heat. It includes the luminescence of inorganic matter or the bioluminescence of human matter, invertebrates and other living organisms. For the luminescence of bacteria, bacterial luminescence is available. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Luxation: The displacement of the particular surface of a bone from its normal joint, without fracture. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphadenitis: Inflammation of the lymph nodes. [NIH] Lymphadenopathy: Disease or swelling of the lymph nodes. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphocytic Choriomeningitis Virus: The type species of arenavirus, part of the LCMLassa complex viruses, producing an inapparent infection in house and laboratory mice. In humans, infection with LCMV can be inapparent, or can present with an influenza-like illness, a benign aseptic meningitis, or a severe meningoencephalomyelitis. The virus can also infect monkeys, dogs, field mice, guinea pigs, and hamsters, the latter an epidemiologically important host. [NIH]
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Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lysosome: A sac-like compartment inside a cell that has enzymes that can break down cellular components that need to be destroyed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrolides: A group of organic compounds that contain a macrocyclic lactone ring linked glycosidically to one or more sugar moieties. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Activation: The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaise: A vague feeling of bodily discomfort. [EU] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH]
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Malate Synthase: An important enzyme in the glyoxylic acid cycle which reversibly catalyzes the synthesis of L-malate from acetyl-CoA and glyoxylate. EC 4.1.3.2. [NIH] Malformation: A morphologic developmental process. [EU]
defect
resulting
from
an
intrinsically
abnormal
Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mannans: Polysaccharides consisting of mannose units. [NIH] Mannosides: Glycosides formed by the reaction of the hydroxyl group on the anomeric carbon atom of mannose with an alcohol to form an acetal. They include both alpha- and beta-mannosides. [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Median survival time: The point in time from either diagnosis or treatment at which half of the patients with a given disease are found to be, or expected to be, still alive. In a clinical trial, median survival time is one way to measure how effective a treatment is. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Mefloquine: A phospholipid-interacting antimalarial drug (antimalarials). It is very effective against Plasmodium falciparum with very few side effects. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological
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color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesothelial: It lines the peritonealla and pleural cavities. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from
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cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metatarsophalangeal Joint: The articulation between a metatarsal bone and a phalanx. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiological: Pertaining to microbiology : the science that deals with microorganisms, including algae, bacteria, fungi, protozoa and viruses. [EU] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]
labeled
with
Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitogen-Activated Protein Kinase Kinases: A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate mitogen-activated protein kinases and are themselves phosphorylated by MAP kinase kinase kinases. JNK kinases (also known as SAPK kinases) are a subfamily. EC 2.7.10.- [NIH]
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Mitogen-Activated Protein Kinases: A superfamily of protein-serine-threonine kinases that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by mitogen-activated protein kinase kinases which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP kinase kinase kinases). Families of these mitogen-activated protein kinases (MAPKs) include extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs) (also known as c-jun terminal kinases (JNKs)), and p38-mitogen-activated protein kinases. EC 2,7,1.- [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modems: Equipment that sends digital information over telephone lines. The term Modem is a short form of the phrase modulator-demodulator. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Monocyte Chemoattractant Protein-1: A chemokine that is a chemoattractant for human monocytes and may also cause cellular activation of specific functions related to host defense. It is produced by leukocytes of both monocyte and lymphocyte lineage and by fibroblasts during tissue injury. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU]
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Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, .): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucocutaneous: Pertaining to or affecting the mucous membrane and the skin. [EU] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]
Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Mummies: Bodies preserved either by the ancient Egyptian technique or due to chance under favorable climatic conditions. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mycobacterial disease: Any disease caused by Mycobacterium other than M. tuberculosis, M. bovis, and M. avium. [NIH] Mycobacteriophages: Viruses whose host is one or more Mycobacterium species. They include both temperate and virulent types. [NIH] Mycobacterium: A genus of gram-positive, aerobic bacteria. Most species are free-living in soil and water, but the major habitat for some is the diseased tissue of warm-blooded hosts. [NIH]
Mycobacterium Infections: Infections with bacteria of the genus Mycobacterium. [NIH] Mycobacterium tuberculosis: A species of gram-positive, aerobic bacteria that produces tuberculosis in man, other primates, dogs, and some animals which have contact with man. Growth tends to be in serpentine, cordlike masses in which the bacilli show a parallel orientation. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH]
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Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] N-acetyl: Analgesic agent. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nebramycin: A complex of antibiotic substances produced by Streptomyces tenebrarius. [NIH]
Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Nelfinavir: A potent HIV protease inhibitor. It is used in combination with other antiviral drugs in the treatment of HIV in both adults and children. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Neopterin: A pteridine derivative present in body fluids; elevated levels result from immune system activation, malignant disease, allograft rejection, and viral infections. (From Stedman, 26th ed) Neopterin also serves as a precursor in the biosynthesis of biopterin. [NIH] Nephrectomy: Surgery to remove a kidney. Radical nephrectomy removes the kidney, the adrenal gland, nearby lymph nodes, and other surrounding tissue. Simple nephrectomy removes only the kidney. Partial nephrectomy removes the tumor but not the entire kidney. [NIH]
Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephropathy: Disease of the kidneys. [EU]
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Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Nevirapine: A potent, non-nucleoside reverse transcriptase inhibitor used in combination with nucleoside analogues for treatment of HIV infection and AIDS. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [NIH] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nocodazole: Nocodazole is an antineoplastic agent which exerts its effect by depolymerizing microtubules. [NIH]
Dictionary 659
Non-nucleoside: A member of a class of compounds, including delavirdine, loviride and nevirapine, that acts to directly combine with and block the action of HIV's reverse transcriptase. [NIH] Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleic Acid Probes: Nucleic acid which complements a specific mRNA or DNA molecule, or fragment thereof; used for hybridization studies in order to identify microorganisms and for genetic studies. [NIH] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one's occupation. [NIH] Odynophagia: A painful condition of the esophagus. [NIH] Ofloxacin: An orally administered broad-spectrum quinolone antibacterial drug active against most gram-negative and gram-positive bacteria. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH]
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Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [NIH] Oligopeptides: Peptides composed of between two and twelve amino acids. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncology: The study of cancer. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Ori region: The point or region (origin) at which DNA replication begins in a bacterium or virus. Plasmids used in rec DNA research always contain an ori region, which gives very efficient initiation of replication. [NIH] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Ototoxic: Having a deleterious effect upon the eighth nerve, or upon the organs of hearing and balance. [EU] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH]
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Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palmitic Acid: A common saturated fatty acid found in fats and waxes including olive oil, palm oil, and body lipids. [NIH] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancytopenia: Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. [NIH] Paradoxical: Occurring at variance with the normal rule. [EU] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Paratuberculosis: An infectious disease caused by Mycobacterium paratuberculosis. Characteristics include chronic debilitation and weight loss. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Paromomycin: An oligosaccharide antibiotic produced by various Streptomyces. [NIH]
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Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Advocacy: Promotion and protection of the rights of patients, frequently through a legal process. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Patient Satisfaction: The degree to which the individual regards the health care service or product or the manner in which it is delivered by the provider as useful, effective, or beneficial. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of Pneumocystis carinii pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Chain Elongation: The process whereby an amino acid is joined through a substituted amide linkage to a chain of peptides. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [NIH] Perceived risk: Estimate or evaluation of risk as observed through personal experience or personal study, and personal evaluation of consequences. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU]
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Pericarditis: Inflammation of the pericardium. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phagosomes: Membrane-bound cytoplasmic vesicles formed by invagination of phagocytized material. They fuse with lysosomes to form phagolysosomes in which the hydrolytic enzymes of the lysosome digest the phagocytized material. [NIH] Phallic: Pertaining to the phallus, or penis. [EU] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions
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between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Phylogeny: The relationships of groups of organisms as reflected by their evolutionary history. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physician Assistants: Persons academically trained, licensed, or credentialed to provide medical care under the supervision of a physician. The concept does not include nurses, but does include orthopedic assistants, surgeon's assistants, and assistants to other specialists. [NIH]
Physicochemical: Pertaining to physics and chemistry. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]
Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Plague: An acute infectious disease caused by Yersinia pestis that affects humans, wild rodents, and their ectoparasites. This condition persists due to its firm entrenchment in sylvatic rodent-flea ecosystems throughout the world. Bubonic plague is the most common form. [NIH]
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Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]
Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pneumoconiosis: Condition characterized by permanent deposition of substantial amounts of particulate matter in the lungs, usually of occupational or environmental origin, and by the tissue reaction to its presence. [NIH] Pneumonectomy: An operation to remove an entire lung. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Pneumothorax: Accumulation of air or gas in the space between the lung and chest wall, resulting in partial or complete collapse of the lung. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation
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of, or exposure to a deleterious agent. [NIH] Policy Making: The decision process by which individuals, groups or institutions establish policies pertaining to plans, programs or procedures. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyneuritis: Inflammation of several peripheral nerves at the same time. [NIH] Polyproteins: Proteins which are synthesized as a single polymer and then cleaved into several distinct proteins. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Portal Hypertension: High blood pressure in the portal vein. This vein carries blood into the liver. Portal hypertension is caused by a blood clot. This is a common complication of cirrhosis. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH]
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Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Prejudice: A preconceived judgment made without adequate evidence and not easily alterable by presentation of contrary evidence. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Preoperative: Preceding an operation. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Private Sector: That distinct portion of the institutional, industrial, or economic structure of a country that is controlled or owned by non-governmental, private interests. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Problem Solving: A learning situation involving more than one alternative from which a selection is made in order to attain a specific goal. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Product Packaging: Form in which product is processed or wrapped and labeled. (From Popline Thesaurus, 1991) Product labeling is also available. [NIH]
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Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Program Development: The process of formulating, improving, and expanding educational, managerial, or service-oriented work plans (excluding computer program development). [NIH]
Program Evaluation: Studies designed to assess the efficacy of programs. They may include the evaluation of cost-effectiveness, the extent to which objectives are met, or impact. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol is used in the treatment or prevention of many disorders including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU]
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Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Protein Splicing: Excision of in-frame internal protein sequences (inteins) of a precursor protein, coupled with ligation of the flanking sequences (exteins). Protein splicing is an autocatalytic reaction and results in the production of two proteins from a single primary translation product: the intein and the mature protein. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. EC 2.7.10. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Proteome: The protein complement of an organism coded for by its genome. [NIH] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH]
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Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Health Practice: The activities and endeavors of the public health services in a community on any level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Public Sector: The area of a nation's economy that is tax-supported and under government control. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Sarcoidosis: A disease of unknown etiology characterized by tuberclelike, granulomatous nodules which may affect the skin, the lungs, the lymph nodes, the bones of the distal extremities, the conjunctiva, the lacrimal gland, the retina and the uveal tract. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH]
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Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pyelonephritis: Inflammation of the kidney and its pelvis, beginning in the interstitium and rapidly extending to involve the tubules, glomeruli, and blood vessels; due to bacterial infection. [EU] Pyrazinamide: A pyrazine that is used therapeutically as an antitubercular agent. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyridoxal Phosphate: 3-Hydroxy-2-methyl-5-((phosphonooxy)methyl)-4pyridinecarboxaldehyde. An enzyme co-factor vitamin. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quinolones: Quinolines which are substituted in any position by one or more oxo groups. These compounds can have any degree of hydrogenation, any substituents, and fused ring systems. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reagent: A substance employed to produce a chemical reaction so as to detect, measure,
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produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regional lymph node: In oncology, a lymph node that drains lymph from the region around a tumor. [NIH] Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]
Regulon: In eukaryotes, a genetic unit consisting of a noncontiguous group of genes under the control of a single regulator gene. In bacteria, regulons are global regulatory systems involved in the interplay of pleiotropic regulatory domains. These regulatory systems consist of several operons. [NIH] Reinfection: A second infection by the same pathogenic agent, or a second infection of an organ such as the kidney by a different pathogenic agent. [EU]
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Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]
Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Replication Origin: The point or region (origin) at which DNA replication begins in a bacterium or virus. Plasmids used in rec DNA research always contain an ori region, which gives very efficient initiation of replication. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Resolving: The ability of the eye or of a lens to make small objects that are close together, separately visible; thus revealing the structure of an object. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH]
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Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [NIH] Retreatment: The therapy of the same disease in a patient, with the same agent or procedure repeated after initial treatment, or with an additional or alternate measure or follow-up. It does not include therapy which requires more than one administration of a therapeutic agent or regimen. Retreatment is often used with reference to a different modality when the original one was inadequate, harmful, or unsuccessful. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Reverse Transcriptase Inhibitors: Inhibitors of reverse transcriptase (RNA-directed DNA polymerase), an enzyme that synthesizes DNA on an RNA template. [NIH] Reverse Transcriptase Polymerase Chain Reaction: A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhamnose: A methylpentose whose L- isomer is found naturally in many plant glycosides and some gram-negative bacterial lipopolysaccharides. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rifabutin: A broad-spectrum antibiotic that is being used as prophylaxis against disseminated Mycobacterium avium complex infection in HIV-positive patients. [NIH] Rifamycins: A group of antibiotics characterized by a chromophoric naphthohydroquinone group spanned by an aliphatic bridge not previously found in other known antibiotics. They have been isolated from fermentation broths of Streptomyces mediterranei. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] Ristocetin: An antibiotic mixture of two components, A and B, obtained from Nocardia lurida (or the same substance produced by any other means). It is no longer used clinically because of its toxicity. It causes platelet agglutination and blood coagulation and is used to
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assay those functions in vitro. [NIH] Ritonavir: An HIV protease inhibitor that works by interfering with the reproductive cycle of HIV. [NIH] Rod: A reception for vision, located in the retina. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Salmonellosis: Infection by salmonellae. [NIH] Sanatorium: This category applies to all those institutions partially or wholly devoted to the diagnosis and treatment of tuberculosis. [NIH] Sanitation: The development and establishment of environmental conditions favorable to the health of the public. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Saprophyte: A saprophytic (= whose nutrition involves uptake of dissolved organic material from decaying plant or animal matter) organism. [EU] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH]
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Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Sequela: Any lesion or affection following or caused by an attack of disease. [EU] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the
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resulting sequence information. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serial Passage: Inoculation of a series of animals or in vitro tissue with an infectious bacterium or virus, as in virulence studies and the development of vaccines. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Seroconversion: The change of a serologic test from negative to positive, indicating the development of antibodies in response to infection or immunization. [EU] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serology: The study of serum, especially of antigen-antibody reactions in vitro. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Sigma Factor: A protein which is a subunit of RNA polymerase. It effects initiation of specific RNA chains from DNA. [NIH] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of
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silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Silicosis: A type of pneumoconiosis caused by inhalation of particles of silica, quartz, ganister or slate. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin test: A test for an immune response to a compound by placing it on or under the skin. [NIH]
Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Social Behavior: Any behavior caused by or affecting another individual, usually of the same species. [NIH] Social Class: A stratum of people with similar position and prestige; includes social stratification. Social class is measured by criteria such as education, occupation, and income. [NIH]
Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Sciences: Disciplines concerned with the interrelationships of individuals in a social environment including social organizations and institutions. Includes Sociology and Anthropology. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Socioeconomic Factors: Social and economic factors that characterize the individual or group within the social structure. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of
Dictionary 679
dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Soybean Oil: Oil from soybean or soybean plant. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrometer: An apparatus for determining spectra; measures quantities such as wavelengths and relative amplitudes of components. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spirochete: Lyme disease. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Spondylitis: Inflammation of the vertebrae. [EU] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Spores: The reproductive elements of lower organisms, such as protozoa, fungi, and cryptogamic plants. [NIH] Spotting: A slight discharge of blood via the vagina, especially as a side-effect of oral contraceptives. [EU] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]
Standardize: To compare with or conform to a standard; to establish standards. [EU] Steady state: Dynamic equilibrium. [EU] Sterile: Unable to produce children. [NIH] Steroid:
A
group
name
for
lipids
that
contain
a
hydrogenated
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cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Streptomycin: O-2-Deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5- deoxy-3-Cformyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-D-streptamine. Antibiotic substance produced by the soil actinomycete Streptomyces griseus. It acts by inhibiting the initiation and elongation processes during protein synthesis. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stringency: Experimental conditions (e. g. temperature, salt concentration) used during the hybridization of nucleic acids. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
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Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Subtalar Joint: Formed by the articulation of the talus with the calcaneus. [NIH] Sulfates: Inorganic salts of sulfuric acid. [NIH] Sulfotransferases: Enzymes which transfer sulfate groups to various acceptor molecules. They are involved in posttranslational sulfation of proteins and sulfate conjugation of exogenous chemicals and bile acids. EC 2.8.2. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]
Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] Synovial Fluid: The clear, viscous fluid secreted by the synovial membrane. It contains mucin, albumin, fat, and mineral salts and serves to lubricate joints. [NIH] Synovial Membrane: The inner membrane of a joint capsule surrounding a freely movable
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joint. It is loosely attached to the external fibrous capsule and secretes synovial fluid. [NIH] Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]
Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Talus: The second largest of the tarsal bones and occupies the middle and upper part of the tarsus. [NIH] Tarsal Bones: The seven bones which form the tarsus - namely, calcaneus, talus, cuboid, navicular, and first, second and third cuneiforms. The tarsus is a skeletal part of the foot. [NIH]
Tarsus: The region of the articulation between the foot and the leg. [NIH] Technology Transfer: Spread and adoption of inventions and techniques from one geographic area to another, from one discipline to another, or from one sector of the economy to another. For example, improvements in medical equipment may be transferred from industrial countries to developing countries, advances arising from aerospace engineering may be applied to equipment for persons with disabilities, and innovations in science arising from government research are made available to private enterprise. [NIH] Teichoic Acids: Bacterial polysaccharides that are rich in phosphodiester linkages. They are the major components of the cell walls and membranes of many bacteria. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetani: Causal agent of tetanus. [NIH] Tetanic: Having the characteristics of, or relating to tetanus. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by Clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss,
Dictionary 683
movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalidomide: A pharmaceutical agent originally introduced as a non-barbiturate hypnotic, but withdrawn from the market because of its known tetratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor alpha from monocytes, and modulates other cytokine action. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thioamides: Organic compounds containing the radical -CSNH2. [NIH] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thrush: A disease due to infection with species of fungi of the genus Candida. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]
Thymosin: A family of heat-stable, polypeptide hormones secreted by the thymus gland. Their biological activities include lymphocytopoiesis, restoration of immunological competence and enhancement of expression of T-cell characteristics and function. They have therapeutic potential in patients having primary or secondary immunodeficiency diseases, cancer or diseases related to aging. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH]
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Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tobramycin: An aminoglycoside, broad-spectrum antibiotic produced by Streptomyces tenebrarius. It is effective against gram-negative bacteria, especially the Pseudomonas species. It is a 10% component of the antibiotic complex, nebramycin, produced by the same species. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tome: A zone produced by a number of irregular spaces contained in the outermost layer of denture of the root of a tooth. [NIH] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Toxoid: The material resulting from the treatment of toxin in such a way that the toxic properties are inactivated whilst the antigenic potency remains intact. [NIH] Toxoplasmosis: The acquired form of infection by Toxoplasma gondii in animals and man. [NIH]
Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH]
Dictionary 685
Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transcutaneous: Transdermal. [EU] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]
Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]
Triad: Trivalent. [NIH]
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Trypanosomiasis: Infection with protozoa of the genus Trypanosoma. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tubercular: Of, pertaining to, or resembling tubercles or nodules. [EU] Tuberculin: A sterile liquid containing the growth products of, or specific substances extracted from, the tubercle bacillus; used in various forms in the diagnosis of tuberculosis. [NIH]
Tuberculin Test: One of several skin tests to determine past or present tuberculosis infection. A purified protein derivative of the tubercle bacilli, called tuberculin, is introduced into the skin by scratch, puncture, or interdermal injection. [NIH] Tuberculoma: A tumor-like mass resulting from the enlargement of a tuberculous lesion. [NIH]
Tuberculostatic: Inhibiting the growth of Mycobacterium tuberculosis. [EU] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Typhimurium: Microbial assay which measures his-his+ reversion by chemicals which cause base substitutions or frameshift mutations in the genome of this organism. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Universal Precautions: Prudent standard preventive measures to be taken by professional and other health personnel in contact with persons afflicted with a communicable disease, to avoid contracting the disease by contagion or infection. Precautions are especially applicable in the diagnosis and care of AIDS patients. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Urease: An enzyme that catalyzes the conversion of urea and water to carbon dioxide and ammonia. EC 3.5.1.5. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness,
Dictionary 687
and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]
Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urography: Radiography of any part of the urinary tract. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Uveal tract: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vacuole: A fluid-filled cavity within the cytoplasm of a cell. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Vancomycin: Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. [NIH] Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or
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unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] Venous: Of or pertaining to the veins. [EU] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH] Ventricles: Fluid-filled cavities in the heart or brain. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viral Proteins: Proteins found in any species of virus. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used
Dictionary 689
together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] War: Hostile conflict between organized groups of people. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] World Health: The concept pertaining to the health status of inhabitants of the world. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Xylulose: A 5-carbon keto sugar. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
691
INDEX 3 3-dimensional, 372, 603, 669 A Abdomen, 603, 613, 618, 631, 645, 647, 649, 661, 662, 663, 679, 680, 683 Abdominal, 9, 177, 180, 181, 185, 285, 295, 603, 625, 661, 663 Abdominal Pain, 603, 663 Abscess, 7, 189, 215, 267, 603 Acatalasia, 603, 615 Acceptor, 603, 649, 661, 681, 685 Acetylcholine, 603, 658 Acetyltransferases, 603 Acidity, 603, 663 Acyl, 19, 63, 70, 444, 603 Acyl Carrier Protein, 70, 603 Adaptability, 603, 616 Adaptation, 41, 76, 82, 86, 99, 104, 343, 497, 603, 656 Adduct, 70, 604 Adenine, 412, 604, 611, 670 Adenosine, 241, 290, 604, 664, 683 Adenosine Deaminase, 241, 290, 604 Adenylate Cyclase, 50, 604 Adjustment, 563, 603, 604 Adjuvant, 15, 47, 57, 67, 77, 103, 329, 380, 512, 604, 635 Adjuvant Therapy, 512, 604 Adrenal Cortex, 604, 623, 668 Adrenal Glands, 604, 607 Adrenergic, 604, 610, 627, 631, 668 Adverse Effect, 604, 628, 677 Aerobic, 382, 604, 654, 656 Afferent, 604, 632 Affinity, 39, 405, 451, 604, 649, 678 Agar, 35, 137, 189, 258, 380, 381, 434, 605, 623, 642 Agarose, 605, 642 Air Sacs, 605, 606 Airways, 400, 605 Alanine, 25, 121, 463, 605 Albumin, 381, 605, 665, 681 Aldehyde Dehydrogenase, 605, 627 Algorithms, 605, 613 Alimentary, 295, 605 Alkaline, 334, 497, 605, 606, 614 Alkaloid, 328, 605, 683 Alkylating Agents, 605, 686
Alleles, 21, 41, 52, 109, 186, 260, 605, 639 Allergen, 605, 625, 676 Allogeneic, 35, 458, 605, 637 Allograft, 605, 657 Alpha-1, 122, 605 Alpha-Defensins, 606, 624 Alternative medicine, 513, 606 Alveoli, 400, 428, 606, 688 Ambroxol, 329, 606 Ambulatory Care, 606 Amikacin, 101, 322, 568, 606 Amino acid, 19, 47, 71, 88, 105, 107, 112, 386, 400, 401, 411, 414, 415, 428, 433, 439, 441, 605, 606, 608, 609, 619, 621, 622, 626, 631, 635, 636, 640, 648, 651, 654, 660, 662, 664, 669, 674, 677, 680, 681, 683, 684, 685, 686 Amino Acid Motifs, 606, 622 Amino Acid Sequence, 107, 135, 386, 411, 414, 428, 439, 441, 606, 608, 621, 635 Ammonia, 604, 606, 636, 686 Ammonium Sulfate, 220, 606 Ampulla, 606, 630 Amyloid, 592, 606 Amyloidosis, 284, 345, 591, 592, 606 Anaemia, 333, 607 Anaerobic, 435, 607 Anaesthesia, 607, 643 Anal, 607, 631, 633 Analog, 10, 70, 607 Analogous, 70, 117, 607, 627, 685 Anaphylatoxins, 607, 620 Anatomical, 607, 618, 643, 676 Androgens, 604, 607, 623 Anemia, 552, 607, 651, 656 Anergic, 52, 54, 77, 367, 549, 607 Anergy, 52, 54, 67, 134, 135, 184, 227, 532, 541, 549, 581, 607 Angiogenesis, 607, 652 Anions, 605, 607, 646, 681 Anisotropy, 607, 633 Ankle, 247, 343, 608 Annealing, 608, 648, 666 Anorexia, 37, 608 Antagonism, 608, 683 Antibacterial, 63, 85, 104, 116, 320, 388, 406, 412, 588, 608, 613, 646, 659, 679, 687 Antibody therapy, 449, 608
692 Tuberculosis
Anticoagulant, 608, 669 Antifungal, 608, 617, 633 Antigen-Antibody Complex, 608, 620 Antigen-presenting cell, 608, 625 Anti-infective, 122, 608, 641, 645 Anti-inflammatory, 258, 608, 623, 636, 661, 667 Anti-Inflammatory Agents, 608, 623 Antimetabolite, 608, 654 Antineoplastic, 605, 608, 623, 634, 654, 658 Antioxidant, 101, 609, 661 Antiseptic, 382, 432, 609 Antitubercular Agents, 42, 112, 347, 609 Antiviral, 59, 609, 634, 644, 657 Anus, 607, 609, 613, 620 Apolipoproteins, 609, 649 Apoptosis, 67, 73, 98, 105, 109, 163, 185, 262, 276, 296, 609 Approximate, 66, 609 Aqueous, 192, 263, 609, 611, 618, 624, 629, 641, 648 Aqueous humor, 192, 609, 618 Arachidonic Acid, 609, 668 Archaea, 609, 654 Arenavirus, 609, 650 Arginine, 105, 329, 415, 512, 607, 609, 658 Aromatic, 609, 664 Arterial, 207, 610, 618, 641, 669, 682 Arterial embolization, 207, 610 Arteries, 610, 613, 622, 650, 654 Arteriovenous, 181, 610 Artery, 610, 613, 623, 629, 662, 670, 675 Articulation, 610, 654, 681, 682 Aseptic, 185, 610, 650, 660 Aspiration, 7, 185, 187, 225, 310, 610 Asthenia, 607, 610 Ataxia, 552, 610, 683 Atenolol, 286, 610 Atrophy, 552, 610 Attenuation, 51, 82, 136, 202, 251, 610 Atypical, 30, 186, 187, 291, 293, 430, 482, 610 Audiovisual Aids, 591, 610 Autoantibodies, 274, 610 Autoantigens, 610 Autoimmune disease, 380, 459, 610 Autolysis, 25, 610 Autopsy, 187, 610 Avian, 266, 610 Azithromycin, 370, 610 B Back Pain, 476, 611
Bacterial Infections, 30, 435, 450, 611, 648 Bacterial Physiology, 105, 121, 604, 611 Bacterial Proteins, 47, 387, 440, 611 Bactericidal, 29, 120, 121, 137, 145, 155, 168, 187, 322, 369, 373, 611, 613, 631 Bacteriophage, 147, 148, 217, 611, 685, 688 Bacteriostatic, 71, 611, 631 Barbiturate, 611, 683 Basal Ganglia, 610, 611 Basal Ganglia Diseases, 610, 611 Base Pair Mismatch, 611, 639 Basement Membrane, 611, 632 Basophils, 611, 637, 648 Benign, 611, 650, 657, 671 Beta-Defensins, 611, 624 Beta-pleated, 606, 611 Beta-Thromboglobulin, 612, 645 Bilateral, 189, 248, 255, 612 Bile, 390, 432, 612, 634, 640, 646, 649, 680, 681 Bile Acids, 612, 680, 681 Bile Acids and Salts, 612 Bile duct, 432, 612 Bile Pigments, 612, 646 Biliary, 612, 639 Biliary Tract, 612, 639 Bilirubin, 605, 612, 641 Binding Sites, 123, 612 Bioassay, 39, 612 Bioavailability, 71, 612 Biological response modifier, 612, 644 Biological therapy, 65, 612, 637 Bioluminescence, 612, 650 Biomass, 86, 612 Biopsy, 8, 176, 196, 206, 579, 602, 612, 662 Biopsy specimen, 176, 206, 612 Biopterin, 613, 657 Biotechnology, 37, 63, 71, 95, 107, 133, 176, 210, 289, 496, 513, 523, 551, 552, 553, 613 Bioterrorism, 46, 613 Biotin, 381, 613, 660 Bladder, 8, 188, 613, 621, 669, 687 Blood Bactericidal Activity, 313, 613 Blood Coagulation, 613, 614, 632, 674, 683 Blood Glucose, 613, 639, 644 Blood Platelets, 613, 683 Blood pressure, 613, 615, 641, 655, 666, 678 Blood vessel, 607, 613, 615, 617, 618, 630, 636, 646, 649, 650, 664, 671, 678, 680, 682, 683, 687 Blot, 11, 27, 39, 108, 168, 179, 395, 613, 660 Body Fluids, 613, 628, 657, 678
Index 693
Bone Marrow, 76, 83, 220, 592, 613, 635, 642, 650, 656, 657, 680 Bone scan, 613, 675 Bowel, 190, 607, 613, 626, 630, 645, 647, 663, 680 Bowel Movement, 613, 626, 680 Brachytherapy, 613, 645, 646, 671, 689 Bradykinin, 614, 658, 665 Branch, 471, 509, 525, 585, 599, 614, 624, 638, 650, 662, 670, 679, 683 Breakdown, 14, 614, 626, 634 Breeding, 402, 614 Broad-spectrum, 606, 614, 659, 674, 684 Bronchi, 614, 631, 683, 684 Bronchial, 16, 37, 205, 399, 614, 639, 640, 683 Bronchiectasis, 114, 614 Bronchioles, 606, 614 Bronchiolitis, 24, 157, 614 Bronchoalveolar Lavage, 27, 39, 105, 131, 250, 614 Bronchoalveolar Lavage Fluid, 27, 250, 614 Bronchoscope, 16, 614 Bronchoscopy, 241, 291, 614 Brucellosis, 241, 334, 353, 401, 402, 458, 485, 489, 614 C Calcaneus, 614, 681, 682 Calcium, 403, 614, 620, 632, 641, 652, 669, 677 Calcium Gluconate, 403, 614 Candidiasis, 546, 614, 633 Candidosis, 614 Capsules, 87, 615, 635 Carbohydrate, 96, 119, 358, 383, 615, 623, 636, 637, 666, 676 Carbon Dioxide, 615, 624, 633, 635, 673, 686 Carcinogen, 604, 615 Carcinogenic, 605, 615, 644, 668, 680 Carcinoma, 215, 248, 615 Cardiac, 615, 629, 631, 657, 673, 680 Cardioselective, 610, 615, 668 Cardiovascular, 77, 588, 615 Cardiovascular disease, 588, 615 Carotene, 319, 615 Case series, 316, 615, 619 Caseation, 403, 615 Case-Control Studies, 53, 161, 615, 631 Catabolism, 42, 615, 686
Catalase, 19, 42, 70, 75, 381, 388, 406, 413, 422, 448, 603, 615 Cations, 615, 646 Caudal, 616, 666 Causal, 266, 616, 631, 676, 682 Cecum, 284, 616, 647 Cefoxitin, 101, 616 Cell Communication, 95, 616 Cell Count, 29, 252, 369, 371, 376, 616 Cell Death, 609, 616, 636 Cell Differentiation, 616, 677 Cell Division, 25, 552, 611, 616, 624, 637, 652, 655, 665, 668, 676 Cell membrane, 18, 24, 616, 625, 646, 664 Cell Physiology, 119, 616 Cell proliferation, 64, 444, 616, 677 Cell Respiration, 616, 654, 673 Cell Size, 616, 633 Cell Survival, 63, 616, 637 Cellobiose, 616 Cellulose, 396, 616, 634, 665 Central Nervous System, 211, 330, 603, 605, 616, 628, 636, 662, 683 Centrifugation, 40, 616 Cerebellar, 610, 617, 672 Cerebral, 185, 191, 306, 399, 610, 611, 617, 631, 651 Cerebral Cortex, 610, 617, 631 Cerebrospinal, 139, 203, 617, 677 Cerebrospinal fluid, 203, 617, 677 Cerebrovascular, 611, 615, 617, 683 Cerebrum, 617, 686 Cerulenin, 11, 617 Cervical, 184, 191, 262, 617 Cervix, 617 Chaperonin 10, 260, 617 Character, 413, 422, 617, 624 Check-up, 569, 617 Chemical Warfare, 617, 624 Chemical Warfare Agents, 617, 624 Chemokines, 23, 38, 44, 58, 92, 110, 113, 125, 253, 617 Chemotactic Factors, 617, 620 Chemotherapeutic agent, 55, 90, 113, 115, 617 Chemotherapeutics, 42, 617 Chest wall, 292, 617, 665 Child Care, 507, 618 Chin, 174, 227, 405, 451, 618, 653 Chlorophyll, 618, 634 Cholelithiasis, 618, 639 Cholera, 485, 618, 677
694 Tuberculosis
Cholesterol, 453, 612, 618, 622, 649, 650, 653, 675, 680 Cholesterol Esters, 618, 649 Chromatin, 54, 609, 618 Chromosomal, 28, 39, 122, 388, 413, 421, 422, 425, 461, 606, 618, 665, 675 Chromosome, 53, 81, 82, 225, 427, 618, 621, 638, 648, 675, 676 Chronic Disease, 16, 37, 59, 130, 506, 618 Chronic renal, 618, 666 Chylomicrons, 618, 649 Ciliary, 609, 618, 656, 687 Ciliary processes, 609, 618 Ciprofloxacin, 45, 147, 243, 568, 618 Cirrhosis, 214, 618, 666 CIS, 29, 618 Civil Rights, 5, 618 Clarithromycin, 136, 138, 171, 568, 618 Clear cell carcinoma, 619, 625 Cleave, 23, 619 Clinical Medicine, 97, 107, 237, 619, 667 Clinical resistance, 85, 619 Clinical study, 322, 497, 619, 622 Clone, 81, 85, 120, 256, 619 Cloning, 27, 29, 53, 65, 80, 90, 96, 111, 169, 337, 613, 619, 644, 648 Coagulation, 263, 613, 619, 665, 683 Codon, 172, 388, 619, 635 Coenzyme, 63, 603, 619, 633 Cofactor, 112, 619, 658, 669, 683 Cohort Studies, 619, 631 Coliphages, 611, 619 Collagen, 606, 611, 619, 632, 633, 635, 652, 665 Collapse, 176, 497, 614, 620, 665 Colloidal, 101, 395, 396, 605, 620, 629 Colon, 263, 552, 620, 647 Colonoscopy, 181, 620 Combination chemotherapy, 7, 225, 620 Combinatorial, 30, 70, 122, 139, 620 Communicable disease, 5, 620, 686 Competency, 128, 620 Complement, 51, 73, 74, 86, 93, 107, 113, 157, 336, 607, 620, 635, 651, 665, 669, 676 Complement Activation, 157, 336, 607, 620 Complementary and alternative medicine, 327, 350, 620 Complementary medicine, 327, 620 Complementation, 71, 76, 621 Computational Biology, 109, 523, 551, 621 Computed tomography, 9, 284, 298, 329, 343, 372, 621, 675
Computerized tomography, 237, 621 Concomitant, 67, 227, 248, 319, 363, 621 Congestion, 621, 631 Conjugated, 112, 145, 445, 459, 612, 621, 624 Conjugation, 28, 445, 621, 681 Conjunctiva, 621, 643, 670 Connective Tissue, 613, 619, 621, 625, 633, 635, 650, 674, 682 Consciousness, 621, 624, 627, 670, 673 Consensus Sequence, 388, 606, 621, 622 Conserved Sequence, 606, 621, 622 Constipation, 622, 663 Constitutional, 5, 622 Constriction, 622, 646, 675 Consultation, 72, 102, 530, 622 Consumption, 14, 354, 486, 622, 625, 659, 673 Contact Tracing, 32, 91, 477, 622 Contamination, 147, 150, 167, 179, 216, 248, 573, 579, 581, 622, 639 Continuum, 102, 545, 622 Contraindications, ii, 538, 622 Contralateral, 37, 285, 622, 672 Control group, 13, 622, 667 Controlled clinical trial, 13, 622 Controlled study, 327, 622 Coordination, 19, 97, 129, 591, 622 Cord Factors, 22, 622 Cornea, 609, 622, 676, 687 Coronary, 615, 622, 623, 654 Coronary heart disease, 615, 622 Coronary Thrombosis, 623, 654 Corpus, 623, 668, 688 Corticosteroid, 192, 623, 667 Cortisol, 605, 623 Cortisone, 623, 667 Cost Savings, 371, 623 Cranial, 623, 632, 663 Crossing-over, 623, 672 Cross-Sectional Studies, 623, 631 Cryptosporidiosis, 610, 623 Crystallization, 32, 198, 623 Culture Media, 605, 623 Cultured cells, 39, 623 Curative, 623, 658, 683 Cutaneous, 182, 189, 240, 306, 414, 614, 623, 648, 650, 687 Cyclic, 50, 117, 604, 616, 623, 637, 658, 668, 683 Cycloserine, 101, 348, 516, 568, 623 Cytochrome, 106, 167, 453, 623
Index 695
Cytogenetics, 624, 675 Cytoplasm, 130, 609, 611, 616, 624, 630, 674, 687 Cytoplasmic Vesicles, 624, 663 Cytosine, 412, 611, 624, 671 Cytotoxic, 21, 24, 29, 41, 48, 57, 64, 95, 131, 417, 457, 624, 671, 677 Cytotoxicity, 24, 57, 624 D Data Collection, 468, 474, 477, 529, 624, 634 Day Care, 507, 624 Decontamination, 399, 544, 624 Defense Mechanisms, 15, 624 Defensins, 16, 606, 611, 624 Degenerative, 498, 624, 639 Deletion, 71, 95, 105, 107, 113, 141, 150, 166, 202, 224, 246, 404, 450, 609, 624 Dementia, 603, 624 Demethylation, 453, 624 Denaturation, 625, 639, 648, 666 Dendrites, 625 Dendritic, 20, 35, 64, 68, 129, 178, 200, 202, 209, 235, 237, 261, 355, 358, 444, 625, 652 Dendritic cell, 20, 35, 64, 68, 129, 178, 200, 202, 209, 235, 237, 261, 444, 625 Density, 49, 83, 114, 617, 625, 633, 649, 660, 666 Depolarization, 625, 677 Dermis, 625, 685 DES, 97, 282, 321, 386, 439, 607, 625 Desensitization, 270, 625 Detoxification, 70, 101, 264, 625 Deuterium, 625, 641 Developed Countries, 7, 133, 179, 404, 428, 450, 625 Diabetes Mellitus, 209, 277, 497, 625, 636, 639, 662 Diagnostic Errors, 579, 581, 625 Diagnostic procedure, 379, 508, 513, 625 Diagnostic Services, 548, 625 Dialyzer, 625, 639 Diaphragm, 625, 665 Diarrhea, 106, 623, 625 Diastolic, 626, 641 Digestion, 605, 612, 613, 626, 645, 649, 680 Digestive system, 378, 626, 656 Dihydrotestosterone, 626, 672 Dilatation, 614, 626, 667, 687 Dimethyl, 453, 626 Diphtheria, 30, 74, 626 Diphtheria Toxin, 30, 626
Diploid, 621, 626, 665 Discrimination, 5, 527, 546, 618, 626 Disease Outbreaks, 394, 626 Disease Progression, 67, 163, 239, 626, 688 Disease Susceptibility, 105, 626 Disease Transmission, 127, 573, 626 Disease Transmission, Horizontal, 626 Disease Transmission, Vertical, 626 Disinfectant, 626, 631 Dislocation, 233, 626 Dissection, 98, 207, 626 Dissociation, 260, 604, 626, 646 Dissociative Disorders, 627 Distal, 99, 627, 670 Disulfiram, 248, 319, 627 Diuresis, 627, 683 Domesticated, 328, 627, 638 Dominance, 286, 389, 627 Dopamine, 355, 627, 658, 664 Dormancy, 86, 627 Dorsal, 288, 627, 666 Double-blind, 13, 327, 368, 627 Drive, ii, vi, 4, 92, 112, 131, 315, 461, 499, 571, 627 Drug Delivery Systems, 296, 627 Drug Design, 80, 121, 487, 517, 518, 627 Drug Interactions, 210, 517, 566, 568, 628 Drug Tolerance, 145, 628, 684 Drug Toxicity, 106, 361, 628 Duct, 606, 628, 632, 675 Duodenum, 612, 628, 630, 680 Dura mater, 628, 653, 661 Dyes, 112, 606, 611, 628, 634, 681 Dysphagia, 267, 628 Dysplasia, 552, 628 Dyspnea, 37, 628 Dystrophy, 552, 628 E Edema, 431, 628, 647 Effector, 15, 21, 27, 29, 47, 49, 57, 62, 68, 90, 116, 603, 620, 628 Effector cell, 15, 27, 57, 62, 628 Efferent, 628, 632 Elastic, 628, 681 Elective, 169, 289, 628 Electrocardiogram, 497, 628 Electrocoagulation, 619, 628 Electrolyte, 623, 629, 654, 678 Electrophoresis, 50, 174, 380, 397, 629, 639, 642 Emaciation, 603, 629 Emboli, 629
696 Tuberculosis
Embolization, 629 Embryo, 62, 616, 629, 643 Emergency Medical Services, 573, 629 Emollient, 629, 636, 659 Emphysema, 591, 629 Empiric, 208, 212, 629 Empyema, 181, 629 Emulsion, 629, 633 Encapsulated, 101, 146, 629 Encephalitis, 629 Encephalomyelitis, 380, 629 Endemic, 7, 49, 56, 92, 104, 204, 302, 402, 404, 411, 450, 618, 629, 651, 679 Endocarditis, 187, 614, 629 Endocardium, 629, 630 Endogenous, 14, 17, 23, 116, 221, 388, 406, 610, 627, 630, 685 Endopeptidases, 630, 662, 669 Endoscope, 630 Endoscopic, 206, 213, 614, 620, 630 Endoscopy, 190, 213, 215, 248, 273, 630 Endothelial cell, 630, 645, 683 Endothelium, 630, 658 Endothelium-derived, 630, 658 Endotoxic, 630, 649 Endotoxin, 630, 686 End-stage renal, 8, 248, 618, 630, 666 Enteritis, 221, 630 Enterocolitis, 630 Environmental Exposure, 630, 660 Environmental Health, 522, 524, 630 Enzymatic, 25, 70, 406, 433, 606, 614, 615, 620, 630, 640, 653, 666 Eosinophil, 235, 630 Eosinophilic, 630 Epidemic, 5, 10, 16, 25, 31, 41, 61, 62, 80, 96, 100, 111, 134, 158, 208, 364, 388, 394, 404, 405, 406, 407, 413, 420, 421, 422, 423, 428, 429, 448, 450, 451, 454, 468, 475, 481, 483, 486, 489, 490, 491, 493, 496, 505, 506, 507, 533, 537, 539, 545, 547, 573, 630, 679 Epidemiologic Studies, 108, 118, 630 Epidermis, 625, 631, 646, 670 Epigastric, 631, 661 Epinephrine, 604, 627, 631, 658, 686 Epistaxis, 183, 631 Epithelial, 24, 118, 163, 202, 611, 631, 639 Epithelial Cells, 24, 118, 163, 611, 631, 639 Epitope, 35, 77, 95, 153, 200, 390, 449, 631 Erythema, 346, 431, 631 Erythrocytes, 607, 613, 631, 661, 672, 676
Erythromycin, 610, 618, 631 Esophageal, 176, 213, 215, 432, 631 Esophagus, 215, 626, 631, 659, 680 Essential Tremor, 552, 631 Estrogen, 528, 631 Ethanol, 382, 631, 633 Eukaryotic Cells, 631, 643, 659, 660 Evoke, 631, 680 Excitation, 631, 633, 658 Excitatory, 632, 636 Exhaustion, 608, 632, 651 Exocrine, 632, 661 Exogenous, 35, 70, 160, 221, 308, 323, 630, 632, 681 Extensor, 632, 670 External-beam radiation, 632, 646, 671, 689 Extracellular, 33, 77, 95, 98, 106, 109, 114, 119, 163, 165, 261, 428, 606, 621, 632, 633, 652, 655, 678 Extracellular Matrix, 114, 621, 632, 633, 652 Extracellular Matrix Proteins, 632, 652 Extracellular Space, 428, 632 Extracorporeal, 337, 632 Extraction, 46, 280, 397, 632 F Facial, 196, 222, 632, 662 Facial Expression, 632 Facial Nerve, 196, 632, 662 Factor V, 632, 671 Family Planning, 523, 632 Farnesyl, 117, 632 Fat, 609, 612, 613, 615, 622, 623, 629, 632, 649, 666, 674, 675, 678, 681 Fatty acids, 51, 70, 106, 112, 133, 605, 632, 636, 649, 668 Feces, 622, 633, 680 Fermentation, 633, 674 Fibrin, 613, 633, 663, 683 Fibroblasts, 633, 645, 655 Fibrosis, 114, 552, 633, 675, 676 Fistula, 215, 263, 633 Fixation, 266, 633, 676 Flatus, 633, 634 Flow Cytometry, 20, 37, 73, 633 Fluconazole, 633 Fluorescence, 78, 204, 389, 633, 634 Fluorescence Polarization, 389, 633 Fluorescent Dyes, 633, 634 Flushing, 627, 634 Focus Groups, 332, 634
Index 697
Fold, 38, 77, 101, 120, 123, 634 Fovea, 633, 634 Fractionation, 606, 634 Frameshift, 634, 686 Frameshift Mutation, 634, 686 Free Radicals, 609, 626, 634 Fungi, 36, 432, 453, 608, 612, 621, 634, 654, 679, 683, 689 Fungus, 497, 614, 634 G Gallbladder, 227, 603, 612, 626, 634 Gallium, 287, 634 Gamma-interferon, 431, 634 Gangrenous, 634, 677 Gas, 133, 227, 606, 615, 633, 634, 635, 640, 658, 665, 670, 673, 688 Gas exchange, 635, 673, 688 Gastric, 38, 205, 227, 399, 572, 635, 640 Gastrointestinal, 213, 215, 227, 264, 271, 295, 614, 618, 631, 635, 651, 680 Gastrointestinal tract, 631, 635 Gelatin, 623, 635, 636, 683 Gels, 50, 635 Gene Fusion, 111, 635 Gene Therapy, 15, 487, 635 Genetic Code, 635, 659 Genetic Counseling, 591, 592, 635 Genetic Engineering, 465, 613, 619, 635 Genetic Markers, 39, 133, 635 Genetic testing, 88, 635, 666 Genital, 7, 225, 228, 254, 618, 619, 635, 687 Genitourinary, 7, 8, 9, 228, 285, 498, 635, 687 Genitourinary system, 9, 635 Genomics, 11, 32, 43, 49, 83, 109, 154, 229, 237, 636 Genotype, 84, 170, 210, 218, 229, 435, 636, 664 Giant Cells, 636, 675 Gland, 604, 623, 636, 650, 652, 657, 661, 662, 664, 669, 676, 680, 683, 684 Glomerular, 7, 636, 673 Glomeruli, 636, 671 Glomerulonephritis, 206, 636 Glomerulus, 636, 657 Glucocorticoid, 319, 636, 667 Glucose, 18, 119, 444, 552, 613, 616, 625, 636, 637, 639, 644, 675 Glucose Intolerance, 625, 636 Glutamate, 636 Glutamic Acid, 381, 636, 658 Glutamine, 55, 156, 230, 636
Glycerol, 381, 434, 636, 664 Glycerophospholipids, 636, 664 Glycine, 606, 612, 636, 658, 677 Glycoprotein, 206, 632, 636, 637, 656, 683, 686 Glycoside, 637, 641, 675 Glycosylation, 55, 119, 637 Gonadal, 637, 680 Governing Board, 637, 667 Government Agencies, 3, 468, 476, 478, 479, 501, 527, 570, 637, 667 Gp120, 251, 637 Grade, 9, 127, 250, 291, 361, 637 Graft, 637, 640, 642 Graft Rejection, 637, 642 Gram-negative, 85, 630, 637, 659, 674, 684 Gram-Negative Bacteria, 630, 637, 674, 684 Gram-positive, 85, 87, 382, 412, 637, 656, 659, 680 Gram-Positive Rods, 87, 637 Granule, 637, 674 Granulocyte, 637, 645 Granuloma, 14, 22, 38, 47, 62, 92, 110, 113, 123, 125, 163, 202, 232, 262, 271, 382, 637 Growth factors, 114, 637 Guanine, 412, 637, 670 Guanylate Cyclase, 637, 658 Guinea Pigs, 11, 12, 17, 38, 65, 76, 153, 157, 175, 230, 295, 335, 413, 422, 638, 650 Gyrase, 40, 638 H Habitat, 131, 638, 656, 658 Habitual, 617, 638 Haematological, 320, 638 Haematology, 277, 638 Haemopoietic, 342, 638 Hair follicles, 625, 638, 689 Half-Life, 120, 638 Haploid, 638, 665 Haplotypes, 418, 458, 638 Haptens, 604, 638 Hawaii, 317, 357, 358, 597, 638 Health Education, 128, 420, 467, 476, 591, 638 Health Status, 638, 689 Heart attack, 615, 638 Hematuria, 8, 638 Heme, 19, 42, 75, 612, 624, 638, 661 Hemiparesis, 9, 639 Hemobilia, 207, 639 Hemodialysis, 7, 8, 625, 639, 647 Hemoglobin, 607, 631, 638, 639, 648
698 Tuberculosis
Hemoglobinopathies, 635, 639 Hemoglobinuria, 552, 639 Hemoptysis, 176, 601, 639 Hemorrhage, 8, 191, 628, 639, 670, 680 Hepatic, 106, 194, 231, 374, 605, 639 Hepatitis, 214, 528, 567, 588, 639 Hepatitis A, 528, 639 Hepatocytes, 639 Hepatotoxicity, 232, 278, 286, 639 Hepatovirus, 639 Hereditary, 592, 639, 673 Heredity, 635, 639 Heteroduplex Analysis, 280, 354, 639 Heterogeneity, 83, 153, 160, 358, 604, 639 Heterotrophic, 634, 639 Heterozygotes, 627, 639 Hip Prosthesis, 273, 640 Histamine, 607, 640 Histidine, 415, 640 Histology, 44, 60, 640, 661 Homeless Persons, 267, 468, 524, 545, 640 Homodimer, 59, 640, 685 Homogeneous, 463, 622, 640 Homologous, 25, 29, 30, 51, 76, 97, 108, 115, 605, 611, 623, 635, 639, 640, 656, 676, 681 Hormonal, 610, 623, 640 Hormone, 604, 612, 623, 625, 631, 640, 644, 645, 653, 668, 674, 677, 682, 684, 685 Hormone therapy, 604, 640 Hospices, 393, 441, 640 Hospitals, Community, 471, 640 Humoral, 66, 104, 162, 222, 236, 409, 637, 640 Humour, 640 Hybrid, 122, 392, 396, 407, 410, 452, 619, 640, 660 Hybridoma, 404, 451, 640 Hydrochloric Acid, 382, 640 Hydrogen, 410, 412, 603, 611, 615, 625, 632, 640, 641, 649, 655, 658, 659, 661, 663, 670, 681 Hydrogen Bonding, 641, 659 Hydrogen Peroxide, 410, 615, 641, 649, 681 Hydrogenation, 641, 671 Hydrolases, 25, 641, 664 Hydrolysis, 25, 36, 604, 616, 641, 662, 664, 669 Hydrophilic, 444, 641 Hydrophobic, 22, 25, 85, 444, 636, 641, 646, 649
Hydroxyproline, 606, 620, 641 Hyperbilirubinemia, 641, 646 Hypercalcemia, 7, 263, 641 Hyperreflexia, 641, 682 Hypersensitivity, 105, 369, 390, 411, 414, 415, 431, 498, 549, 605, 625, 630, 641, 674, 676 Hypertension, 9, 528, 615, 641, 666, 668 Hypnotic, 611, 641, 683 Hypotension, 627, 641 I Id, 324, 331, 345, 587, 588, 590, 598, 600, 641 Idiopathic, 592, 641, 675 Ileum, 616, 641 Imidazole, 613, 640, 641 Immaturity, 129, 641 Immune function, 372, 641, 685 Immune response, 11, 12, 14, 15, 17, 18, 20, 21, 27, 37, 40, 44, 48, 49, 54, 57, 59, 62, 65, 66, 68, 77, 78, 86, 91, 98, 100, 104, 109, 110, 113, 116, 119, 125, 131, 156, 236, 238, 254, 374, 386, 416, 417, 425, 440, 444, 456, 457, 461, 604, 607, 608, 610, 623, 637, 638, 641, 642, 651, 676, 678, 680, 687, 688 Immune Sera, 641, 642 Immunoassay, 66, 143, 423, 424, 459, 642 Immunocompromised, 8, 12, 16, 74, 103, 120, 193, 194, 265, 396, 412, 506, 528, 642 Immunocompromised Host, 194, 642 Immunodeficiency syndrome, 42, 294, 433, 473, 507, 526, 536, 542, 549, 560, 572, 642 Immunodiffusion, 605, 642 Immunodominant Epitopes, 396, 642 Immunoelectrophoresis, 341, 605, 642 Immunoglobulin, 138, 164, 169, 290, 608, 642, 655 Immunologic, 22, 68, 129, 374, 390, 444, 455, 463, 617, 642, 651, 671 Immunomodulator, 47, 211, 642 Immunosuppressant, 605, 642, 654 Immunosuppressive, 14, 67, 636, 642 Immunosuppressive therapy, 642 Immunotherapy, 143, 165, 238, 262, 385, 436, 438, 464, 612, 625, 642 Impairment, 43, 610, 642, 653 Implant radiation, 643, 645, 646, 671, 689 In situ, 26, 62, 67, 83, 402, 643 In Situ Hybridization, 62, 83, 643
Index 699
In vivo, 15, 23, 26, 37, 39, 41, 42, 49, 55, 59, 63, 68, 74, 76, 77, 78, 79, 81, 82, 83, 88, 92, 95, 99, 100, 105, 109, 114, 119, 120, 125, 131, 134, 155, 163, 169, 208, 245, 398, 417, 425, 444, 457, 461, 463, 635, 643, 649 Incision, 643, 645, 647 Incubated, 396, 399, 643 Incubation, 395, 643 Indicative, 17, 390, 404, 417, 450, 457, 482, 643, 662, 687 Induration, 431, 643 Infarction, 612, 623, 643, 654, 668 Infection Control, 4, 5, 469, 471, 475, 476, 479, 481, 499, 502, 506, 526, 544, 545, 574, 578, 643 Infiltration, 16, 23, 109, 636, 643 Influenza, 485, 643, 650 Ingestion, 144, 332, 643, 665 Inhalation, 21, 44, 103, 399, 412, 428, 604, 644, 665, 678 Initiation, 44, 56, 97, 203, 208, 276, 398, 533, 586, 644, 660, 673, 677, 680, 685 Initiator, 97, 644, 645 Inlay, 644, 673 In-line, 63, 644 Inner ear, 644, 687 Innervation, 632, 644 Inoculum, 35, 37, 644 Inorganic, 410, 644, 650, 681 Inositol, 444, 644 Inotropic, 610, 627, 644 Inpatients, 182, 541, 644 Insertional, 22, 644 Insight, 27, 28, 58, 61, 65, 86, 90, 99, 100, 118, 127, 412, 644 Instillation, 39, 644 Insulin, 372, 380, 644 Insulin-dependent diabetes mellitus, 380, 644 Interferon-alpha, 644 Interleukin-1, 136, 141, 142, 157, 163, 194, 202, 232, 242, 243, 244, 262, 644, 645 Interleukin-10, 136, 243, 244, 645 Interleukin-12, 141, 142, 163, 194, 202, 232, 242, 262, 645 Interleukin-2, 143, 175, 250, 279, 645 Interleukin-4, 144, 186, 645 Interleukin-8, 162, 186, 336, 358, 645 Intermittent, 106, 362, 364, 366, 375, 376, 506, 537, 556, 645, 650, 663 Internal radiation, 645, 646, 671, 689
International Agencies, 472, 645 Interstitial, 7, 109, 613, 614, 632, 645, 646, 657, 673, 689 Intestinal, 206, 244, 292, 432, 606, 615, 623, 630, 645, 651 Intestine, 612, 613, 630, 645, 647 Intoxication, 645, 689 Intracellular Membranes, 624, 645, 653 Intramuscular, 173, 403, 645 Intravascular, 263, 645 Intravenous, 9, 81, 83, 175, 403, 645 Intrinsic, 45, 605, 611, 645 Invasive, 8, 38, 133, 307, 423, 642, 645, 651 Invertebrates, 645, 650 Involuntary, 336, 611, 631, 645, 657 Iodine, 325, 403, 645 Ionization, 97, 646 Ions, 337, 603, 611, 626, 629, 640, 646 Irradiation, 287, 646, 689 Ischemia, 610, 646 Isocitrate Lyase, 42, 322, 461, 462, 646 Isoenzyme, 290, 646 Isonicotinic, 19, 76, 388, 406, 413, 422, 646 Isoprenoid, 116, 117, 646 J Jaundice, 320, 528, 641, 646 Joint Capsule, 646, 681 K Kanamycin, 101, 568, 606, 646 Kb, 81, 522, 646 Keratinocytes, 645, 646 Keto, 646, 689 Keyhole, 445, 646, 647 Keyhole limpet hemocyanin, 445, 647 Kidney Disease, 378, 522, 552, 647 Kidney Failure, 630, 647 Kidney Transplantation, 291, 647 Kinetic, 19, 75, 85, 647 L Labile, 12, 620, 632, 647 Laceration, 647, 682 Lacrimal, 632, 647, 670 Lacrimal gland, 647, 670 Laparoscopy, 181, 248, 273, 647 Laparotomy, 7, 647 Large Intestine, 616, 626, 645, 647, 672, 678 Laryngeal, 177, 196, 248, 249, 277, 647 Larynx, 177, 647, 684 Laser therapy, 252, 647 Latency, 42, 59, 78, 82, 83, 91, 97, 173, 221, 391, 402, 647 Lavage, 21, 49, 205, 399, 647
700 Tuberculosis
Laxative, 605, 647 Least-Squares Analysis, 647, 672 Lectin, 647, 653 Leishmaniasis, 182, 458, 486, 648, 662 Lens, 609, 648, 673, 688 Lethal, 24, 37, 97, 115, 611, 626, 648 Leucine, 136, 424, 460, 648 Leucocyte, 200, 253, 605, 630, 648 Leukemia, 552, 635, 648 Leukocytes, 16, 77, 142, 611, 613, 617, 644, 648, 655, 661, 686 Levofloxacin, 101, 155, 195, 240, 250, 369, 370, 568, 648 Library Services, 598, 648 Life cycle, 125, 634, 648 Life Cycle Stages, 125, 648 Ligament, 648, 669 Ligands, 21, 112, 122, 648 Ligase, 70, 121, 150, 154, 166, 211, 224, 354, 399, 420, 648 Ligase Chain Reaction, 150, 166, 211, 224, 399, 420, 648 Ligation, 648, 669 Likelihood Functions, 648, 672 Linear Models, 648, 672 Linkage, 53, 126, 250, 616, 635, 648, 662 Lip, 187, 248, 573, 574, 649 Lipid A, 112, 297, 356, 444, 649 Lipid Peroxidation, 192, 649, 661 Lipid Peroxides, 319, 649 Lipophilic, 36, 88, 649 Lipopolysaccharides, 649, 674 Lipoprotein, 89, 242, 298, 637, 649, 650 Liposarcoma, 9, 649 Liposomes, 33, 649 Liver scan, 649, 675 Lobe, 16, 649, 661 Local Government, 474, 649 Localization, 73, 76, 77, 81, 92, 171, 250, 649 Localized, 8, 125, 358, 606, 626, 629, 633, 643, 649, 665, 682, 686 Locomotion, 649, 665 Logistic Models, 649, 672 Long-Term Care, 6, 649 Loop, 55, 251, 586, 650 Low-density lipoprotein, 649, 650 Luciferase, 23, 96, 166, 202, 281, 430, 650 Lumbar, 288, 295, 611, 650 Luminescence, 430, 650 Lupus, 253, 650, 682 Luxation, 626, 650
Lymph, 16, 37, 199, 262, 303, 617, 630, 640, 650, 657, 670, 672, 675 Lymph node, 16, 37, 199, 303, 617, 650, 657, 670, 672, 675 Lymphadenitis, 188, 650 Lymphadenopathy, 262, 650 Lymphatic, 37, 399, 630, 643, 650, 679, 683 Lymphatic system, 399, 650, 679, 683 Lymphocyte, 15, 62, 119, 157, 236, 280, 297, 369, 603, 608, 650, 651, 652, 655 Lymphocyte Count, 236, 603, 650 Lymphocytic, 380, 650 Lymphocytic Choriomeningitis Virus, 380, 650 Lymphoid, 12, 390, 608, 648, 651 Lymphokines, 651 Lymphoma, 277, 552, 651 Lysine, 85, 651 Lysosome, 119, 651, 663 Lytic, 96, 292, 651, 677, 688 M Macrolides, 120, 651 Macrophage Activation, 49, 113, 651 Magnetic Resonance Imaging, 7, 284, 651, 675 Maintenance therapy, 549, 651 Major Histocompatibility Complex, 18, 21, 52, 157, 465, 638, 645, 651 Malabsorption, 106, 552, 651 Malaise, 602, 614, 651 Malaria, 182, 230, 234, 458, 485, 526, 651 Malaria, Falciparum, 651 Malaria, Vivax, 651 Malate Synthase, 461, 462, 652 Malformation, 181, 652 Malignant, 190, 552, 603, 609, 652, 656, 657, 671 Malignant tumor, 652, 656 Malnutrition, 15, 146, 337, 342, 343, 399, 488, 605, 610, 652, 656 Manifest, 448, 652 Mannans, 634, 652 Mannosides, 444, 652 Mastitis, 652, 677 Matrix metalloproteinase, 114, 652 Maximum Tolerated Dose, 103, 628, 652 Median survival time, 51, 652 Mediate, 29, 60, 82, 119, 137, 297, 450, 627, 652 Mediator, 49, 645, 652 Medical Records, 502, 503, 652, 674 Medical Staff, 73, 640, 652
Index 701
MEDLINE, 523, 551, 552, 652 Mefloquine, 120, 652 Meiosis, 652, 656, 681 Melanin, 652, 664, 686 Melanocytes, 652, 653 Melanoma, 552, 653 Membrane, 24, 88, 89, 116, 142, 260, 383, 445, 459, 616, 620, 621, 624, 625, 631, 637, 647, 649, 653, 656, 660, 663, 664, 665, 666, 669, 673, 674, 677, 681, 685, 688 Membrane Lipids, 653, 664 Membrane Proteins, 116, 649, 653 Memory, 14, 21, 48, 77, 95, 120, 137, 431, 443, 444, 592, 608, 624, 653 Meninges, 250, 616, 628, 653 Meningitis, 4, 77, 147, 174, 203, 217, 319, 345, 346, 495, 633, 650, 653 Mental Disorders, 378, 653, 670 Mental Health, iv, 9, 378, 522, 539, 550, 653, 670 Mental Processes, 627, 653, 670 Mentors, 110, 119, 653 Mercury, 633, 653 Mesothelial, 92, 653 Meta-Analysis, 185, 653 Metabolic disorder, 88, 653 Metabolite, 365, 413, 422, 606, 626, 653, 667 Metastasis, 652, 653 Metatarsophalangeal Joint, 180, 654 Methionine, 71, 294, 415, 626, 654, 681 Methotrexate, 272, 654 Methyltransferase, 318, 654 MI, 122, 123, 132, 172, 181, 209, 215, 263, 280, 330, 602, 654 Microbe, 99, 109, 654, 684 Microbiological, 123, 280, 281, 317, 370, 498, 654 Microorganism, 118, 387, 427, 619, 654, 662, 688 Micro-organism, 387, 654, 664, 676 Microscopy, 50, 73, 127, 188, 195, 220, 263, 387, 399, 472, 525, 611, 639, 654, 659 Microspheres, 33, 89, 654 Microtubules, 654, 658 Migration, 23, 62, 125, 212, 397, 474, 651, 654 Mineralization, 16, 654 Mineralocorticoids, 604, 623, 654 Minority Groups, 524, 545, 654 Mitochondria, 410, 617, 654, 660
Mitogen-Activated Protein Kinase Kinases, 654, 655 Mitogen-Activated Protein Kinases, 60, 336, 654, 655 Mitosis, 609, 655 Mobility, 111, 655 Mobilization, 533, 655 Modeling, 32, 91, 158, 255, 481, 628, 655 Modems, 73, 655 Modification, 55, 102, 122, 158, 606, 635, 655 Modulator, 655 Molecule, 18, 41, 67, 71, 88, 90, 96, 115, 116, 157, 392, 393, 441, 444, 608, 611, 612, 619, 620, 626, 628, 630, 631, 632, 637, 639, 641, 644, 646, 647, 655, 659, 661, 665, 671, 672, 677, 681, 685, 687 Monoclonal, 118, 169, 387, 404, 405, 440, 448, 449, 451, 463, 646, 655, 671, 689 Monoclonal antibodies, 118, 387, 404, 405, 440, 449, 451, 655 Monocyte, 92, 114, 144, 165, 206, 261, 332, 358, 655 Monocyte Chemoattractant Protein-1, 92, 358, 655 Mononuclear, 11, 29, 47, 57, 67, 81, 109, 200, 202, 297, 299, 637, 655, 686 Monotherapy, 120, 580, 655 Morphological, 629, 634, 652, 656 Morphology, 8, 73, 136, 609, 638, 651, 656 Mucins, 656, 675 Mucociliary, 606, 656 Mucocutaneous, 648, 656 Mucolytic, 614, 656 Mucositis, 656, 683 Multicenter study, 179, 214, 219, 656 Multidrug resistance, 388, 448, 656 Multiple Myeloma, 592, 656 Multivalent, 55, 656 Mummies, 191, 656 Muscle Fibers, 656 Muscular Atrophy, 552, 656 Muscular Dystrophies, 628, 656 Mycobacterial disease, 71, 94, 235, 382, 386, 399, 408, 414, 415, 440, 656 Mycobacteriophages, 90, 281, 656 Mycobacterium Infections, 373, 374, 656 Myelin, 380, 656 Myelofibrosis, 285, 657 Myeloma, 640, 657 Myocarditis, 380, 626, 657 Myocardium, 654, 657
702 Tuberculosis
Myotonic Dystrophy, 552, 657 N N-acetyl, 25, 85, 182, 317, 354, 383, 657 Naive, 68, 119, 251, 417, 457, 657 Natural killer cells, 645, 657 Natural selection, 233, 657 Nausea, 627, 657, 686 NCI, 1, 377, 521, 618, 657 Nebramycin, 657, 684 Nelfinavir, 362, 365, 657 Neoplasia, 190, 552, 657 Neoplasm, 657, 686 Neoplastic, 651, 657 Neopterin, 307, 657 Nephrectomy, 9, 248, 657 Nephritis, 7, 657 Nephropathy, 647, 657 Nerve, 271, 498, 604, 610, 618, 625, 628, 632, 644, 652, 658, 660, 661, 666, 673, 676, 680, 685, 687 Nervous System, 191, 552, 604, 616, 652, 658, 663, 688 Networks, 26, 73, 359, 371, 658 Neural, 337, 604, 606, 640, 658 Neurologic, 7, 514, 658 Neuropathy, 272, 658 Neurotransmitter, 603, 604, 606, 614, 616, 627, 636, 640, 658, 677, 680 Neutralization, 23, 658 Neutrons, 646, 658, 671 Neutrophil, 16, 172, 239, 363, 658 Nevirapine, 194, 658, 659 Niacin, 88, 324, 509, 658 Niche, 43, 87, 106, 658 Nickel, 435, 658 Nitric Oxide, 60, 146, 150, 153, 171, 211, 336, 455, 658 Nitrogen, 76, 85, 162, 357, 392, 454, 455, 605, 607, 632, 633, 636, 658 Nocodazole, 89, 658 Non-nucleoside, 658, 659 Nosocomial, 10, 128, 217, 265, 420, 422, 469, 476, 502, 543, 659 Nuclear, 111, 121, 337, 611, 621, 631, 659 Nuclei, 412, 544, 621, 635, 651, 655, 658, 659, 670 Nucleic Acid Hybridization, 413, 421, 422, 640, 659 Nucleic Acid Probes, 412, 414, 415, 659 Nucleolus, 659, 674 Nucleotidases, 641, 659
Nucleus, 609, 611, 618, 623, 624, 625, 631, 652, 655, 658, 659, 668, 670, 680, 682 Nutritional Status, 164, 327, 659 O Observational study, 254, 659 Occupational Exposure, 481, 485, 506, 526, 576, 580, 583, 585, 659 Odynophagia, 267, 659 Ofloxacin, 188, 266, 317, 568, 659 Ointments, 659, 661 Oligonucleotide Probes, 648, 660 Oligopeptides, 105, 660 Oncogene, 552, 660 Oncology, 660, 672 Opacity, 625, 660 Open Reading Frames, 51, 89, 123, 425, 461, 660 Operon, 43, 89, 116, 263, 660, 673 Ophthalmology, 13, 266, 267, 292, 633, 660 Opportunistic Infections, 68, 107, 125, 471, 537, 546, 603, 660 Organ Culture, 660, 684 Organelles, 616, 624, 653, 660, 665 Ori region, 660, 673 Osmosis, 660 Osmotic, 114, 605, 660 Ototoxic, 606, 660 Outpatient, 660 Overall survival, 370, 660 Ovum, 648, 661, 668, 689 Oxidation, 42, 75, 603, 609, 624, 649, 661 Oxidation-Reduction, 42, 661 Oxidative Stress, 76, 339, 661 Oxygenase, 75, 661 P Pachymeningitis, 653, 661 Palliative, 640, 661, 683 Palmitic Acid, 36, 661 Palsy, 196, 661 Pancreas, 225, 291, 303, 603, 613, 626, 644, 661 Pancreatic, 7, 181, 225, 269, 552, 661 Pancreatic cancer, 552, 661 Pancytopenia, 320, 514, 661 Paradoxical, 88, 238, 270, 276, 661 Paraffin, 145, 148, 176, 195, 661 Paralysis, 222, 639, 661 Parasite, 76, 116, 661 Paratuberculosis, 134, 136, 144, 145, 146, 151, 266, 382, 401, 402, 661 Parietal, 661, 663, 665 Paromomycin, 145, 373, 661
Index 703
Parotid, 662, 675 Paroxysmal, 552, 662 Patch, 126, 431, 662, 685 Pathologic, 609, 612, 615, 622, 641, 662, 670, 687 Pathologic Processes, 609, 662 Pathologies, 662 Pathophysiology, 61, 93, 164, 482, 662 Patient Advocacy, 592, 662 Patient Compliance, 36, 54, 404, 450, 524, 545, 548, 662 Patient Education, 537, 559, 596, 598, 602, 662 Patient Satisfaction, 371, 662 Pelvic, 662, 669 Pelvis, 603, 650, 662, 671, 687 Penicillin, 399, 528, 608, 662 Pentamidine, 481, 662 Peptide Chain Elongation, 619, 662 Peptide Hydrolases, 630, 641, 662 Perceived risk, 183, 662 Perception, 130, 394, 662, 676 Percutaneous, 196, 248, 310, 662 Pericarditis, 253, 663 Pericardium, 663, 682 Peripheral blood, 11, 21, 64, 77, 92, 119, 202, 203, 262, 291, 299, 316, 644, 663 Peripheral Nervous System, 658, 661, 663, 680 Peritoneal, 7, 272, 663 Peritoneal Cavity, 663 Peritoneal Dialysis, 7, 663 Peritoneum, 663 Peritonitis, 304, 663 Peroxide, 389, 406, 663 Petroleum, 661, 663 PH, 134, 181, 200, 280, 562, 663 Phagocyte, 73, 663 Phagocytosis, 50, 69, 93, 118, 125, 142, 328, 340, 663 Phagosomes, 35, 99, 101, 306, 356, 663 Phallic, 633, 663 Pharmaceutical Preparations, 616, 631, 635, 663 Pharmacokinetic, 106, 362, 365, 366, 663 Pharmacologic, 638, 663, 684 Phenotype, 44, 52, 62, 92, 96, 129, 203, 388, 621, 663 Phenylalanine, 258, 415, 664, 686 Phospholipases, 106, 664, 677 Phospholipids, 35, 106, 444, 632, 644, 649, 653, 664, 669
Phosphoric Monoester Hydrolases, 641, 664 Phosphorus, 614, 664 Phosphorylation, 655, 664, 669 Photocoagulation, 619, 664 Phylogeny, 228, 664 Physical Examination, 372, 617, 664 Physician Assistants, 34, 664 Physicochemical, 61, 664 Physiologic, 89, 638, 664, 668, 672 Physiology, 59, 90, 99, 111, 121, 354, 664 Pigments, 612, 615, 664, 665 Pilot Projects, 474, 664 Pilot study, 367, 664 Pituitary Gland, 623, 664 Plague, 5, 341, 359, 479, 485, 490, 491, 496, 507, 664 Plasma cells, 608, 656, 657, 665 Plasma protein, 605, 665 Plasmid, 27, 78, 81, 396, 430, 433, 665, 687 Plastids, 617, 660, 665 Platelet Activation, 665, 677 Platelet Aggregation, 607, 658, 665 Platelets, 612, 658, 661, 665, 683 Platinum, 650, 665 Pleura, 665 Pleural, 92, 199, 237, 241, 314, 653, 665 Pneumoconiosis, 665, 678 Pneumonectomy, 251, 665 Pneumonia, 16, 24, 44, 157, 208, 212, 278, 372, 435, 546, 622, 662, 665 Pneumothorax, 189, 255, 665 Point Mutation, 75, 413, 422, 665 Poisoning, 628, 645, 653, 657, 665 Policy Making, 637, 666 Polycystic, 552, 666 Polyethylene, 102, 666 Polymers, 121, 666, 669 Polymorphic, 170, 186, 273, 317, 666 Polyneuritis, 626, 666 Polyproteins, 174, 308, 666 Polysaccharide, 25, 32, 43, 67, 122, 383, 411, 444, 605, 608, 616, 666 Polyunsaturated fat, 335, 666 Portal Hypertension, 285, 666 Portal Vein, 666 Posterior, 288, 295, 607, 610, 611, 627, 661, 666, 676 Postsynaptic, 666, 677 Post-translational, 27, 56, 63, 666 Potentiates, 644, 667 Potentiation, 667, 677
704 Tuberculosis
Practicability, 667, 685 Practice Guidelines, 550, 587, 667 Preclinical, 41, 100, 102, 135, 667 Precursor, 609, 627, 628, 630, 632, 657, 664, 667, 669, 685, 686 Predisposition, 53, 667 Prednisolone, 376, 667 Prednisone, 528, 667 Prejudice, 196, 667 Prenatal, 629, 667 Preoperative, 318, 667 Primary endpoint, 44, 667 Private Sector, 472, 476, 477, 667 Problem Solving, 45, 477, 667 Prodrug, 43, 667 Product Packaging, 127, 667 Progeny, 621, 668 Progesterone, 668, 680 Program Development, 533, 668 Program Evaluation, 4, 482, 527, 531, 532, 668 Progression, 6, 42, 52, 53, 54, 66, 109, 373, 376, 499, 607, 668 Progressive disease, 113, 370, 668 Projection, 624, 668, 672 Promoter, 25, 27, 52, 54, 59, 80, 82, 84, 100, 120, 123, 273, 307, 398, 668 Prophase, 656, 668, 681 Propranolol, 610, 668 Prospective study, 255, 304, 668 Prostaglandin, 99, 335, 668 Prostaglandins A, 668, 669 Prostate, 552, 669 Protease, 84, 106, 114, 334, 530, 538, 539, 657, 669, 675 Protease Inhibitors, 106, 530, 538, 539, 669 Protein Conformation, 606, 669 Protein Kinase C, 654, 655, 669 Protein Splicing, 63, 669 Protein-Serine-Threonine Kinases, 655, 669 Proteinuria, 656, 669 Proteolytic, 605, 620, 669 Proteome, 55, 85, 669 Protocol, 51, 86, 397, 405, 452, 669 Protons, 640, 670, 671 Protozoa, 612, 621, 648, 654, 670, 679, 686 Protozoan, 623, 651, 670 Proximal, 19, 60, 93, 627, 670 Psoriasis, 513, 514, 670, 674 Psychiatry, 271, 316, 633, 670, 688 Psychic, 653, 670, 676
Psychoactive, 670, 689 Psychology, 126, 627, 670 Public Health Practice, 239, 572, 574, 670 Public Policy, 523, 547, 670 Public Sector, 472, 670 Pulmonary Sarcoidosis, 195, 670 Pulmonary Ventilation, 670, 673 Pulse, 655, 670 Purines, 670, 677 Purpura, 231, 670 Purulent, 9, 400, 603, 671, 687 Pyelonephritis, 284, 671 Pyridoxal, 413, 422, 671 Pyridoxal Phosphate, 413, 422, 671 Pyrimidines, 671, 677 Q Quaternary, 294, 669, 671 Quinolones, 120, 488, 671 R Race, 117, 356, 481, 529, 541, 618, 654, 671 Radiation, 603, 604, 630, 632, 633, 634, 642, 645, 646, 671, 675, 689 Radiation therapy, 603, 604, 632, 634, 645, 646, 671, 689 Radioactive, 613, 624, 638, 641, 643, 645, 646, 649, 655, 659, 671, 675, 689 Radiography, 556, 671, 687 Radiolabeled, 88, 111, 389, 646, 671, 689 Radiological, 193, 279, 282, 283, 556, 662, 671 Radiology, 247, 279, 310, 321, 329, 399, 490, 494, 556, 671 Radiotherapy, 613, 646, 671, 689 Randomized, 13, 40, 202, 207, 279, 368, 373, 377, 628, 671 Reagent, 24, 96, 386, 424, 436, 437, 439, 640, 650, 671 Recombinant Proteins, 130, 453, 672 Recombination, 28, 97, 108, 611, 621, 635, 672 Reconstitution, 104, 672 Rectum, 263, 609, 613, 620, 626, 633, 634, 647, 669, 672 Recurrence, 212, 283, 672 Red blood cells, 631, 661, 672, 675 Red Nucleus, 610, 672 Reductase, 19, 70, 71, 112, 273, 294, 321, 654, 672 Refer, 1, 620, 633, 634, 649, 657, 658, 659, 672, 684 Refraction, 607, 672, 679
Index 705
Refractory, 47, 63, 280, 302, 380, 398, 629, 672 Regeneration, 672 Regional lymph node, 44, 672 Regression Analysis, 36, 672 Regulon, 26, 74, 77, 79, 672 Reinfection, 124, 144, 160, 283, 308, 323, 370, 388, 481, 672 Relapse, 42, 53, 283, 364, 370, 375, 376, 673 Reliability, 397, 673 Remission, 651, 672, 673 Renal failure, 4, 673 Replication Origin, 97, 673 Repressor, 17, 30, 59, 100, 660, 673 Resection, 59, 673 Resolving, 119, 673 Respiration, 189, 241, 320, 615, 655, 673 Respirator, 585, 673, 688 Respiratory distress syndrome, 255, 673 Respiratory failure, 337, 400, 673, 688 Respiratory Physiology, 275, 299, 330, 673, 688 Respiratory System, 310, 605, 656, 673 Response rate, 364, 673 Restoration, 7, 285, 388, 406, 671, 672, 673, 683, 689 Resuscitation, 35, 673 Retina, 192, 648, 670, 673, 675, 687, 688 Retinoblastoma, 244, 552, 673 Retinoids, 674, 688 Retreatment, 316, 674 Retrospective, 156, 168, 180, 193, 209, 270, 292, 318, 674 Retrospective study, 193, 209, 270, 292, 674 Retroviral vector, 418, 458, 635, 674 Reverse Transcriptase Inhibitors, 530, 674 Reverse Transcriptase Polymerase Chain Reaction, 389, 674 Reversion, 674, 686 Rhamnose, 433, 674 Rheumatism, 300, 303, 674 Rheumatoid, 253, 272, 273, 300, 306, 512, 513, 592, 674 Rheumatoid arthritis, 253, 272, 273, 300, 306, 512, 513, 592, 674 Rhinitis, 674, 677 Ribose, 604, 674 Ribosome, 123, 674, 685 Rifabutin, 106, 286, 362, 365, 366, 376, 516, 530, 563, 568, 674 Rifamycins, 148, 206, 229, 530, 674
Rigidity, 665, 674 Risk patient, 506, 531, 674 Ristocetin, 674, 687 Ritonavir, 530, 675 Rod, 412, 610, 611, 637, 675 S Saliva, 423, 424, 675 Salivary, 626, 632, 661, 675 Salivary glands, 626, 632, 675 Salmonellosis, 401, 402, 675 Sanatorium, 355, 489, 497, 507, 675 Sanitation, 470, 675 Saponins, 675, 680 Saprophyte, 164, 675 Sarcoidosis, 176, 277, 320, 346, 675 Satellite, 488, 506, 532, 675 Saturated fat, 661, 675 Scans, 372, 675 Schizoid, 675, 689 Schizophrenia, 675, 676, 689 Schizotypal Personality Disorder, 676, 689 Sclera, 621, 676, 687 Sclerosis, 200, 552, 676 Sebaceous, 625, 676, 689 Secretory, 84, 209, 384, 606, 676 Sediment, 676 Sedimentation, 220, 266, 617, 676 Segmental, 283, 285, 676 Segmentation, 676 Segregation, 672, 676 Seizures, 662, 676 Semen, 669, 676 Semisynthetic, 616, 618, 676 Sensitization, 11, 153, 414, 415, 676 Sepsis, 294, 514, 676 Septic, 610, 676 Septicaemia, 676, 677 Sequela, 251, 676 Sequence Analysis, 108, 200, 676 Sequencing, 51, 88, 108, 123, 132, 138, 143, 159, 166, 192, 425, 461, 666, 677 Serial Passage, 390, 677 Serine, 75, 114, 150, 603, 630, 654, 669, 677 Seroconversion, 239, 304, 677 Serologic, 112, 216, 217, 290, 642, 677 Serology, 66, 396, 489, 677 Serotypes, 417, 457, 677 Sex Determination, 552, 677 Sexually Transmitted Diseases, 567, 589, 622, 677 Shock, 17, 57, 114, 207, 263, 380, 387, 440, 617, 677, 685
706 Tuberculosis
Shunt, 42, 461, 462, 677 Sigma Factor, 26, 76, 141, 391, 412, 426, 677 Signal Transduction, 69, 82, 99, 167, 282, 644, 677 Signs and Symptoms, 7, 34, 364, 673, 677 Silicon, 87, 677, 678 Silicon Dioxide, 678 Silicosis, 131, 133, 678 Skeletal, 274, 607, 656, 678, 682 Skeleton, 494, 646, 668, 678 Skull, 237, 303, 678, 682 Small intestine, 616, 618, 628, 630, 640, 641, 645, 678 Smallpox, 355, 486, 678, 687 Social Behavior, 344, 678 Social Class, 117, 678 Social Environment, 678 Social Sciences, 107, 678 Social Support, 532, 678 Social Work, 341, 678 Socioeconomic Factors, 527, 678 Sodium, 380, 381, 403, 516, 654, 678 Soft tissue, 613, 678 Solvent, 631, 636, 660, 678 Somatic, 640, 652, 655, 663, 679 Soybean Oil, 666, 679 Specialist, 73, 592, 679 Spectrometer, 122, 679 Spectroscopic, 75, 112, 679 Spectrum, 17, 97, 194, 222, 293, 679 Sperm, 607, 618, 679 Spinal cord, 616, 617, 618, 628, 629, 653, 658, 661, 663, 679 Spirochete, 679, 682 Spleen, 47, 51, 65, 417, 457, 607, 640, 650, 675, 679 Spondylitis, 184, 679 Sporadic, 673, 679 Spores, 87, 412, 644, 679 Spotting, 423, 679 Sputum, 12, 38, 61, 66, 89, 91, 99, 126, 127, 136, 140, 143, 150, 156, 158, 167, 170, 173, 175, 177, 182, 202, 211, 219, 223, 224, 241, 251, 260, 276, 281, 300, 314, 323, 370, 372, 396, 397, 399, 400, 409, 412, 429, 481, 497, 525, 546, 581, 582, 679 Stabilization, 112, 679 Staging, 675, 679 Standardize, 113, 679 Steady state, 110, 679 Sterile, 419, 610, 679, 686
Steroid, 376, 612, 623, 675, 679 Stimulus, 59, 627, 628, 631, 644, 645, 647, 680, 683 Stomach, 227, 603, 626, 631, 635, 640, 647, 657, 663, 678, 679, 680 Stool, 38, 620, 647, 680 Strand, 29, 143, 412, 666, 680 Streptococcal, 380, 680 Streptococcus, 458, 680 Streptomycin, 101, 147, 373, 421, 563, 568, 680 Stress, 8, 25, 70, 76, 87, 269, 330, 338, 391, 412, 623, 634, 655, 657, 661, 667, 674, 680 Stringency, 253, 680 Stroke, 378, 522, 615, 680 Stromal, 227, 680 Structure-Activity Relationship, 45, 680 Subacute, 643, 680 Subclinical, 154, 156, 643, 676, 680 Subcutaneous, 628, 634, 680 Subspecies, 164, 246, 270, 679, 680 Substance P, 623, 631, 653, 672, 674, 676, 680 Substrate, 45, 63, 70, 85, 112, 116, 396, 423, 424, 453, 641, 681 Substrate Specificity, 45, 453, 681 Subtalar Joint, 247, 681 Sulfates, 528, 681 Sulfotransferases, 95, 681 Sulfur, 71, 96, 632, 654, 681 Sulfuric acid, 606, 681 Superoxide, 75, 109, 410, 681 Superoxide Dismutase, 109, 410, 681 Supplementation, 13, 327, 333, 336, 340, 512, 681 Support group, 368, 532, 591, 681 Supportive care, 640, 681 Suppression, 39, 59, 97, 98, 623, 681 Suppressive, 67, 681 Surfactant, 107, 118, 131, 681 Survival Rate, 660, 681 Symphysis, 618, 669, 681 Synaptic, 658, 677, 681 Synergistic, 45, 56, 171, 681 Synovial, 250, 646, 681 Synovial Fluid, 681, 682 Synovial Membrane, 250, 646, 681 Syphilis, 356, 435, 436, 682 Systemic lupus erythematosus, 250, 286, 682 Systolic, 641, 682
Index 707
T Talus, 247, 681, 682 Tarsal Bones, 614, 682 Tarsus, 682 Technology Transfer, 31, 682 Teichoic Acids, 637, 682 Telangiectasia, 552, 682 Temporal, 46, 123, 171, 682 Terminator, 619, 682 Testosterone, 672, 682 Tetani, 682 Tetanic, 682 Tetanus, 445, 682 Tetracycline, 46, 682 Thalamic, 610, 682 Thalamic Diseases, 610, 682 Thalidomide, 373, 374, 518, 683 Theophylline, 297, 670, 683 Therapeutics, 50, 55, 74, 402, 411, 412, 426, 461, 487, 517, 526, 683 Thermal, 607, 627, 658, 666, 683 Thioamides, 447, 683 Thorax, 215, 241, 340, 344, 603, 650, 683 Threonine, 75, 150, 654, 669, 677, 683 Threshold, 641, 683 Thrombin, 632, 633, 665, 669, 683 Thrombocytopenia, 342, 683 Thrombomodulin, 669, 683 Thrombosis, 612, 669, 680, 683 Thrombus, 623, 643, 665, 683, 688 Thrush, 614, 683 Thymidine, 88, 412, 683 Thymosin, 47, 683 Thymus, 350, 642, 650, 683 Thyroid, 275, 645, 684, 686 Thyroid Gland, 275, 684 Thyroid Hormones, 684, 686 Thyroxine, 605, 664, 684 Tissue Culture, 9, 50, 82, 411, 684 Tobramycin, 400, 684 Tolerance, 54, 73, 251, 369, 603, 636, 684 Tome, 348, 350, 684 Tomography, 337, 338, 621, 675, 684 Tooth Preparation, 604, 684 Topical, 513, 631, 641, 661, 684 Toxic, iv, 43, 79, 373, 432, 448, 605, 621, 622, 624, 626, 629, 630, 642, 649, 658, 662, 684, 687 Toxicology, 102, 103, 524, 684 Toxin, 30, 445, 626, 630, 682, 684 Toxoid, 445, 684 Toxoplasmosis, 546, 549, 610, 684
Trace element, 658, 677, 684 Trachea, 614, 647, 684 Transcriptase, 143, 389, 658, 659, 674, 685 Transcription Factors, 49, 111, 114, 685 Transcutaneous, 104, 685 Transdermal, 126, 685 Transduction, 69, 677, 685 Transfection, 613, 635, 685 Transfer Factor, 642, 685 Transferases, 85, 158, 637, 685 Transforming Growth Factor beta, 67, 685 Translation, 537, 606, 631, 669, 685 Translational, 46, 94, 126, 685 Translocation, 619, 631, 685 Transmitter, 603, 627, 652, 685 Transplantation, 8, 204, 248, 288, 338, 618, 642, 651, 685 Trauma, 190, 318, 611, 639, 683, 685 Treatment Failure, 42, 308, 323, 365, 370, 376, 685 Treatment Outcome, 58, 239, 275, 319, 685 Triad, 180, 685 Trypanosomiasis, 458, 662, 686 Tubercular, 43, 82, 130, 374, 409, 415, 686 Tuberculin Test, 127, 304, 464, 528, 529, 587, 686 Tuberculoma, 192, 292, 686 Tuberculostatic, 646, 686 Tuberous Sclerosis, 552, 686 Tumour, 173, 184, 227, 299, 305, 686 Typhimurium, 130, 686 Tyrosine, 336, 415, 627, 686 U Ulcer, 382, 686 Ulceration, 321, 686 Ultrasonography, 284, 686 Unconscious, 624, 641, 686 Universal Precautions, 473, 502, 503, 504, 506, 526, 566, 686 Uracil, 88, 412, 671, 686 Urea, 686 Urease, 339, 658, 686 Uremia, 647, 673, 686 Ureters, 687 Urethra, 669, 687 Urinary, 7, 8, 9, 188, 193, 194, 237, 307, 317, 346, 588, 618, 623, 635, 686, 687 Urinary tract, 7, 8, 623, 687 Urinary tract infection, 623, 687 Urine, 8, 9, 218, 226, 252, 309, 372, 399, 412, 512, 613, 627, 635, 638, 639, 669, 687 Urogenital, 635, 687
708 Tuberculosis
Urography, 237, 687 Uterus, 617, 623, 668, 687 Uvea, 687 Uveal tract, 670, 687 Uveitis, 263, 273, 346, 687 V Vaccinia, 146, 418, 458, 687 Vacuole, 105, 687 Vagina, 614, 617, 625, 679, 687 Vaginitis, 614, 687 Vancomycin, 101, 687 Variola, 687 Vascular, 625, 630, 639, 643, 658, 683, 684, 687 Vasodilation, 627, 687 Vasodilators, 658, 687 Vector, 15, 27, 33, 387, 440, 463, 644, 685, 687 Vegetative, 612, 687 Vein, 610, 645, 659, 662, 666, 675, 688 Venereal, 682, 688 Venous, 185, 201, 610, 612, 669, 688 Venous Thrombosis, 185, 201, 612, 688 Ventilation, 502, 544, 573, 688 Ventilator, 673, 688 Ventricles, 617, 688 Vertebrae, 7, 679, 688 Vertebral, 7, 247, 259, 294, 318, 688 Veterinary Medicine, 316, 382, 523, 688
Viral Load, 68, 252, 358, 688 Viral Proteins, 417, 457, 688 Viral vector, 418, 458, 688 Visceral, 648, 663, 688 Vitamin A, 164, 311, 363, 644, 688 Vitreous, 263, 648, 673, 688 Vitreous Body, 673, 688 Vivo, 49, 77, 79, 80, 92, 105, 118, 131, 135, 150, 155, 156, 332, 689 Vulgaris, 350, 689 W War, 355, 393, 441, 504, 509, 617, 689 White blood cell, 9, 608, 637, 643, 648, 650, 651, 655, 657, 658, 665, 689 Windpipe, 684, 689 Withdrawal, 362, 689 Womb, 582, 687, 689 Wound Healing, 652, 689 X Xenograft, 607, 689 X-ray therapy, 646, 689 Xylulose, 116, 689 Y Yeasts, 614, 634, 664, 689 Z Zebrafish, 62, 689 Zygote, 621, 689 Zymogen, 669, 689
Index 709
710 Tuberculosis
Index 711
712 Tuberculosis
