HEMOPHILIA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES
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 ©2004 by ICON Group International, Inc. Copyright ©2004 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., 1960Hemophilia: 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: 0-597-83978-6 1. Hemophilia-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.
Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail:
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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 hemophilia. 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 HEMOPHILIA ............................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Hemophilia .................................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 70 The National Library of Medicine: PubMed ................................................................................ 73 CHAPTER 2. NUTRITION AND HEMOPHILIA ................................................................................. 119 Overview.................................................................................................................................... 119 Finding Nutrition Studies on Hemophilia................................................................................. 119 Federal Resources on Nutrition ................................................................................................. 123 Additional Web Resources ......................................................................................................... 123 CHAPTER 3. ALTERNATIVE MEDICINE AND HEMOPHILIA........................................................... 125 Overview.................................................................................................................................... 125 National Center for Complementary and Alternative Medicine................................................ 125 Additional Web Resources ......................................................................................................... 130 General References ..................................................................................................................... 132 CHAPTER 4. DISSERTATIONS ON HEMOPHILIA............................................................................. 133 Overview.................................................................................................................................... 133 Dissertations on Hemophilia...................................................................................................... 133 Keeping Current ........................................................................................................................ 134 CHAPTER 5. CLINICAL TRIALS AND HEMOPHILIA ....................................................................... 135 Overview.................................................................................................................................... 135 Recent Trials on Hemophilia...................................................................................................... 135 Keeping Current on Clinical Trials ........................................................................................... 136 CHAPTER 6. PATENTS ON HEMOPHILIA ....................................................................................... 139 Overview.................................................................................................................................... 139 Patents on Hemophilia ............................................................................................................... 139 Patent Applications on Hemophilia ........................................................................................... 162 Keeping Current ........................................................................................................................ 176 CHAPTER 7. BOOKS ON HEMOPHILIA ........................................................................................... 177 Overview.................................................................................................................................... 177 Book Summaries: Federal Agencies............................................................................................ 177 Book Summaries: Online Booksellers......................................................................................... 180 The National Library of Medicine Book Index ........................................................................... 183 Chapters on Hemophilia............................................................................................................. 184 Directories.................................................................................................................................. 190 CHAPTER 8. MULTIMEDIA ON HEMOPHILIA ................................................................................ 191 Overview.................................................................................................................................... 191 Video Recordings ....................................................................................................................... 191 Audio Recordings....................................................................................................................... 192 Bibliography: Multimedia on Hemophilia.................................................................................. 192 CHAPTER 9. PERIODICALS AND NEWS ON HEMOPHILIA ............................................................. 195 Overview.................................................................................................................................... 195 News Services and Press Releases.............................................................................................. 195 Newsletters on Hemophilia ........................................................................................................ 200 Newsletter Articles .................................................................................................................... 200 Academic Periodicals covering Hemophilia ............................................................................... 201 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 203 Overview.................................................................................................................................... 203 U.S. Pharmacopeia..................................................................................................................... 203
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Commercial Databases ............................................................................................................... 204 Researching Orphan Drugs ....................................................................................................... 205 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 209 Overview.................................................................................................................................... 209 NIH Guidelines.......................................................................................................................... 209 NIH Databases........................................................................................................................... 211 Other Commercial Databases..................................................................................................... 217 The Genome Project and Hemophilia......................................................................................... 218 APPENDIX B. PATIENT RESOURCES ............................................................................................... 223 Overview.................................................................................................................................... 223 Patient Guideline Sources.......................................................................................................... 223 Associations and Hemophilia ..................................................................................................... 232 Finding Associations.................................................................................................................. 234 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 237 Overview.................................................................................................................................... 237 Preparation................................................................................................................................. 237 Finding a Local Medical Library................................................................................................ 237 Medical Libraries in the U.S. and Canada ................................................................................. 237 ONLINE GLOSSARIES................................................................................................................ 243 Online Dictionary Directories ................................................................................................... 246 HEMOPHILIA DICTIONARY .................................................................................................... 247 INDEX .............................................................................................................................................. 319
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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 hemophilia 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 hemophilia, 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 hemophilia, 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 hemophilia. 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 hemophilia, 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 hemophilia. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON HEMOPHILIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on hemophilia.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and hemophilia, 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 “hemophilia” (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: •
Hepatitis C in Adults and Adolescents with Hemophilia: A Randomized, Controlled Trial of Interferon Alfa-2b and Ribavirin Source: Hepatology. 36(4 Part 1): 967-972. October 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Adolescents and adults with inherited disorders of coagulation have one of the highest prevalence rates of hepatitis C among known risk groups. Few data are available on the use of combination therapy with interferon and ribavirin in this population. This article reports on a study in which patients 13 years of age and older (n = 113) who were positive for hepatitis C virus (HCV) RNA and negative for HIV were randomized to receive interferon alfa-2b plus ribavirin or interferon alfa-2b alone for 48
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Hemophilia
weeks, with 24 weeks of posttreatment follow up. Patients started on interferon alone who remained positive for HCV RNA at week 12 crossed over to treatment with interferon plus ribavirin. Of the 113 patients, 37 were younger than 18 years. At the end of treatment, 18 of 56 patients (32 percent) treated with interferon plus ribavirin and 6 of 57 patients (11 percent) treated with interferon alone were negative for HCV RNA. Sustained virologic response in the combination arm was 29 percent (16 of 56) compared with 7 percent (4 of 57) for those started on interferon alone. Among adolescents younger than 18 years who were treated with combination therapy, 10 of 17 (59 percent) had sustained response compared with 6 of 39 (15 percent) of adult patients on the same regimen. The authors conclude that in this trial of therapy for HCV in patients with inherited bleeding disorders, sustained virologic response rate was significantly improved for patients treated with interferon and ribavirin compared with those started on interferon alone. Adolescents treated with combination therapy had a significantly higher sustained response than adults did on the same regimen. 1 figure. 5 tables. 25 references. •
AIDS, Hemophilia, and Prevention Efforts Within A Comprehensive Care Program Source: American Psychologist; Vol. 43, No. 11. Contact: University of Oklahoma, Health Sciences Center, Mental Health Clinic, PO Box 26901, Oklahoma City, OK, 73190-3048, (405) 271-4219. Summary: Approximately 92 percent of the persons with severe hemophilia A in the United States have been exposed to HIV from contaminated blood products. This article describes HIV prevention efforts initiated by the federally funded comprehensive hemophilia program. The authors point out that comprehensive care centers are useful for the delivery and evaluation of educational and preventive efforts. Since the majority of people with hemophilia receive health services from the centers, it is possible to use these existing structures to facilitate multicenter studies of AIDS prevention programs. The article discusses treatment center prevention and education services targeted to the spouses and sexual partners of persons with hemophilia, and adolescents and children with hemophilia and HIV/AIDs.
•
When the Bleeding Won't Stop: A Case Report on a Patient with Hemophilia Source: JADA. Journal of the American Dental Association. 124(12): 64-67. December 1993. Summary: This article presents a case report of a 39-year-old male who developed severe prolonged bleeding after periodontal surgery because of a previously undetected clotting Factor XI deficiency (Hemophilia C). The author also discusses the diagnosis and treatment of this bleeding disorder. The author reminds readers that unexplained prolonged postsurgical bleeding should alert the practitioner to possible previously undiagnosed bleeding or a clotting disorder. 3 figures. 22 references.
•
Living With Hemophilia and HIV: Comfort Versus Cure Contact: National Hemophilia Foundation, Hemophilia and AIDS/HIV Network for Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (800) 424-2634, http://www.hemophilia.org. Summary: This article reprint focuses on communication between the HIV patient and his/her physician with an emphasis on the conflict between patient comfort and cure. It is very difficult for physicians to think about both immediately fatal worries and the so-
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called minor things that affect patient comfort. In some states the issue has grown into initiatives that deal with such issues as the treatment of pain. The problem becomes more widespread when the patient interacts with a range of health professionals, such as the holistic healer and psychotherapist, who may divert the patient's attention from the discomfort and yet compound the medical and/or emotional problem. Several examples of this are provided. According to the author, it is vital that the health care provider know the right questions to ask the patient to alleviate pain and its associated depression. Pain initiatives attempt to suggest more detailed ways of having a conversation about pain, and focusing on details. •
HIV Transmission Between Two Adolescent Brothers With Hemophilia Source: Morbidity and Mortality Weekly Report; Vol. 42, No. 49. 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 reprint of a journal article discusses an incident involving HIV transmission between two adolescent brothers, both with hemophilia. After summarizing the case history, the article outlines laboratory findings and the results of the epidemiologic investigation. The investigation rules out casual contact transmission, and finds that transmission most likely took place when the brothers shared a razor.
Federally Funded Research on Hemophilia The U.S. Government supports a variety of research studies relating to hemophilia. 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 hemophilia. 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 hemophilia. The following is typical of the type of information found when searching the CRISP database for hemophilia: •
Project Title: 2001 WORKSHOP ON GENE THERAPIES FOR HEMOPHILIA Principal Investigator & Institution: Verma, Inder M.; Professor; National Hemophilia Foundation 116 W 32Nd St, 11Th Fl New York, Ny 10001 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: (provided by applicant): Hemophilia is a genetic disorder of blood coagulation affecting approximately 17,000 individuals in the United States. The two
2 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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Hemophilia
most common forms of hemophilia are hemophilia A and hemophilia B, caused by defects or deficiencies in clotting factors VIII and IX, respectively. While treatment is effective for many people with hemophilia, it consists of life-long, intravenous infusions with clotting factor administered during or after a bleeding event. This therapy has many drawbacks, and thus gene therapy has been investigated as a means of curing hemophilia. Hemophilia is among those genetic disorders most likely to be amenable to gene therapy because it results from defects within single genes. Gene therapy for hemophilia would transfer functioning clotting factor genes into cells in a person with hemophilia, enabling that individual's body to manufacture clotting factor proteins. There has been considerable success in pre-clinical studies in using various viral vectors to obtain sustained expression of clotting factor in animals. Three human trials are now underway, two of which employ viral vectors; the third is an ex vivo, nonviral study. A number of research questions remain unanswered, and progress in the field is facilitated by holding regulaily-convened workshops where investigators can discuss the current state of their work. The National Hemophilia Foundation proposes to hold another in a series of gene therapy workshops April 19-21, 2001 at The Salk Institute for Biological Studies in La Jolla. California. The last workshop in March of 2000 looked at a number of questions related to immune responses to various viral vectors and transgenes, and a special pre-workshop summit will focus on the circumvention of such immune responses. Other concerns to be addressed include identification of the best target tissues for transgene expression; the safety of gene therapy retreatment; the risks associated with each vector system; the effect of hepatitis C and HIV infection and treatment on gene therapy; and ethical concerns in the use of human subjects, including clarification of patient and physician rights and responsibilities. The workshop affords a critically important opportunity for open communication and debate among basic researchers, clinicians, federal regulators, representatives of pharmaceutical companies, and members of the bleeding disorders community as human clinical trials proceed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: 5TH ANNUAL MEETING, AMERICAN SOCIETY OF GENE THERAPY Principal Investigator & Institution: Brenner, Malcolm K.; Professor; American Society of Gene Therapy 611 E Wells St Milwaukee, Wi 53202 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 30-JUN-2003 Summary: The emerging field of gene therapy has had its first successes in children with severe combined immune deficiency and in adults with hemophilia. Responses have also been observed in patients with an ever-broadening range of otherwise intractable cancers. It is also evident that the biological complexity associated with obtaining effective gene transfer mandates a multi-disciplinary approach to the field, involving collaboration between basic and clinical researchers and between industry and academia. This meeting provides a unique environment to foster such interactions, allowing individuals to be updated on a broad range of scientific issues, knowledge of which will be essential if the potential of this powerful new approach to be realized. The ASGT 5TH Annual Meeting will be held June 5-9, 2002 in Boston. The meeting will include 3 keynote addresses, 12 symposia (4 speakers each), presidential symposia, special symposia on future biology, 20 colloquia (selected from submitted abstracts), 12 workshops (6 speakers each), 24 educational seminars, 20 meet-the professor sessions, poster viewing, a high school teacher outreach program and public education. The areas covered in the meeting will be gene therapy approaches to cardiovascular disease, cancer, genetic diseases, infectious diseases, musculo-skeletal disorders, neural disorders, and hematopoiesis. The workshops are designed to discuss the improvements
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in delivery systems, production of vectors, novel vector systems, and specific diseases. The "meet-the-professor" sessions are designed to promote interaction among young investigators and faculty. Young scientists will have opportunities to present their work in colloquia and at poster sessions. Based on the 4th Annual Meeting and a recent increase in membership, we expect nearly 2,500 participants. We have planned a program where 10-15% of the participants will have an opportunity to make oral presentations. Because of the breadth of gene therapy, we seek "cross-institutional support" from the NIH, including, but not limited to, NHLBI, OD, NCI, NEI, NHGRI, NIA, NIAID, NIAMS, NICHD, NIDCR, NIDDK, NIGMS, NIMH, and NINDS. Emphasis on extensive participant of young practitioners in the field give the ASGT meeting a unique niche as the premier scientific meeting in gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: A MINI-AD VECTOR FOR TREATMENT OF FACTOR VIII DEFICIENCY Principal Investigator & Institution: Raschke, William; Genstar Therapeutics 10865 Altman Row, Ste 200 San Diego, Ca 92121 Timing: Fiscal Year 2001; Project Start 09-AUG-1999; Project End 29-SEP-2003 Summary: (provided by applicant): The inherited blood coagulation disorder hemophilia A results from deficiency in the expression or function of FVIII. The MiniAdF VIII vector is a "gutless" adenovirus vector designed to restore production of human FVIII by delivering the entire FVIII cDNA to somatic cells. Nonclinical pharmacology, toxicology and biodistribution studies have been performed. Importantly, physiological levels of FVIII were produced in vivo, and these levels persisted for an extended period of time, resulting in phenotypic correction in hemophilic mice and dogs. The objective of this clinical study is to evaluate through dose escalation the safety of intravenous infusion of MiniAdFVIII vector in severe hemophilia A patients without inhibitors. Additional objectives of this study are as follows: (1) to evaluate through dose escalation the ability of an intravenous infusion of MiniAdFVIlI vector to produce circulating, functional levels of FVIII, (2) to evaluate the effect of MiniAdFVIIl vector therapy on the frequency and severity of bleeding events following defined dose escalation, (3) to evaluate immunologic responses following the administration of MiniAdF VIII vector by monitoring anti-adenoviral and anti-FVIII antibody titers in blood, and (4) to determine the functional FVIII expression profile by measuring the level, time course, and duration of functional and circulating FVIII. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: A3: HUMAN THALASSEMIA, HEMOPHILIA
MOLECULAR
GENETICS:
SICKLE
CELL,
Principal Investigator & Institution: Cadilla, Carmen L.; University of Puerto Rico Med Sciences Medical Sciences Campus San Juan, Pr 00936 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AAV DIRECTED MUSCLE GENE THERAPY FOR HEMOPHILIA B Principal Investigator & Institution: Monahan, Paul E.; Pediatrics; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599
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Hemophilia
Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 30-NOV-2003 Summary: The adeno-associated virus (AAV) is a dependent parvovirus whose unique biology recommends it as a safe and efficient vector for gene therapy. In the absence of co-infection with a helper virus (adenovirus), the wtAAV integrates and persists in the host cell genome in a latent state, a property that would be attractive if reproduced by recombinant AAV (rAAV) vectors. We recently demonstrated the ability of muscle to serve as a platform for rAAV gene therapy in vivo, both in mouse and in a large animal model (the Chapel Hill strain of hemophilia B dogs). The overall goals of the proposed research are to improve AAV muscle gene therapy for hemophilia by investigating the molecular steps involved in rAAV transduction in primary muscle cells and by optimizing rAAV/F.IX vectors. Specific Aim I. Analysis of conversion of ssDNA to HMW DNA in vivo: A: Determine the molecular fate of rAAV vectors of skeletal muscle in vivo. This aim will require examining total genomic DNA from rAAV-infected muscle to determine the time course for conversion of input ssDNA to a form capable of persistence (HMW DNA). Levels of transgene expression and of DNA replication activity will be investigated in parallel to define a mechanism for the apparent amplification of transgene expression over time in non-dividing cells (mature muscle) following rAAV gene delivery. B: Determine the capacity of skeletal muscle to integrate rAAV in vivo. The ability of wild-type AAV to integrate into the host cell genome has led to the unproven assumption that sustained expression from rAAV vectors occurs via transcription form integrated rAAV sequences. Using a mouse model developed in our laboratory, which has the human integration site for wtAAV, we will seek to demonstrate stable vector (rAAV/F.IX) integrated into the skeletal myocyte genome. Specific Aim II. To test whether low levels of F.IX expression following rAAV gene therapy can be improved by higher specific activity F.IX variants and by repeat administration of rAAV/F.IX with alternative capsid structures. A: Factor IX variants have been constructed to study interactions of the protein with neighboring clotting cascade proteins. Constructs, including a chimeric protein with the EGF-1 domain of F.IX replaced by that of factor VII, and F.IX including a single point mutations in the catalytic domain will be investigated after in vivo delivery using rAAV vectors. B: Readministration of transgene using alternative serotype rAAV. While cellular immune response does not limit rAAV transgene expression, neutralizing antibodies predictably develop. By using alternative serotypes of capsid virus for packaging of transgene (AAV2, AAV3, AAV4), sequential administrations may elude the development of neutralizing antibodies to AAV, and allow augmented transgene expression after readministration of the therapeutic vector. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIVATION OF PROTHROMBIN Principal Investigator & Institution: Mann, Kenneth G.; Professor and Chair; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2001; Project Start 30-SEP-1991; Project End 31-AUG-2006 Summary: This research program is aimed at understanding how thrombin is generated and how thrombin generation is regulated. Our approach to these questions comes via the convergence of four separate directions associated with 1) the physical properties of coagulation enzyme complexes, their constituents and how these complexes can assemble into efficient enzyme catalysts. 2) Studies in which multiple coagulation catalysts/inhibitors are mixed to attempt to duplicate the performance of the combined catalyst system associated with the tissue factor pathway of thrombin expression. 3) To study this process in minimally modified biological systems (whole blood) to evaluate
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the correctness of hypothesis derived from purified systems. 4) To create mathematical models which can be used to define, on a quantitative basis, the process of blood clotting and its regulation both to aid in experimental designs 1,2,3, and also to aid in the evaluation of the pharmacologic agents and the diagnosis and treatment of hemostatic and thrombotic diseases. The aim of the present investigation is to understand the nature of procoagulant and anticoagulant vitamin-K dependent complexes and their regulation during the process of thrombin generation. Studies will employ physical chemistry techniques including hydrodynamics and fluorescence spectroscopy, (the latter both in solution and on surfaces) in closed systems and under flow to study complexes on synthetic membranes and cells. Reactions will be followed using both synthetic and natural substrates to monitor both presteady state and steady state kinetic events. Natural and recombinant inhibitors will be used to study the regulation of procoagulant and anticoagulant processes associated with thrombin generation. We will integrate the detailed information available through studies of individual reactions with that obtained from multi-reaction center systems. Conversely, the processes noted to occur in the whole blood system will direct appropriate attention in the purified system analyses. We anticipate developing a quantitative evaluation of the biologically relevant chemistry associated with the complex reactions which occur simultaneously during a blood clotting event. These data have significance in interpreting normal physiology and in developing approaches to correct the coagulation pathology associated with thrombosis and hemophilia. The techniques we develop will provide tools for the evaluation of potential pharmacological intervention in hemostatic and thrombotic disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASSESSMENT OF HD-AD VECTORS AND FACTOR IX AND APOA-1 Principal Investigator & Institution: Beaudet, Arthur L.; Professor and Chair; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: The overall goals of this project are to further define the safety and toxicity of helper-dependent adenoviral (HD-Ad) vectors, to delineate the pathogenesis of the thrombocytopenia observed with the HD-Ad vectors, to attempt to identify mechanisms to circumvent the thrombocytopenia, to develop experience with these vectors in primates, and to move incrementally towards clinical trials with these very promising HD-Ad vectors. The pathogenesis of the thrombocytopenia will be studied in mice, focusing on direct interactions between platelets and vector and between endothelial cells and vector. One very important aim will be to evaluate safety, toxicity, and shortterm expression using high doses of HD-Ad vectors in juvenile baboons. Because of the desire to initiate clinical trials with maximum safety, we are comparing the expression of factor IX and apolipoprotein A-I (apo A-I) with IM administration utilizing a musclespecific promoter and IV administration aimed at expression in hepatocytes. Another aim will be to put in place all of the necessary reagents and commitments to prepare GMP quality HD-Ad vector suitable for use in pre-clinical and clinical studies. Toxicity studies with GMP quality vector will be conducted in mice and baboons. In longer-term experiments in baboons, we will test whether over-expression of apo A-I will protect against atherosclerosis in baboons. Finally, we propose to develop a clinical trial to introduce the HD-Ad vectors into the clinic using either IM or IV administration. No IRB-approved protocol is available at present, but the major possibilities under consideration include expression of factor IX in patients with hemophilia B or expression of apo A-I in patients with coronary artery disease and low production of
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apo A-I. The long-term significance of this project is to attempt to develop HD-Ad vectors designed to increase expression of the LDL receptor and/or apo A-I in humans. If successful, this approach could have a major impact on prevention or reduction of atherosclerosis in the human population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOSYNTHESIS OF BLOOD CLOTTING PROTEINS Principal Investigator & Institution: Furie, Bruce; Chief, Coagulation Unit; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-APR-1987; Project End 31-AUG-2003 Summary: (Adapted from investigator's abstract) The vitamin K-dependent blood coagulation proteins undergo co- or post-translational processing that includes gamma carboxylation. This protein modification is required for calcium-dependent membrane binding. The propeptide of the molecule contains the gamma carboxylation recognition site which directs gamma carboxylation, and a propeptide cleavage consensus sequence. The current proposal aims to define the consensus sequence for the gamma carboxylation recognition site using combinatorial chemical peptide synthesis and combinatorial phage display. The three dimensional structure of a synthetic fully carboxylated profactor IX analog will be solved to determine the structure of the propeptide and its relationship to the Gla domain. To prove that the propeptide is sufficient to direct gamma carboxylation, in vivo carboxylation of chimeras of prothrombin propeptide joined to truncated P-selectin and PSGL-1 will be studied to assess carboxylation of glutamic acids in proteins that normally do not undergo gamma carboxylation. The cDNA encoding a protein required for gamma carboxylation in a CHO cell line characterized by defective carboxylation but with normal carboxylase activity will be identified by expression cloning. The physiological roles of furin and proprotein convertase 7 (PC7) in propeptide cleavage of the vitamin K-dependent proteins will be determined using furin deficient CHO cells, and experiments will be performed to identify the consensus sequence of PC7-mediated peptide bond cleavage. Experiments in this proposal will extend understanding of the role of the propeptide in vitamin K-dependent carboxylation and the identification of the enzymes that cleave the propeptide during the biosynthesis of these gamma carboxyglutamic acid-containing proteins. Gamma carboxylation and propeptide cleavage are the posttranslational events that limit the expression of the biologically active recombinant proteins and define protein expression levels for gene therapy of hemophilia B. Detailed knowledge of these processes will improve our understanding of the biology of these proteins and has potential for improvements in hemophilia therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BLOOD CLOTTING PROTEINS Principal Investigator & Institution: Mosesson, Michael; Brookhaven Science AssocBrookhaven Lab Brookhaven National Lab Upton, Ny 11973 Timing: Fiscal Year 2001 Summary: The original fibrinogen study is one of our oldest collaborations. A human mutation produces a hemophilia due to a single amino acid change in fibrinogen called fibrinogen Metz. We labeled this site with Au, and localized it to high resolution with the STEM. Other studies label the non-covalen0epolymerization sites on fibrinogen by synthesizing the tetrapeptide that binds there and adding a cysteine for gold attachment This pentapeptide also specifically targets the"epolymerization site and has now been
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Au-labeled to structurally map this site. This demonstrates the power of these techniques to map important functional subrnolecular sites and domain at high resolution. We are also studying intermediates in the formation of fibrin polymers using fibrinogen modified in various ways or labeled with clusters. A paper on early intermediates in fibrin polymerization has been published.': Nanogold has been used to label thrombin to map its binding site(s) on fibrinogen. The labeling has been good, but excess gold has been difficult to remove so the mapping is still inconclusive. Factor VM is what is defective in hemophilia. Baxter Healthcare has it cloned in different expression systems. They am interested in compared the factor VHI from these systems with the one from human plasma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CATABOLISM OF COAGULATION FACTOR VIII Principal Investigator & Institution: Saenko, Evgueni L.; American National Red Cross Rockville, Md 20855 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: (Investigator's abstract) Factor VIII (fVIII) is an important plasma component required for haemostasis, since genetic defects in this molecule cause a life-threatening coagulation disorder known as Hemophilia A. This genetic disease is treated by repeated infusions of expensive fVIII products. A more effective therapy can be provided if the molecular basis of fVIII clearance is understood and a novel recombinant fVIII protein with a prolonged lifetime in circulation is developed. We have previously found that the low density lipoprotein receptor-related protein (LRP), the main endocytic liver receptor, and cell surface heparan sulfate proteoglycans (HSPGs) cooperate in the clearance of fVIII, since simultaneous blocking of these two receptor systems dramatically prolonged the lifetime of fVIII in mice. While in purified system both LRP and HSPGs were shown to interact with fVIII via the sites located within the A2 domain, the precise molecular events responsible for fVIII catabolism are currently not well characterized. We propose to identify the amino acid residues critical for fVIII interaction with LRP and HSPGs by mutational analysis of the regions previously identified as LRP and HSPGs binding sites of fVIII. The mutations will be introduced into B-domain depleted recombinant fVIII, which is functionally identical to plasmaderived fVIII and is presently used for Hemophilia A therapy. We will express these fVIII mutants in mammalian cells and test them for binding to LRP and heparin, used as model of HSPGs, in purified systems. The catabolism of the mutants will be examined in vitro using LRP-expressing cells and in vivo in a murine model of Hemophilia A. These experiments will identify fVIII mutants with reduced binding to LRP and HSPGs and will clarify the role of these two receptor systems in fVIIII clearance. The proposed studies should develop an insight into the mechanism of fVIII regulation in circulation and will provide a basis for generation of a novel type of recombinant fVIII products, having a prolonged lifetime in circulation. Development of such fVIII derivatives, which may be prospective for less expensive Hemophilia A therapy, is the long-term goal of our studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CD4+ T CELL RESPONSE TO PORCINE FACTOR VIII Principal Investigator & Institution: Conti-Fine, Bianca M.; Distinguished Mcnight University Profess; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070
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Timing: Fiscal Year 2001 Summary: Patients with severe hemophilia A, after therapeutic exposure to factor VIII (fVIII), may develop inhibitory antibodies (Ab) to fVIII, that make their treatment difficult and costly. Antigen (Ag)-specific tolerance can be induced by administering the Ag through routes [e.g. nasal subcutaneous (s.c.)] that stimulate an immune response, than to abrogate an established response. In hemophilia patients with inhibitors, prevention of their further inhibitory response to forms of fVIII antigenically different from human fVIII may be easier to obtain that abrogation of their existing response to human fVIII. Porcine fVIII (pfVIII) is a possible such alternative to human fVIII. Mice genetically deficient in fVIII are a good model of hemophilia A, including appearance of inhibitors after intravenous (i.v.) Exposure to fVIII. To determine whether tolerization procedures using synthetic epitopes recognized by pfVIII-specific CD4+ cells prevent an immune response to pfVIII, in hemophilia A mice which already had inhibitors to human fVIII, will help development of similar treatments for hemophilia patients. The specific aims will be: 1) To determine the epitopes recognized and the cytokines secreted by anti- fVIII CD4+ cells in hemophilia A mice immunized with pfVIII, using overlapping peptides spanning the pfVIII sequence. To know the epitope repertoire of anti-pfVIII CD4+ cells, and whether they are of the Th1, Th2 or other subsets will help selecting the best tolerization procedures. 2) To determine whether prior i.v. exposure of hemophilia A mice to human fVIII affects the epitopes recognized by anti-pfVIII CD4+ cells after i.v. administrations of pfVIII. 3) To use synthetic pfVIII peptides forming CD4+ epitope sequences, for tolerization procedures in hemophilia A mice. Nasal tolerization procedures will be attempted first, using synthetic pfVIII CD4+ epitopes. If nasal tolerization will not prevent development of CD4+ and Ab responses to pfVIII, s.c. OR I.V. tolerization procedures will be attempted, using the same pfVIII epitope peptides. 4) To investigate the epitope repertoire of anti-pfVIII CD4+ cells in hemophilia patients treated sequentially with human and porcine fVIII to assess whether the characteristics of the anti-fVIII CD4+ cells in the mice are representative of those of CD4+ cells in hemophilia patients treated with human and porcine fVIII. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELLULAR IMMUNITY TO HEPATITIS C VIRUS IN HIV Principal Investigator & Institution: Graham, Camilla S.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (Provided by Applicant) The epidemics of HIV and hepatitis C virus (HCV) infections meet in individuals with parenteral exposure to blood, including injecting drug users (IDU) and persons with hemophilia, where rates of coinfection range from 60-90 percent. Coinfected individuals have a significantly increased risk of progression to end-stage liver disease, though mechanisms by which HIV modifies the course of HCV are poorly understood. It is paradoxical that HIV, an immunosuppressive state, leads to an accelerated progression of liver disease, and that HAART is associated with liver failure as well. Our central hypothesis is that both peripheral and intrahepatic HCV-specific cellular immune responses are qualitatively and quantitatively different in patients coinfected with HIV compared with those with HCV monoinfection, and that this is not solely a function of the degree of immunosuppression. Our goals are to determine whether coinfected individuals have an altered cellular immune response to HCV, to determine if immune reconstitution impacts HCV-specific cellular immunity, and if cellular immune responses to HCV are associated with improved outcome with anti-HCV therapy. To address these hypotheses we are examining HCV-specific cellular
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immune responses in three groups: 1) individuals with HCV/HIV versus HCV alone, 2) individuals with HIV/HCV prior to HAART and during immune reconstitution, and 3) individuals with HIV/HCV who are entering a protocol of interferon-ribavirin therapy. We are using ELISPOTS to characterize secretion of interferon-gamma, tumor necrosis factor alfa, and interleukin-10 at the single cell level in peripheral mononuclear cells and liver-infiltrating lymphocytes in these populations. We are complementing these functional assays with flow cytometry to phenotypically characterize lymphocyte populations. Determining alterations in cellular immune responses to HCV in individuals with HIV may help us to understand the pathophysiology underlying the accelerated progression of severe liver disease as well as help define subgroups of persons with HIV who may benefit from treatment of hepatitis C. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHIMERAPLASTY FOR FACTOR IX AND VII GENE EXPRESSION Principal Investigator & Institution: Steer, Clifford J.; Professor and Director; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001 Summary: Site-specific correction of defective genes by homologous recombination has been achieved at only very low frequencies in the treatment of inherited metabolic diseases by gene therapy. Recently, a synthetic RNA/DNA hybrid duplex, oligonucleotide designed to align in perfect register with the homologous genomic sequence except for a single base mismatch was show to promote targeted single nucleotide (nt) conversion in genomic DNA in rat hepatocytes The process exploits the cell's efficient endogenous DNA mismatch repair pathways, thereby, making it a novel approach to gene therapy. The main objective of t his research project is to evaluate the utility of these molecules in correcting the single nt mutations associated with hemophilia. This objective tests our hypothesis that gene correction in effected hepatocytes will improve the phenotype associated with the disease. The first specific aim is to optimize (1) in vitro our non-viral asialoglycoprotein receptor hepatocytespecific delivery systems, and (ii) chimeric RNA/DNA oligo oligonucleotide design for maximal conversion of the G to A transition at nt 1477 in the hemophilia B factor IX gene expressed in the Chapel Hill strain of dogs. The second specific aim is to evaluate the capacity of these molecules/delivery systems to promote targeted single nt conversion to correct the G to A transition in the canine factor IX in vivo. The non-viral delivery systems and chimeric oligonucleotides identified in Specific Aim 1 will be utilized. The relevant metabolic parameters will be monitored to quantitate the therapeutic effect of in situ genomic correction. Optimization of the dosing regimen, as well as the delivery vehicle and route of administration will be established. The third specific aim is to evaluate the potential of this technology in altering the genomic factor VII gene to produce the optimized factor VIIa mutations devised in Project 2. The initial work will be performed in vitro using cultured hepatocytes to optimize the delivery and design of the chimeric oligonucleotides. The selected factor VIIa mutation will then be generated in vivo and evaluated in collected hemophilia A phenotype in a factor VIII deficient mouse model. The relevant metabolic parameters will be monitored to quantitate the therapeutic effect of in situ genomic correction. Optimization of the dosing regimen, as well as the delivery vehicle and route of administration will be established. The long term goal of this research proposal is to: (i) to optimize non-viral delivery systems and oligonucleotide design that will promote the utility of RNA/DNA oligonucleotides for correcting single nt mutations associated with hemophilia; (ii) elucidate the optimal parameters for in vivo therapeutic correction of single nt
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mutations using this technology in the Chapel Hill strain of hemophilia B dogs, and (iii) evaluate the use of this technology for creating factor VIIa variants in vivo and there therapeutic benefit. The comparison of the in vitro and in vivo correction results will establish the feasibility for in vivo gene therapy approach using this technology for treatment of hemophilia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--ANIMAL Principal Investigator & Institution: Van Dyke, Terry A.; Associate Professor; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The Animal Core Facility will serve as an integral component of the UNC PPG. It is composed of rodent models for Pulmonary and Hematologic disorders and will be utilized by all projects. This core will provide in vivo models to the investigator for establishing preclinical studies necessary before initiating clinical trials. Some of the services the animal core will provide are related to deriving new animal models for airway and hemophilia gene therapy (Projects 3 and 4) through transgenic and knock out/knock in technology. These techniques are an established service to be offered to investigators who lack the facilities or expertise to create these invaluable resources. Breeding, maintaining, and distribution of animals is a major objective of the core facility and will be used by Projects 1, 2, 3, and 4. Apart from the routine breeding and maintaining of animals, the availability of the highly trained personnel of the Animal Core provides additional benefits to this research program. The UNC Animal Models Core Facility provides top-quality services at a manageable cost. Highly trained staff is directly engaged with researchers, and collaborations and resource sharing are facilitated. Perhaps most importantly, the facility provides assistance and guidance at many levels (i.e. creating genetically modified mice, from building, a DNA construct to phenotypic characterization of the animals). Thus, we can prevent a conceptually simple but technically demanding aspect of these proposals from becoming a serious obstacle to their success. The mouse facility has excellent records of success in creating, maintaining, and breeding animal models and these resources will be an added value to the overall goal of the UNC PPG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--HUMAN APPLICATIONS LABORATORY Principal Investigator & Institution: Hughes, Joseph; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001 Summary: The Human Applications Laboratory (HAL) of the Institute of Human Gene Therapy (IHGT) was established in 1993 to provide manufacturing capability for pilot human experiments. This facility provided clinical grade retrovirus for an ex vivo trial of gene therapy in familial hypercholesterolemia. More recently HAL has focused on recombinant adenoviruses providing support to six clinical trials including those involving cystic fibrosis and ornithine transcarbamylase. The concept of HAL has evolved to incorporate production, quality control and development of improved methods for manufacturing. The pilot manufacturing facility recently underwent substantial renovations and restructuring to allow the concurrent production of different classes of vectors. An important priority is the development of manufacturing and purification methods for adeno-associated virus (AAV). Clinical grade production
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of AAV should come on-line later this spring with planned applications to a number of genetic diseases such as hemophilia, retinitis pigmentosa, lysosomal storage diseases, and inherited myopathies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DATA AND SERUM SPECIMEN COLLECTION SYSTEM FOR HEMOPHILIA Principal Investigator & Institution: Dimichele, Donna M.; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001 Summary: A prospective multi-center study to maintain the health status of people with hemophilia and other congenital bleeding disorders. Blood samples and data will be collected. The blood will be tested for HIV and the hepatitis virus and the data will be used to assess the complications of hemophilia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENT AND PHARMACOLOGY OF NOVEL LIPIDIC RAHF Principal Investigator & Institution: Balasubramanian, Sathyamangala; Assistant Professor; Pharmaceutical Sciences; State University of New York at Buffalo Suite 211 Ub Commons Amherst, Ny 14228 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Hemophilia A is an inherited bleeding disorder caused by deficiency of Factor VIII, a blood coagulation protein that functions as a cofactor in the coagulation cascade. It is transmitted as a defect on the X chromosome and affects 1 male in 5000. Recent advances in biotechnology and protein engineering, together with cloning of the gene coding for Factor VIII, have made it feasible to manufacture recombinant human Factor VIII (rAHF). The recombinant preparation promises to be a source of unlimited supply, together with the freedom from the complications of transmission of blood-borne viruses. However, rAHF induces antibody type immune response or inhibitors. It has been shown that immune response for a therapeutic protein is caused by the existence of aggregates, frequent administration and existence of natural antibodies for specific epitope region of the protein. Furthermore, a moderately-short circulating half-time limits the duration of pharmacological effect. The overall goal of this proposal is to develop a lipid-based delivery vehicle for AHF to overcome the immune response and extend circulating halflife (Inhibitor Treatment for Hemophilia using Lipid Protein System, ITHELPS). The rationale to use lipidic protein complexes is three fold: (1) the epitope region of the protein binds to phospholipids, and thus by engineering a lipid-protein complex one could shield the epitope region; (2) the lipidic components can interact with intermediate structures in the unfolding/denaturation pathway, thus stabilizing protein structure during storage and reconstitution, thereby avoiding protein aggregate formation, and (3) the lipid-protein complexes, analogous to liposomal particles, may increase the circulation half-life of the rAHF, thus reducing the frequency of administration. In support of these hypotheses, preliminary studies were carried out to develop rationally a lipidic rAHF. The liposomal vesicles stabilized the protein against aggregation and a prototype formulation with lipidic rAHF was achieved. We propose to characterize the molecular topology, pharmacokinetic behavior and immune response of this novel, rationally developed lipidic rAHF. Further, we propose to investigate liposomal clearance mechanisms, including endocytosis and its role in altering the circulation time and immune response
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of lipidic rAHF. We also propose to study the epitope specificity of rAHF antibodies and the mechanism of immune response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DNA INTEGRATION USING TN5 TRANSPOSASE FOR GENE THERAPY Principal Investigator & Institution: Wooddell, Christine I.; Mirus Corporation 505 S Rosa Rd, #104 Madison, Wi 53711 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2002 Summary: APPLICANT?S Gene therapy will allow for the treatment of both acquired and genetic diseases at the most fundamental level by introduction of therapeutic genes. Despite advances in delivery of foreign genes, achieving high and stable levels of expression has been problematic. The use of plasmid DNA for gene therapy has many advantages, including safety, accommodation of large genes, ease of production, and low cost. Plasmid DNA is lost, however, as cells divide. Viral integration of a transgene into the host genome prevents loss of the gene. Integration is hypothesized to be responsible for the long-term expression of some transgenes delivered through viral vectors. Disadvantages of viral vectors include safety concerns, cost, and difficulties in production. In order to achieve nonviral integration of a transgene and then expression at therapeutically useful levels, we propose to deliver the gene in pre-formed synaptic complexes of hyperactive Tn5 transposase dimers bound to DNA elements flanking the transgene to be integrated. This integration requires no specific sequence in the target DNA (the genome). During Phase I, we will verify that these synaptic complexes can be delivered into mammalian cells in culture and that the bacterial transposase can indeed effect integration in mammalian cells. In Phase II, the use of pre-formed Tn5 transposase-DNA complexes will be optimized and incorporated into gene therapy approaches such as the transplantation of cells genetically modified ex vivo (e.g., fibroblasts, keratinocytes, and myoblasts) or the direct gene transfer into cells in vivo (e.g., hepatocytes). These studies will form the basis for the commercial development of Tn5 transposase-mediated integration of transgenes into mammalian cells in vitro as a research tool, and for gene therapy ex vivo and in vivo. PROPOSED COMMERCIAL APPLICATION: A gene integration system could have immediate application for ex vivo gene therapy (e.g., transplantation of genetically modified fibroblasts, keratinocytes, hemopoietic stem cells, and myoblasts). Mirus will immediately commercialize (on the basis of the Phase I studies) reagents for enabling the more efficient integration of cells in culture (in conjunction with our line of transfection reagents) and cells in vivo (on the basis of Phase II studies). Its commercial development will be accomplished by initiation of pre-clinical trials using model disorders such as hemophilia and licensing to larger pharmaceutical and biotechnology companies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ECTOPIC GENE EXPRESSION OF FVIII IN MEGAKARYOCYTES Principal Investigator & Institution: Poncz, Mortimer; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001 Summary: Coagulation Factor (F) VIII is mostly made in the liver. Its deficiency is the mot common inherited severe bleeding disorder. Present treatment involves intravenous infusions of FVIII. This therapy has drawbacks, and while efforts are underway to develop a form of somatic gene therapy, successful programs have yet to
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be achieved. The objective of this application is to develop an alternative approach, ectopically expressing FVIII in platelets. Preliminary studies show that transgenic mice expressing human (hu) FVIII driven by the murine (mu) Platelet Factor 4 (PF4) promoter can ameliorate the bleeding diathesis in FVIII-deficient (FVIII) mice. Specific aims are as follows: (1) Complete the analysis of the initial founder lines expressing huFVIII. These studies will further document the platelet-specific nature of the huFVIII, document its level of expression, and more fully define the degree of correction of the FVII/Iphenotype. (2) Improve the efficiency of the construct for huFVIII expression in megakaryocytes. This aim will try several construct variations to obtain higher levels of huFVIII expression platelets, and correlate levels of expression with phenotypic improvement. (3) Assess the efficacy of megakaryocyte expression of huFVIII in the context of a viral transfer system in a murine model. These studies will further test our model of whether huFVIII expression in hematopoietic stem cells is a viable approach for the treatment of Hemophilia A using retroviral constructs. These vectors will be tested on FVIII-mice recipients and the bleeding diathesis, the level of platelet huFVIII expression and the duration of correction will be determined. These studies will provide a useful pre-clinical evaluation of the proposed approach to genetic therapy for FVIII deficiency. We believe that ectopically expressed FVIII will be a viable way to treat FVIII deficiency, resulting in a longer FVIII half-life and in the delivery of FVIII in a concentrated fashion at the site of injury. We also believe that this approach may provide a source of "protected" FVIII that would be useful in patients with inhibitors. Finally, we believe that this approach may serve as a model for gene therapy to deliver other proteins in concentrated fashion to a site of injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECTS OF COMBINED ANTIRETROVIRAL THERAPY ON COAGULATION FACTORS Principal Investigator & Institution: Eyster, M E.; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2002 Summary: Effects of Combination Antiretroviral Therapy including Indinavir Sulfate on Coagulation Factors, on Platelet Aggregation and on Factor VIII/IX in HIV-1 Seropositive patients with Hemophilia A or B. The objectives of this protocol are to assess whether, in the specific population being studied, a combined therapy of indinavir sulfate NRTIs induces changes in prospectively identified elements of the coagulation system. It is recognized apriori, that due to the nonfeasibility of having a group in which indinivar sulfate is not added to combination NRTI therapy, it will be impossible to determine what changes in the coagulation system, if any, would have been observed in the absence of indinivar sulfate. However, to help assess changes in the pharmacokinetic half-life and recovery of infused factor VIII, protease inhibitorexperienced HIV-1 seropositive hemophilia A patients will serve as a laboratory control group. We hypothesize that after 12 weeks of treatment, coadministration of indinavir sulfate and NRTIs to protease inhibitor-naive HIV-1 seropositive hemophilia A patients will decrease the pharmacokinetic half-life of infused factor VIII compared to preindinavir sulfate therapy baseline relative to changes observed in the laboratory control group. Secondarily, during a 52 week coadministration of indinavir sulfate and combination NTRI therapy to protease inhibitor-naive HIV-1 seropositive hemophilia patients after 12 weeks of treatment: the pharmacokinetic recovery of infused factor VIII in hemophilia A patients will be reduced, relative to changes observed in the laboratory control group; the pharmacokinetic half-life of infused factor IX in hemophilia B
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patients will be reduced and the pharmacokinetic recovery of infused factor IX in hemophilia B patients will be reduced. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFICACY AND SAFETY OF AAV GENE TRANSFER FOR HEMOPHILIA Principal Investigator & Institution: Arruda, Valder R.; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant) This career development award application outlines detailed plans for mentored training of Dr. Valder R. Arruda. The research plan details experiments related to AAV-mediated gene transfer for hemophilia B. In previous work we showed long-term expression of biologically active Factor IX in small as well as large animal models of hemophilia B following intramuscular injection of an AAV vector expressing human blood coagulation Factor IX. These data served as the basis for a clinical trial in which subjects with severe hemophilia B were treated by intramuscular injection with an AAV serotype 2-derived vector expressing human Factor IX. There has been no evidence of systemic or local toxicity in the treated subjects, but a dose has not yet been reached at which all subjects in a dose cohort achieve therapeutic levels of gene expression. The overall foal of the work proposed in this application is to evaluate several hypotheses that may lead to safer and more effective gene transfer. In the first aim, I will test the hypothesis that alternate serotypes of AAV, specifically AAV-1 and AAV-6, can direct higher levels of transgene expression in hemophilic doffs and human muscle cells. As shown in preliminary data, we have already shown in mice that these alternate serotypes can direct transgene expression at levels 10-20 fold higher than equivalent doses of an AAV-2 derived vector. However it is important to determine whether this effect is confined only to murine cells or is more widely observed. If higher levels of transgene expression are observed in human myotubes, we will be able to use this cell culture system to determine the mechanism(s) responsible for the higher expression. In the second aim, we propose to use a novel vector delivery technique to address a problem that plagues muscle-directed gene transfer, namely how to achieve transduction of large numbers of cells without Innumerable intramuscular injections. We hypothesize that we can achieve more extensive delivery to skeletal muscle tissue through the use of a technique in which vector is infused into the arterial circulation along with vasodilatory agents. This technique may allow more efficient delivery of vector and thus render muscle-directed gene transfer more feasible. Finally we propose to study molecular and cellular consequences of transduction of skeletal muscle by AAV vectors using microarray technology. This aim addresses one of the most difficult safety issues in gene transfer, i.e. long-term consequences of vector transduction. The data from these experiments will allow us to plan additional safety studies in relevant animal models to assess the long-term safety of treatment with AAV vectors. Other components of this application outline formal coursework, seminar participation, training in responsible conduct of research, and consultation with a formal committee that will enhance the applicant?s career development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENHANCED VITAMIN K DEPENDENT PROTEINS IN HEMOPHILIA Principal Investigator & Institution: Nelsestuen, Gary L.; Professor; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070
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Timing: Fiscal Year 2001 Summary: This project takes advantage of new understanding about membrane association by vitamin K-dependent proteins. Key proteins of the coagulation cascade (factors VII and IX) display low affinity for membranes. This affinity can be increased to that of high affinity vitamin K-dependent proteins by site directed mutations. In vitro assays show that these changes have a large impact on activity of factor VII and VIIa in vitro, using assays that mimic biological conditions. Enhancement is realized in both tissue factor dependent as well as tissue factor- independent systems. Six specific aims include: 1. Identify the site- directed mutant forms of human factor VIIa that have the highest activity, in vitro. Express these proteins in quantities suitable for studies in the mouse and rabbit. 2. Develop a reliable assay for bleeding challenge in quantities suitable for studies in the mouse and rabbit. 2. Develop a reliable assay for bleeding challenge in the hemophilic mouse, that provides the ability to test efficacy of factor VIIa mutants. 3. Test Efficacy of human factor VIIa mutants in the mouse model, using mutants identified in specific aim 1 and methods identified in specific aim 2. 4. Express site-directed mutants of mouse factor VIIa which correlate with the best human factor VIIa mutations. Test these in the mouse by procedures developed for the human protein molecules described in specific aims 2-3. 5. Test in vitro anti-coagulant properties of human active site-blocked factor VIIa molecules described in specific aim 1, to determine the best mutants to be tested in the rabbit model. 6. Obtain preliminary evidence for potential uses of other vitamin K-dependent proteins which have mutations in the Gla domain and increased affinity for membranes. These may include especially factors IX or X. The project uses site-directed protein mutation, protein expression, purification, and characterization by protein chemistry and numerous coagulation tests. In vivo testing will be carried out in mice and rabbits. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EPIDEMIOLOGY AND IMMUNOLOGY OF HEMOPHILIA A INHIBITORS Principal Investigator & Institution: Ragni, Margaret V.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2004 Summary: (Adapted from the Applicant's Abstract) The purpose of this study is to determine the risk factors associated with inhibitor formation in hemophilia A and to study the mechanism of tolerance in the murine hemophilia A model. Clinical data on 364 individuals with hemophilia and inhibitors, and stored frozen plasma and white cells on 189 of these, identified in the Hemophilia Malignancy Study (HMS), and the hemophilia A murine model are available for study. Inhibitor formation in individuals with hemophilia is a difficult therapeutic challenge, refractory to standard treatment, potentially life-threatening, costly, and a potential complication of new treatment, such as gene therapy. The major hypothesis of this study is that suppression of immunoregulatory cytokines will prevent factor VIII inhibitor formation in the hemophilia A murine model: if successful, a treatment protocol could be developed for individuals identified to be at highest risk for inhibitor formation. Through this approach to the epidemiology and immunology of inhibitor formation, the investigators may improve the health care of individuals with hemophilia. The specific aims include: (1) A case-control study comparing prevalent hemophilia patients with inhibitors identified in the HMS Study with three age-matched controls without inhibitors to determine clinical and laboratory characteristics associated with inhibitor development. (2) a histocompatibility study identifying patterns of HLA Class II antigens by molecular
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typing in hemophilic subjects identified in HMS, with and without inhibitors, which may be linked to inhibitor formation. (3) An animal tolerance study in the hemophilia A murine model, evaluating blockade of T cell costimulatory pathways by CTLA4-Ig and anti-CD40L mAb, to prevent inhibitor formation. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EPIDERMIS-TARGETED GENE THERAPY FOR HEMOPHILIA A Principal Investigator & Institution: Fakharzadeh, Steven S.; Dermatology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 10-AUG-2001; Project End 31-JUL-2005 Summary: This is a grant by a new investigator who proposes to use the skin as a target tissue for gene therapy in diseases where a soluble factor is curative. The rationale for the experiments is that keratinocytes are secretory cells. The candidate heritable disorder for the proposed studies is Hemophilia A, caused by the deficiency of a secreted protein (factor VIII) that, when present even at low levels, is corrective. Preliminary experiments by Dr. Fakharzadeh show that skin transplants from transgenic mice over-expressing factor VIII maintain high levels of the coagulation factor in factor VIII deficient mice and the rate of clotting is improved. Successful completion of the planned experiments are critical for developing cutaneous factor VIII gene therapy for treating Hemophilia A. Strategies for optimizing factor VIII expression, delivery to the circulation, and activity are proposed in five subheadings in Aim 1. These include comparisons performed in factor VIII deficient mice: of human factor VIII levels generated by transgenes targetted to express the coagulation factor in basal or suprabasal epidermis; of the circulating levels of factor VIII following structural alterations (expression as a single peptide chain, as an inactivation resistant form, or as a species-specific form); and of the levels of factor VIII following stabilization by coexpressing factor VIII with vWF. Aim 2 deals with the treatment of immunoincompetent knock-out mice following grafting of gene transduced human keratinocytes. The humoral response of naive knock-out mice to human factor VIII is characterized in Aim 3. First, an immunocompetent Factor VIII ko mouse will be generated that is compatible with the donor skin but not the product. Second, the humoral response (anti-factor VIII antibody formation and their inhibitory responses) are monitored in the immunocompetent ko model. Third, the cell-mediated response is characterized by monitoring factor VIII-reactive T lymphocytes, helper T cells, and cytotoxic T lymphocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EVOLUTION /REARRANGEMENTS
OF
PRIMATE
GENOME
SEQUENCE
Principal Investigator & Institution: Nelson, David L.; Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 11-JUN-2001; Project End 31-MAY-2006 Summary: The overall aim of this project is to define the evolutionary origins of local, low-order repeated sequences that contribute to genetic diseases in humans. This project will contribute materials and expertise to project I- III and assist with characterization of sequences under study in the laboratories of Drs. Morrow, Lupski and Shaffer. In addition, this project will carry out analysis of regions of the human X chromosome that carry out similar sequences involved in genetic disease. This effort will be carried out in conjunction with a project to define the molecular breakpoint of chromosomal
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rearrangements that have occurred among the great apes. The data developed in this project will lead to a greater understanding of the origin of sequence subject to instability in disease. Furthermore, understanding the molecular causes and effects of genome change may lead to greater insight into the evolutionary process. Four specific aims are proposed: 1. Characterize the LCR22 from chromosome 22 in higher primates to determine their evolutionary origins. 2. Analyze the region-specific low-copy repeat gene clusters in proximal human chromosome 17 and determine their evolutionary origins. 3. Determine the subtoleromeric DNA structures on distal human 1p and analyze their structures and chromosomal distribution among the great apes. 4. Determine the evolutionary origin of two local repeats on the human X chromosomethose involved in deletions of Xp22.3 leading to steroid sulfatase deficiency and those involved in Xq28 inversions resulting in Hemophilia A. Successful completion of these aims will refine hypotheses regarding the mechanisms responsible for generating the sequences that lead to high frequency rearrangements associated with human genetic disease. It is anticipated that understanding the features involved in these regions will help to predict additional region subject to similar changes. This will in turn lead to recognition of the molecular basis for mental retardation and development of refined diagnostic assays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FACTOR IX MOUSE MODELS FOR HEMOPHILIA B GENE THERAPY Principal Investigator & Institution: Stafford, Darrel W.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Current efforts toward gene replacement therapy for the hemophilias using viral vectors show promise for long-term gene expression (over 1 year) of biologically active secreted proteins (i.e. > 1% of factor IX) in relevant animal models (hemophilia B mouse and dog models) without significant toxicity. Animal studies, in particular, underscore the importance of eliminating transient antibodies to the vector-expressed gene product and optimizing vector delivery and expression as the pressing challenges for assured success of human clinical trials. Generation of ideal animal models and more efficient vector cassettes could advance this phase of development immensely. Recently, we have been successful in developing Factor IX (FIX) molecules with higher specific activity due to increased affinity for Factor VIII or elevated catalytic activity. A single point mutant with threefold higher binding affinity for collagen IV is anticipated to maintain hemostasis at a lower concentration of plasma factor IX levels. Combining these viriants should generate FIX molecules with additional increases in activity. To effectively test these constructs in vivo, we have engineered a FIX deficient animal model using ("knock-out") technology that allows for specific reinsertion ("knock-out") of gene cassettes. With this model, we can assess the biological activity of the above proposed mutants which should provide a better understanding of FIX activity in vivo as well as assist in determining the potential lifelong efficacy and safety of these gene cassettes for viral vector delivery. An additional objective of this proposal is to generate normal as well as clinically relevant mutant human FIX mice using this approach. It is anticipated that we will be able to generate custom designed humanized FIX mouse models (CRM+/CRM-; inhibitor negative tolerant or inhibitor positive) thereby mimicking spontaneous mutants now seen in the clinic, for thorough characterization in the mouse. These animals will be important for studying Therapeutic levels required from vectors and potential immune response that may be generated in mutant human FIX mouse background. Therefore, the major focus of this proposal will
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be related to testing the molecular and biological consequences of human and variant factor IX gene products expressed in a "knock-in" FIX deficient mouse model. The longterm objective is to better understand the molecular role of FIX in vivo with the hope of enhancing effective gene therapy in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FACTOR HEMOPHILIA B
IX
RECOVERY
(MONONINE
VS
BENEFIX)
IN
Principal Investigator & Institution: Kisker, C Thomas.; Professor of Pediatrics; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002 Summary: This study is evaluating the recovery and half life of factor IX following Mononine coagulation factor IX (human) and monoclonal anti-body purified Benefix coagulation factor IX (recombinant) administration in children with hemophilia B. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FACTOR VIII INTERACTIONS IN INTRINSIC XASE Principal Investigator & Institution: Fay, Philip J.; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2001 Summary: Hemophilia A, the most common of the severe, inherited bleeding disorder, resulting from a deficiency of defect in factor VIII. The activated form of factor VIII, factor VIIIa, functions as a co-factor for the factor IVa-dependent activation of factor X, increasing the kcat for this reaction by several orders of magnitude. We propose to elucidate fine point structural detains of inter-protein interactions that will define mechanisms for the regulation of this critical plasma protein and activity of the intrinsic factor Xase, applying physical and biochemical approaches and utilizing molecular biological methods. The first aim will study interactions of factors VIIIa and IXa. Our goal is to define mechanisms that contribute to rate enhancement and that are responsible for a novel interactive process resulting in reciprocal regulation of cofactor and enzyme activities. To this end we will (i) construct and analyze recombinant factor VIII and A2 subunit containing point mutations in a putative factor IXa-interactive surface loop, (ii) quantitate binding parameters binding parameters, (iii) assess contribution of factor IVa to factor VIIIa subunit stability, (iv) determine geometry within the intrinsic factor Xase, (v) evaluate the role of C-terminal acidic region in factor IVa-catalyzed inactivation of the co-factor and (vi) determine factor Xase stability using a cleavage- resistant factor VIII and a novel factor IXa molecule. The second aim studies a newly identified interactions between factor VIII and substrate factor X. Our goal is to characterize this interaction and determine its functional significance. Proposed studies will (i) identify the interactive region in factor VIIIa and quantitate binding parameters and (ii) determine the consequence the consequence of this interaction in terms of product generation and regulation of factor Xase activity. A final aim will study activated protein C (APC) catalyzed inactivation of factor VIIIa. Our goal is to define mechanisms contributing to substrate site selectivity and decay of factor Xase on the endothelial cell (EC) surface. Studies will (i) quantitate rates of attack by APC and factor IXa at a common bond in factor VIIIa, (ii) evaluate factor VIIIa inactivation resulting solely from cleavage at the A2 site and (iii) assess the basis for the role of protein S in defining site selectivity. Experiments will characterize factor VIIIa-dependent inactivation of factor Xase by APC on the EC, a physiologic surface where this pathway
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potentially represents the dominant mode for factor Xase damping. Definition of these issues will yield valuable insights into the biochemistry of the native as well as dysfunctional factor VIII molecules, and provide information for the design of superior therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FACTOR VIII INTRAMUSCULAR GENE THERAPY Principal Investigator & Institution: Mccormack, William M.; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 10-SEP-2001 Summary: (provided by applicant): The post-translational processing of B-domain deleted blood coagulation factor eight (BDD-FVIII) is complex and requires von Willebrand factor (vWF) for efficient secretion. The candidate proposes to co-express BDD-FVIII and vWF in muscle cells by transfection of Cl C12 myocytes and to perform assays on the conditioned media and the cells to assess secretory efficacy. A helperdependent adenoviral vector (HDV) system has been developed that has a large carrying capacity, low toxicity, long term expression and can accommodate an effective promoter as well as other transgenes in addition to BDD-FVIII. This HDV system will be used to co-express vWF and BDD-FVIII in mice via direct intramuscular injection. Studies of these transformed mice will include clotting activity of secreted BDD-FVIII, serum levels of vWF, and antibody response to the vector, FVIII and vWF. Muscle biopsies will be analyzed by H&E staining, immuunohistofluoresence, X-gal staining and northern analysis for BDD-FVIII and vWF mRNA. Achievement of efficient FVIII secretion from direct gene delivery into muscle will allow for a safer avenue to pursue in vivo gene therapy of hemophilia A in animal models and eventually in human patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FIBROBLAST PRODUCING HUMAN FACTOR VIII IN HEMOPHILIA A Principal Investigator & Institution: Roth, David A.; Assistant Professor of Medicine; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FLUOROGENIC ASSAYS FOR FACTOR VLLA AND TISSUE FACTOR Principal Investigator & Institution: Jenny, Richard J.; Haematologic Technologies, Inc. Box 1021, 57 River Rd Essex Junction, Vt 05452 Timing: Fiscal Year 2003; Project Start 08-MAY-2003; Project End 31-OCT-2003 Summary: (provided by applicant): Factor Vlla and Tissue Factor (TF) are essential proteins for the initiation of blood coagulation. Blood coagulation is initiated when cryptic TF becomes exposed on the surface of vascular cells where it can bind circulating factor Vlla. The factor Vlla/TF complex catalyzes the activation of certain blood zymogens that propagate the coagulation event. The amount of circulating factor Vlla has been shown to be a good indicator of hemostatic potential and for this reason is a potential risk indicator for the development of cardiovascular disease. In addition, over the past decade recombinant factor Vlla has become the drug of choice for treating hemophilia A and B patients who have developed inhibitors to factors VIII and IX
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respectively. Formation of the factor Vlla/TF complex is also the basis of specific coagulation assays. The Prothrombin time (PT assay) utilizes either natural or synthetic thromboplastin reagents to initiate coagulation in-vitro. Thus in addition to its in-vivo role, TF also has in-vitro applications. Furthermore, TF is not only present in the vasculature, but also in a numerous other tissues and cells including brain, lung, placenta, platelets, monocytes and tumor cells. In addition to its "normal" role in hemostasis, it is also known to be involved in the metastasis of tumor cells. The fact that TF and factor Vlla play such important roles both in-vivo and in-vitro, indicates that rapid and direct assays for these proteins could be of great utility. At the present time, reliable assays for factor Vlla and tissue factor that can be applied to simple as well as complex biological systems do not exist. The goal of this phase I proposal is to demonstrate the feasibility of developing fluorogenic-based assays that may be used to directly measure factor Vlla and TF in simple and complex biological systems. To accomplish this goal, the following specific aims are proposed: 1) To utilize aminonapthalene-based fluorogenic substrates for factor Vlla to develop basic assays that may be used to quantitate factor Vlla and TF in simple and well defined systems; b) to further develop the assay for tissue factor and demonstrate the ability to measure TF in more complex biological systems; and c) to further develop the assay for factor Vlla and demonstrate the ability to measure factor Vlla in more complex biological systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTION OF FACTOR VIII ON THE PLATELET MEMBRANE Principal Investigator & Institution: Gilbert, Gary E.; Assistant Professor of Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: The importance of the factor VIIIa-factor IXa enzyme complex is illustrated by hemophilia in which the absence of either protein causes life-threatening bleeding. In our investigations over the past 5 yrs we have found that on membranes with low mole fractions of acidic phospholipid, resembling cell membranes, factor VIII exhibits stereoselective affinity for phosphatidyl-L-serine containing binding sites. The phosphatidylserine (PS)-containing sites are highly specific so that no plasma proteins will compete efficiently with factor VIII for binding. We have also found that factor VIIIa binds to factor IXa with moderately high affinity in the absence of phospholipid membranes but the catalytic efficiency of the factor VIIIa-factor IXa complex is greatly enhanced by binding to PS containing membranes. These findings lead us to the following three hypotheses. First, membrane-bound factor VIIIa provides high affinity membrane binding sites for factor IXa and high affinity binding requires the correct conformation of the factor IXa active site. We will measure binding of factor IXa, derivatized in the active site by a fluorescein-labeled tripeptide substrate (Glu-Gly- Argchloromethyl ketone), to factor VIIIa that is bound to phosphatidyl- L-serine-containing synthetic membranes vs. platelets. For comparison factor IXa will be derivatized with a non-physiologic tripeptide substrate (D-Phe-Pro-Arg chloromethyl ketone) that alters the active site conformation of thrombin and apparently of factor IXa. Second, individual phospholipid molecules or small aggregates of phospholipids activate the factor VIIIa-factor IXa complex by causing a change in the conformation of the enzyme complex. We propose experiments with soluble phospholipids and with phospholipids in mixed micelles to distinguish moieties that activate the factor VIIIa-factor IXa complex from those that are inert constituents of the membrane matrix. Experiments with antibodies to the phospholipid-binding structures of factor IXa and factor VIIIa, and with modified forms of factors X, will indicate whether the complex is altered at a
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site distant from the membrane. Third, the high specificity of PS-containing membranes for factors VIIIa results from spontaneous arrangement of membrane phospholipids into microdomains which function as specific binding sites on platelet membranes. We will prepare monoclonal antibody fragments that recognize PS-containing microdomains in order to better characterize microdomains and to investigate their importance as functional receptors for factors VIII. Completion of the proposed studies will substantially increase our understanding of the role of the platelet phospholipids in activating the factor VIIIa-factor IXa complex. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE THERAPY DEVICE FOR TREATMENT OF HEMOPHILIA B Principal Investigator & Institution: Buffington, Deborah A.; Nephros Therapeutics, Inc. 1995 Highland Dr, Ste F Ann Arbor, Mi 48108 Timing: Fiscal Year 2001; Project Start 01-SEP-1998; Project End 09-MAY-2003 Summary: (Unedited Applicant's Abstract): The goal of this proposal is to develop a novel gene therapy delivery device for treatment of the genetic disorder. Hemophilia B. a devastating and costly (over a billion dollar market) disease characterized by spontaneous internal bleeding. The planned experiments will provide a cell therapy delivery vehicle for implantation into a large vessel of an animal. and eventually, a patient suffering from this genetic defect. Specific Aim 1 plans to test two IVD prototype fabrications for the ability to support adequate myoblast cell number and FIX secretion rates to achieve clinically significant FIX levels. Specific Aim 2 plans to optimize the in vitro cFIX production rates of the selected D/D prototype. Specific Aim 3 plans to introduce this IVD prototype with autologous canine myocytes transduced with hFIX gene into a normal dog where it will be secured in the vena cava by a Greenfield filter anchor (GFA). The hemocompatibility of this device within the vena cava, and myocytes viability will be assessed over various periods of time (up to 6 weeks). Specific Aim 4 plans to test the cFIX production rates and biological activity of cFIX transduced autologous canine myoblasts in the cell IVD prototype in a Hemophilia B dog model. The successful completion of these studies will provide 'proof of concept' for utilization of the IVD as a gene therapy' treatment of hemophilia B. The ultimate goal is to develop a novel cell and gene therapy delivery system (comprised of a cell-filled IVD anchored by means of a Greenfield filter) that is introducable and retractable via a percutaneous catheter insertion through the femoral vein into the inferior vena cava. The IVD may be used to deliver any desired compound via cell or gene therapy. This approach may be the key enabling technology for both the gene therapy and cell therapy industries, providing a safe means to implant a retrievable device to introduce gene products directly into the systemic circulation of an individual with a genetic disorder. PROPOSED COMMERCIAL APPLICATION: Not Available Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE THERAPY FOR BLOOD PROTEIN DEFICIENCIES Principal Investigator & Institution: Ponder, Katherine P.; Associate Professor of Internal Medicine; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 15-SEP-1996; Project End 31-DEC-2005 Summary: Hemophilia B occurs in 1:30,000 males and is associated with a life-long bleeding diathesis. Although IV injection of Factor IX can prevent or stop bleeding, this treatment is inconvenient, expensive, and can transmit infections. Hepatic gene therapy could permanently correct the clinical manifestations of hemophilia. Retroviral vectors
26
Hemophilia
(RV) can result in long-term and therapeutic levels of expression of coagulation factors from the liver in rodents, and are currently being used in a clinical trial for Hemophilia A in humans. However, there are two major problems that must be solved before RVmediated hepatic gene therapy will be used routinely: 1) identify ways to achieve a higher efficiency of stable gene transfer without major toxicity; and 2) identify methods for blocking an immune response to the therapeutic gene in the context of RV-mediated hepatic gene therapy. This project will address both of these issues. The first aim is to determine if delivery of an RV expressing the canine Factor IX (cFIX) cDNA into the liver can reduce the bleeding manifestations of Hemophilia B dogs obtained from a colony that rarely makes antibodies to the canine protein. This should allow us to quantify gene expression without the confounding issue of an immune response. Initial studies will use neonatal dogs, as their high baseline level of hepatocyte replication allows transduction of 9 percent of liver cells. Subsequent studies will use hepatocyte growth factor to induce replication in young adult dogs. Animals will be evaluated for cFIX levels, development of antibodies, bleeding, and for other adverse effects. The second aim will address the second major problem of RV-mediated hepatic gene therapy, that of immune responses to the therapeutic gene product. In this aim, we will try to block immune responses to the de novo expression of a transgene from an RV in mice by either performing neonatal gene transfer, or by injecting immunoinhibitory agents at the time of gene therapy in young adults. Although mice are optimal for initial studies due to cost considerations, approaches that function in inbred mice sometimes fail in outbred larger animals. We will therefore test any immunomodulatory approaches that function in mice for their efficacy in normal and Hemophilia B dogs in Aim III. Success in this project might lead to a safe, effective, and permanent therapy for Hemophilia B. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE THERAPY FOR HEMOPHILIA A Principal Investigator & Institution: Hebbel, Robert P.; Professor and Vice-Chairman; Octagen Corporation 1 Bala Ave, Ste 300 Bala Cynwyd, Pa 19004 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-DEC-2003 Summary: (provided by applicant): Extensive efforts to develop a safe and effective method of gene therapy for hemophilia A have not met with success. In this project the applicant will test a promising ex vivo approach to delivering factor VIII using a recently identified population of cells called blood outgrowth endothelial cells or BOEC. The principal investigator has shown that engineered BOEC may safely be used to provide sustained, therapeutic Levels of fVIII in a mouse model of hemophilia A. The Specific Aim of this project is to demonstrate that engineered BOEC can be used to achieve therapeutic levels of canine coagulation factor VIII in the hemophilia A dog. In this study, BOEC will be obtained from two hemophilia A dogs, transfected with fVIII and infused into the same animals. Coagulation factor VIII levels will be assayed over time. If therapeutic levels are detected, cuticle bleed times will also be determined. If, as expected, affirmative results are obtained in this study, the applicant intends to pursue a full preclinical development plan for the BOEC technology and to file an IND for the hemophilia A indication. PROPOSED COMMERCIAL APPLICATION: BOEC represent a novel platform technology for gene therapy and other medical applications. Success in this and subsequent studies could lead to the ultimate approval of BOEC technology as a preferred therapy for hemophila A and other indications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE THERAPY FOR HEMOPHILIA B Principal Investigator & Institution: Kurachi, Kotoku; Professor; Human Genetics; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 31-JAN-2004 Summary: Gene therapy studies, which began in the early 1980's, have now reached the point where critical importance of basic studies into the diseases and the biology associated with gene transfer have become widely acknowledged. In particular, studies on hemophilia B (factor IX deficiency) have greatly contributed to the understanding of gene transfer biology in general and have highlighted specific issues which must be systematically studied before safe and truly robust clinical human gene therapies can be developed. To date, most of these fundamental issues remain to be addressed. The studies detailed in this proposal will continue to focus study on hemophilia B by vigorously addressing selected critical issues and gaining insights into the basic biology underlying gene transfer. Studies proposed have three major aims centered on factor IX (FIX) as the model gene: Aim 1, delineation of the biology and mechanisms involved in muscle- targeted gene transfer; Aim 2, development of a robust FIX AAV (adenoassociated virus) - mediated gene transfer system; Aim 3, characterization of the immune responses to IX, delivered as a purified protein and by gene transfer approaches, and development of methods for induces immune tolerance. Establishment of an extensively studied and mechanistically well- understood gene therapy for hemophilia B will serve as a model for future gene therapy studies, and will provide an exciting foundation for development of clinical therapies, not only for hematological and metabolic diseases requiring systemic or local delivery of gene products, but also for other diseases such as muscular disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE THERAPY FOR THE HEMOPHILIAS Principal Investigator & Institution: Walsh, Christopher E.; Professor; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-OCT-2002 Summary: (provided by applicant): Effective gene therapy will revolutionize the treatment of the hemophilias. Recombinant adeno-associated virus (rAAV) vectors are considered among the most promising viral vectors for hemophilia gene therapy. The non-pathogenic nature of AAV, the ability to transduce mitotic and post-mitotic cells, and the capacity for stable persistence of rAAV/transgene sequences are unique among all viral vectors. A major obstacle in the application of rAAV in gene therapy for hemophilia A (factor VIII deficiency) is the conflict of the limited packaging capacity of rAAV and the large size of the human FVIII gene. The major rate-limiting aspect of this delivery system has always been the small packaging capacity (5kb) of rAAV. Factor VIII with its large cDNA (7.0 Kb) is an excellent model to test a variety of new approaches for AAV-mediated gene transfer. Here we present compelling evidence supporting the use of AAV vectors for the expression human factor VIII gene therapy. We developed several different novel approaches for the expression of functional factor VIII. First, we developed rAAV vectors carrying a truncated version of the full-length FVIII cDNA. Removal of the B-domain sequence of factor VIII (~4.0 Kb) results in a fully functional protein (termed B-domain deleted, BDD FVIII which express therapeutic levels of functional FVIII in vivo. Despite truncation of the FVIII sequence, the use of
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Hemophilia
small (<250 bp) enhancer/promoter elements is still required for AAV packaging. Further truncation of the FVIII sequence and modification of the transcriptional elements are proposed. Second, AAV dimerization can be used to overcome vectorpackaging limitations. AAV proviral DNA is characterized by head-to-tail concatamers. Here, the FVIII gene is divided and packaged into two individual AAV vectors. Dimerization dramatically increased by amplifying the conversion of single to doublestrand intermediates. Third, a totally novel RNA repair strategy relies on the use of spliceosome-mediated trans-splicing. Here two independent pre-messenger RNA transcripts are spliced together via the native cellular splicing machinery. We present molecular, protein and functional data demonstrating correction of the FVIII knockout mouse phenotype using this method. Fourth, AAV type 2 is the predominant serotype used for gene transfer studies. We propose that alternate AAV serotypes differ in terms of their cellular tropism. We demonstrate that non-type 2 AAV serotypes effect significantly higher levels of factor IX expression and will be used to test factor VIII expression. Each method will be optimized and in AAV vectors for FVIII production and tested in vivo using immunodeficient and FVIII knockout mice and hemophilic A canines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE THERAPY FOR TREATMENT OF HEMOPHILIA A Principal Investigator & Institution: Herweijer, Hans; Director of Preclinical Research; Mirus Corporation 505 S Rosa Rd, #104 Madison, Wi 53711 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 30-SEP-2002 Summary: (provided by applicant): Gene therapy promises to be a singular advance in the treatment of both acquired and genetic diseases at the most fundamental levels of pathology. Hemophilia A patients express insufficient levels of factor VIII. This protein is primarily expressed in the liver. A novel method of intravascular injection of plasmid DNA expression vectors results in highly efficient transfection of hepatocytes. This project will use this simple and innovative gene transfer approach to develop a gene therapy protocol for the treatment of hemophilia A. Despite the promise of this nonviral gene therapy approach, there are two problems that have to be solved for it to be clinically-viable: 1) current plasmid DNA expression vectors do not result in long term expression; 2) gene transfer is often accompanied by hepatocyte damage. In this Phase I application, experiments are proposed to developed plasmid DNA expression vectors that will enable long-term expression of human factor VIII (hF8). We will generate vectors with liver specific promoters and hF8 genomic sequences. Recently, a similar plasmid DNA expression vector was described that expressed human factor IX for more than 6 months. Phase II will focus on developing the surgical approaches for delivering the naked pDNA to the liver with minimal liver toxicity, using catheter-based techniques frequently used in clinical practice. These experiments will generate the preclinical data required for a human trial application. These gene delivery techniques can also be used for the development of gene therapy protocols for applications such as other clotting factor abnormalities, phenylketonuria, alpha 1 -antitrypsin deficiency, complement factor deficiencies, and other hematologic or metabolic disorders. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE THERAPY PULMONARY & HEMATOLOGIC DISORDERS Principal Investigator & Institution: Samulski, Richard J.; Director, Gene Therapy Center; Pharmacology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: ABSTRACT (provided by the applicant) The goal of this PPG, Gene Therapy for Pulmonary and Hematologic Disorders, is to facilitate translation of basic knowledge of gene delivery to safe and rigorous human clinical trials. The long-range goal is to provide novel therapeutic modalities for treating monogenetic diseases such as Hemophilia and Cystic Fibrosis. The major objectives in the UNC PPG are: (1) the development of highly efficient and high titer viral vectors, optimum expression, and safe persisting delivery systems, and (2) development of novel animal models for better defining rate limiting steps involved in target cell transduction, analysis of long term high level vector gene expression, and expression of normal and mutant human genes (e.g. FIX, CFTR). Four basic science projects and four cores are proposed. The basic research projects are proposed to focus on understanding rate-limiting steps in effective gene transfer. Projects 1 and 2 focus on AAV (Samulski) and Lentivirus (Olsen and Kafri), respectively. These projects are aimed at understanding and overcoming inefficient gene delivery related to virus entry and persistent transgene expression. The goal of the proposed studies is to generate new knowledge about the safety and biological efficacy of gene delivery, which will provide information important to the design of future clinical trials. Projects 3 and 4 involve animal models for airway (Boucher) and hemophilia (Stafford) disorders, respectively. These studies aim to define the host-associated rate limiting step(s) for understanding of the cell biology of the target tissue for efficient in vivo gene delivery and translating improvements in vector development. Specifically, goals include increasing access to airway epithelia (Project 3), development of novel models (e.g. a humanized hemophilia mouse, Project 4). This work will be supported by four cores, Administrative (Core A), Vector (Core B), Animal (Core C), and Morphology (Core D). The PPG is a highly interactive program comprised of clinical investigators and expert basic laboratories designed to optimize vectors and to test their interactions with target cells in vitro and in vivo. The ultimate goal of the UNC PPG is to achieve safe, effective, gene delivery in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENETICS AND BIOCHEMISTRY OF A MURINE RETROPOSON Principal Investigator & Institution: Martin, Sandra L.; Professor; Cellular & Structural Biology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-JUL-1988; Project End 30-JUN-2002 Summary: LINE-1 (long interspersed repeated sequence one, or L1) is a major dynamic force in the mammalian genome. Retrotransposition deposits the progeny of L1 throughout the genome, sometimes leading to gene disruption, modified expression of adjacent genes, and/or transduction of neighboring DNA. In addition, L1, as interspersed, repetitive DNA, provides a substrate for homologous recombination of mispaired sequences, leading to gene duplication, deletion, chromosome translocation and, potentially, exon shuffling. All of these dynamic events can lead to disease; in fact, LINE-1 insertional mutagenesis has been found to be responsible for hemophilia and muscular dystrophy, as well as breast and colon cancer in humans. Thus, it is extremely important to understand the details of the intermediates involved in retrotransposition
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and the mechanisms used to control their expression and movement in vivo. If the normal control mechanisms of L1 expression and retrotransposition become deranged and during development (gametogenesis or early embryogenesis) or in somatic cells in response to environmental insults, movement and rearrangement of L1 sequences could be instrumental in the generation of genetic diseases, birth defects and cancer. LINE-1 retrotransposition begins with transcription of a full-length, sense-strand L1 RNA and requires two L1-encoded polypeptides. These proteins probably also catalyze the reverse transcription and integration of SINEs (short interspersed repeated sequences) and processed pseudogenes, thereby amplifying the effects of LINE-1 in mammalian genome dynamics. Our long-range goal is to understand the retrotransposition process in detail, including the biochemical intermediates involved as well as its control in genetic and evolutionary time. Specifically, the studies proposed here are designed to: 1) Elucidate the role of the L1-encoded ORF1 protein during retrotransposition by characterizing its nucleic acid and protein- protein interaction activities in detail, as well as to test this protein for its ability to promote complementary strand annealing and strand-exchange; 2) Isolate the mouse genomic DNA progenitor of one of the promoters that was acquired by mouse LINE-1 recently in evolutionary time, and; 3) Employ our newly developed transposon tray assay to characterize the types of insertions that occur, as well as determine the frequency of endogenous L1 and L1-mediated retrotransposition events in the presence and absence of external agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETICS OF INHIBITOR FORMATION IN HEMOPHILIA Principal Investigator & Institution: Gill, Joan C.; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2004 Summary: Hemophilia A is a severe hemorrhagic disorder due to deficiency of coagulation factor VIII. Approximately 15 to 20 percent of severely affected patients develop antibodies to factor VIII with replacement therapy. These antibodies, termed inhibitors, neutralize factor VIII therapy causing significant morbidity and mortality. Recent studies in animal models suggest that inhibitors are also likely to hinder the success of gene therapy approaches. Several lines of evidence, including analyses of hemophilic brother pairs and animal models, indicate that the propensity to develop inhibitors is strongly influenced by genetic factors other than the specific factor VIII mutation or histocompatibility (MHC) locus type. This proposal aims to employ newly developed techniques for genetic linkage analysis and genome scanning to identify the inhibitor susceptibility genes. At least 200 well characterized severe hemophilia A brother pairs, both concordant and discordant for inhibitor formation, and other informative family members will be identified through a collaborative network of investigators in over 70 hemophilia treatment centers. Samples will be collected, and a repository of genomic DNA accompanied by a clinical and epidemiologic data base characterizing the hemophilic inhibitor phenotype including screening for the intron 22 inversion mutation, will be created. A panel of candidate genes that are likely to play a positive or negative role in inhibitor development will then be examined through fine mapping of polymorphic markers in the regions of interest, including the MHC, immunoglobulin genes, the T-cell receptor genes, and selected cytokine and cytokine receptor genes. If candidate genes fail to account for the genetic susceptibility to inhibitor development, a total 10 cM genome scan utilizing approximately 350 highly polymorphic microsatellite repeat markers will be performed. Linkage analysis will include both non-parametric testing of brother pairs for multiple susceptibility genes
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and more powerful parametric methods for one and two gene models in extended pedigrees. Identification of new genomic regions linked to inhibitor development will then be explored with fine mapping of the chromosomal areas and gene cloning techniques. The DNA bank and database will also be a uniquely valuable resource for future studies of patients with hemophilia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HCV GENOMIC VARIABILITY IN HIV INFECTED HEMOPHILIACS Principal Investigator & Institution: Sherman, Kenneth E.; Associate Professor; Internal Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: Hemophiliacs with symptomatic disease are multiply exposed to blood products including factor concentrates to correct the Internet clotting factor deficiencies. Prior to routine use of heat inactivation and screening of donor blood for specific viral pathogens, hemophilia patients were routinely exposed to, and infected with, viruses such as hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV). Cohort studies in hemophiliacs suggest several clinically and scientifically important findings that warrant further detailed investigation including; a) Liver disease progression may be altered in hemophiliacs infected with HCV with more rapid progression to liver failure and death; b) The source of infection from large pools of concentrate that were potentially infected by multiple discreet donors leads to a high risks of mixed infection represented by both genotype and quasi species heterogeneity; c) The HIV coinfected hemophiliacs may have different clinical outcomes and an altered immune response may facilitate our understanding of the underlying process of mutant virus selection, and the associated clinical outcomes. The overall goals of this proposal include the study and characterization of the genomic RNA of HCV in infected hemophilic patients with and without confection with HIV. In the retrospective Phase 1, we utilize the NCI Multi center Hemophiliac Cohort Study serum bank database to study the relationship between progression to decompensated liver disease and quasi species variability in the viral envelope hyper variable and core domain. Heteroduplex analysis will be used to rapidly screen samples from index patients and matched controls using samples longitudinally collected over a 10 year or longer period of time. Peptides will be produced from unique quasi species and these peptides will be evaluated for their function as CTL epitomes. Phase 2 involves the initiation and performance of a clinical intervention trial designed to determine variable kinetic response rates to PEG-interferon+ribavirin between hemophiliacs with HCV alone vs HCV/HIV coinfected subjects. Quasi species populations will be modified/cloned, sequencing will be performed to generate families of closely related core peptides that will be studied for their ability to bind and stimulate an immune response. Treatment nonresponders will be followed in a prospective cohort study for up to 3 additional years so that the evolution of the virus, and its associated immune response in this group can be evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HEMOPHILIA A & B AAV VECTOR DELIVERY: FACTORS VIII & IX Principal Investigator & Institution: Glader, Bertil E.; Professor of Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001
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Summary: Hemophilias A and B are due to mutations in the factor VIII and IX genes, respectively. These diseases are good models for gene therapy because of the relatively straightforward clinical parameters that include measurement of the transgene product by simple blood measurements and changes in clotting based on plasma levels. Patients with less than 1% clotting activity have very severe disease, between 1 to 5% a more moderate disease, and 5 to 20% mild disease. A wide-range of circulating factor is well tolerated making gene regulation unnecessary for gene therapy approaches. The liver is the organ in which these two clotting factors are normally synthesized. This makes it an attractive target for gene therapy approaches. While factor IX may be treatable with muscle delivery of a factor IX cDNA, factor VIII produced in the muscle is not efficiently secreted in the bloodstream. Moreover, there are still a number of issues that are unresolved when the muscle and liver approaches for treating FIX deficiency are directly compared. These include the relative risks of inhibitor formation, the ability to reach therapeutic versus curative levels of factor, and the relative dose of vector required to achieve a given level of plasma factor concentration. Recombinant AAVmediated liver gene transfer has proven to be safe as well as efficacious in both small and large animal models of hemophilia. The goal of the proposal is to develop two phase I rAAV-mediated liver-based clinical trials for the treatment of hemophilias A and B. Our primary goal will be address the safety of this approach in humans. The secondary goal will be demonstrated phenotypic improvement in patients with hemophilia. The trial design here will also provide useful information for future liverbased clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEMOSTASIS CLINICAL RESEARCH NETWORK PROTOCOLS Principal Investigator & Institution: Leissinger, Cindy A.; Medicine; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Patients with disorders of hemostasis are subject to long term problems and risks, difficult treatment decisions and risks associated with treatment itself. Many of these risks and complications can be lessened or prevented by appropriate intervention strategies. Advances in the management of patients with bleeding disorders of relatively low incidence require: 1) that clinical studies utilize a multi-institutional cooperative network in order to accrue sufficient numbers of patients to achieve meaningful answers; and 2) that patients be educated on the vital importance of participation in such studies. The purpose of this project is to develop a Hemostasis Core Clinical Research Unit at Tulane University as part of the NIH Transfusion Medicine/Hemostasis Clinical Research Network. This Unit will be developed using some of the basic infrastructure and services of the Tulane Center for Bleeding Disorders, which is dedicated to the care and advancement of patients with disorders of hemostasis. Once established, this Core Research Unit will provide access to clinical trials for hemostasis patients from the Center for Bleeding Disorders, the Bone Marrow Transplant Unit and from throughout the network of Tulane affiliated hospitals and clinics. In addition, two clinical trial protocols have been developed as part of this proposal. The first, A prospective randomized crossover study of activated prothrombin complex concentrates (aPCCs) as prophylactic therapy in hemophilia A patients with inhibitors, is a long-term protocol designed to evaluate the efficacy of aPCCs in the prevention of bleeds in this very complicated group of patients. The second, short-term protocol, A prospective study of ribavirin for the treatment of HIVassociated
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immunopathic thrombocytopenic purpura (ITP), was developed to test a novel pharmacologic agent in the management of HIV-ITP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEPATIC GENE TRANSFER FOR TREATMENT OF HEMOPHILIAS A &B Principal Investigator & Institution: Kay, Mark A.; Professor; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: There has been good progress made in the area of gene therapy for hemophilia during the past 5 years. The goal is to continue our studies towards hepatic gene transfer into the liver with the goal of developing a curative therapy for hemophilias A and B. Our laboratory is interested in comparing three promising viral vectors for hepatic gene transfer for hemophilia. We plan to do studies to further understand the biology of the vectors as it relates to transduction of hepatocytes in vivo. This information will be used to develop preclinical trials for these vectors by testing the most promising approaches in two animal models, mouse and canine hemophilias. The aims are to: (1) Compare the safety and hepatic transduction efficiencies of mouse Moloney, human foamy, and human lenti viruses, and determine their abilities to express clotting factors in vivo. (2) Further develop rAAV vectors for hepatic gene therapy for hemophilia. (3) Determine the potential use of an Adenoviral/AAV hybrid virus that is devoid of all viral genes for hemophilia gene therapy. We believe these studies will further our understanding of three important classes of viral vectors for hepatic gene transfer and develop the principles required for a clinical trial for the treatment of hemophilias A and B. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HEPATITIS C IN CLINICALLY DISCORDANT HEMOPHILIC SIBLINGS Principal Investigator & Institution: Fried, Michael W.; Associate Professor of Medicine; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: The clinical spectrum of hepatitis C is variable and the factors responsible for these divergent outcomes with chronic hepatitis C infection remain unknown. We propose to study a cohort of hemophilic siblings infected with hepatitis C to define the natural history, immunologic, and genetic factors that influence its clinical outcome. Patients with hemophilia have a prevalence rate of hepatitis C as high as 90 percent. The sex-linked pattern of inheritance of hemophilia allows us to identify a cohort of siblings both of who have been infected with hepatitis C. Hemophilic siblings are an attractive population to study because: 1) They are all males; 2) Siblings will be relatively close in age; 3) The mode of HCV acquisition is identical; 4) The age at acquisition of hepatitis C is similar 5) The date of acquisition can be confidently estimated upon their factor replacement history; 6) Hemophilic sibs share significant amounts of genetic material. Hemophilic siblings with hepatitis C will undergo a detailed clinical evaluation to stage their liver disease and to identify sibling pairs with clinically and/or histologically discordant levels of disease activity. These siblings pairs will be further studied to define antigen recognition patterns of peripheral CD8 plus CTL and CD4 plus cells and determine their functional significance. Using peripheral
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blood mononuclear cells, CD8 plus cells will be assayed for CTL activity against three overlapping vaccinia/HCV constructs covering the entire HCV genome followed by fine cloning to identify HCV-specific CTL epitopes. Peripheral CD4 plus cells will be tested for their ability to proliferate to HCV antigens. Using stimulation index, we will quantitate the presence and magnitude of this response. We will also try to identify immunodominant regions targeted by cytotoxic T cells using HLA class I matched hemophilic siblings. Finally, we will identify specific host genes that are preferentially expressed or repressed in patients with delayed progression of their HCV disease. We will quantitate the expression of mRNAs encoding host antiviral defense and immunoregulatory elements in peripheral blood mononuclear cells (PBMCs) and liver tissue from sibling pairs that have discordant chronic hepatitis C using mRNA libraries that will be screened by high density oligonucleotide arrays. The expression levels of these genes (including, but not limited to, interferon alpha, beta, and gamma; IRF-1 and IRF-2; interferon induced protein kinase; the cellular protein activator of PKR (PACT) RNase L; interferon-inducible RNA-specific adenosine deaminase; a ribonuclease specific for inosine- containing RNA; chemokine receptors CCR1, CCR3, CCR5, and their signal transduction elements; 2'-5'-oligoadenylate synthetase; tumor necrosis factor; FAS receptor; signal transduction components of these antiviral pathways, and both type 1 and 2 cytokines) will be correlated with delayed progression and diminished pathogenesis in paired hemophilic siblings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HISTIDYL IMIDAZOLE LIGAND IN METALLOPROTEINS Principal Investigator & Institution: Valentine, Joan S.; Professor; Chemistry and Biochemistry; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-JAN-1980; Project End 31-MAR-2002 Summary: (Adapted from applicant's abstract) Copper containing proteins play important roles in organisms ranging from bacteria and yeast to plants and animals. Three different copper-containing proteins are the focus of this research project. The overall objectives are to understand the properties and biological functions of wild type copper-zinc superoxide dismutases (CuZn SOD), to understand why mutant human CuZn SOD proteins cause familial amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), to understand the properties and biological functions of stellacyanins and the copper binding domains of human blood coagulation factor VIII, and to prepare novel synthetic metalloproteins using the genes for CuZn SOD and stellacyanin as starting points. CuZnSOD is an antioxidant enzyme that catalyzes the disproportionation of superoxide. Approximately 50 different single mutations in human CuZn SOD have individually been linked to an inherited form of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Results of transgenic mouse studies point to a toxic gain of function for these mutations rather than a loss of their antioxidant function as the cause of the disease. Human ALS mutant CuZn SODs have been prepared in our laboratory and have been found to have lost several of the properties characteristic of wild type CuZn SOD other than its SOD activity. These properties are highly likely to be essential to CuZnSOD in performing its normal biological functions. Moreover, the loss of these properties in the ALS mutant enzymes will likely prove to be linked to the gain of the new toxic property that is involved in the mechanism of causation of the disease. Preparation and characterization of these human mutant ALS CuZn SOD proteins for the purpose of identifying their disease-causing properties is a major objective of this project. Studies of another copper protein, stellacyanin, are designed to test the
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hypothesis that this blue copper protein is a cell wall protein that is involved in plant defense mechanisms. Another human protein, blood coagulation factor VIII, is involved in causing hemophilia A. It possesses protein sequences characteristic of blue copper binding sites, but no structural information nor characteristics of these sites are yet known. The copper-binding domains of this protein will be expressed, purified, and characterized. A major objective of this research is to understand the role of copper in human coagulation factor VIII and how it is related to the overall function of this protein in the blood clotting process. Finally, new metalloproteins will be designed, based on CuZn SOD and stellacyanin. They will be prepared using site-directed mutagenesis, expressed, and purified and their new properties will be characterized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HIV-1 PATIENTS WITH HEMOPHILIA A OR B Principal Investigator & Institution: Liles, Darla; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HUMAN APPLICATION OF AAV MEDIATED MUSCLE DIRECTED FACTOR IX GENE TRANSFER Principal Investigator & Institution: Cohen, Alan R.; Professor and Chairman; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001 Summary: Project #4. Hemophilia B is an X-linked bleeding disorder resulting from a deficiency of coagulation factor IX. Studies of patients treated with prophylactic factor IX protein infusions to maintain plasma levels >1% show that the chronic arthropathy and life-threatening hemorrhages associated with the disease may be prevented. This experience and the ongoing concern about blood-borne diseases transmitted by the use of factor concentrates forms the rationale for a gene transfer approach to treating hemophilia. Our group has developed a solid preclinical experience with gene transfer using an adeno-associated viral (AAV) vector to mediate transfer of the gene for factor IX to muscle. We have shown an absence of local or systemic toxicity due to AAV injection in rodents and dogs, and demonstrated proof of principle that ultrasoundguided intramuscular administration of AAV containing a species-specific transgene in dogs with hemophilia B results in expression of factor IX in muscle and therapeutically meaningful levels of factor IX (1-2%) in the plasma. Persistent of high-titer antibodies to factor IX or the presence of vector sequences in the semen have been demonstrated in this large animal model. Herein, we propose to carry out studies in humans with severe hemophilia B. Aim #1 details 2 studies using AAV to direct expression of human factor IX in muscle in patients with hemophilia B after ultrasound guided injection of vector into muscle. In the first a dose-escalation study 3 groups of 3 patients will be evaluated for toxicity. The second is a dose finding and efficacy study to determine the dose of AAV-hFIX that results in 5-7% plasma factor IX levels (0.25- 0.35 mug/mL), and to show efficacy of this dose in a group of approximately 25 patients by assessing number of bleeds, factor concentrate use and clinical effect using a hemophilia-specific health assessment tool that we will design. In Aim #2 we will measure levels of circulating reporter gene in rabbits following ultrasound guided administration of AAV in order to determine the optimal volume of injectate, concentration of vector, and the number of
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injection sites. In Aim #3, we will characterize the human immune response to vector proteins and the expressed factor IX transgene, including surveillance for the formation of anti-factor IX. Experiments in ultrasound guided injection of vector. Given the preclinical experience using this strategy, the proposed studies are likely to result in the first long-lived meaningfully correction of a human genetic disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HUMAN CTL RESPONSES TO ADENOVIRUS GENE THERAPY VECTORS Principal Investigator & Institution: Flomenberg, Phyllis R.; Medicine; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2001; Project Start 15-JAN-1999; Project End 31-DEC-2001 Summary: The goal of this proposal is to define the mechanisms involved in the generation of human adenovirus-specific cytotoxic T lymphocytes (CTLs) in order to help design new strategies for evading the immune response to adenovirus gene therapy vectors. Adenoviruses are under extensive investigation as gene therapy vectors for a broad spectrum of heart, lung, and blood diseases including cystic fibrosis, hemophilia, and atherosclerosis. However, data from animal models indicate that the immunogenicity of adenovirus vectors interferes with the efficacy of adenovirusmediated gene therapy. Administration of early region 1(E1)-deleted adenovirus vectors to mice, a host in which adenovirus infection is naturally restricted, results in the generation of adenovirus-specific CTLs which destroy adenovirus-transduced cells within a few weeks. Further analysis of this problem requires study of human CTL responses against adenovirus. We have successfully amplified memory adenovirusspecific CTLs in peripheral blood mononuclear cells from healthy adults and documented that these responses are major histocompatiblity complex (MHC)-restricted and mediated by CD8+ T cells. Based on our studies, it is likely that the presence of memory cellular immune responses will pose a major additional obstacle for adenovirus-mediated gene therapy in man. We postulate, however, that human adenovirus-specific CTLs may be targeted against a limited number of immunodominant epitopes. Therefore, it may be possible to reduce the immunogenicity of adenovirus vectors by elimination of such epitopes. As a second approach, it may be possible to take advantage of mechanisms which adenovirus has developed to evade host immune responses. The Ad early region 3 (E3) codes for proteins which help make cells resistant to CTLs and tumor necrosis factor, but this region is deleted or poorly expressed from most adenovirus vectors. We postulate that constitutive expression of E3 region proteins may help reduce the immunogenicity of adenovirus vectors. We propose to address these hypotheses by analysis of human CTL responses against adenovirus in vitro. These studies will provide an experimental basis for the design of more effective adenovirus gene therapy vectors for future human trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMMUNE TOLERANCE TO FACTOR IX IN HEMOPHILIA B Principal Investigator & Institution: Sabatino, Denise E.; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUL-2002 Summary: (provided by applicant): Hemophilia B is a genetic disease caused by a deficiency of clotting factor IX. Current therapy for Hemophilia B patients is protein therapy and clinical trials are currently underway for a gene therapy approach. With the
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current protein therapy, a small percentage (3 percent) of patients develop inhibitory antibodies that neutralize the F.IX protein activity rendering treatment ineffective. Attempts to eliminate inhibitory antibodies by infusing high doses of F.IX or by immunosuppressive treatment are not always successful. We hypothesize that effective immune tolerance strategies will enable current therapies for Hemophilia B to be successful for all patients. In this proposal we hypothesize that Hemophilia B mice can be tolerized to FIX by oral administration of FIX. In the first aim we will determine if oral tolerance to human FIX can be achieved in neonatal or adult Hemophilia B mice. Specifically, we will generate mouse whey acidic protein promoter-human Factor IX transgenic mice and characterize the levels of hF.IX in the mouse milk. These transgenic mice will be used to determine whether ingestion of milk from the mWAP-hF.IX female mice is able to tolerize the newborn Hemophilia B mice to hF.IX. Adult Hem B mice will be fed hFIX in their water to determine if feeding the antigen to adult Hem B mice is able to induce tolerance. In the second aim we will determine if tolerance to human F.IX can be achieved by continuous expression of FIX in gut epithelium of Hemophilia B mice. This will demonstrate if adult Hem B mice can be tolerized to FiX and if continuous expression of F.IX in gut tissue may facilitate the induction of tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOLOGY OF FACTOR IX GENE TRANSFER TO LIVER Principal Investigator & Institution: Herzog, Roland W.; Assistant Profess0r; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Hemophilia B is the X-linked bleeding disorder caused by absence of functional coagulation factor IX (F.IX). Pre-clinical studies in animal models have shown that gene transfer mediated by an adeno-associated viral (AAV) vector results in sustained expression of F.IX and partial correction of the coagulation deficiency. A Phase I clinical trial has been carried out based on intramuscular administration of vector to patients with severe hemophilia B, and a Phase I trial for liver-directed gene transfer (by infusion of the vector into the hepatic circulation) is now approved. Currently, the most serious complication of treatment for hemophilia by protein-based therapy is the formation of inhibitory antibodies against the coagulation factor. Using murine and canine models, we have demonstrated sustained F.IX expression with the muscle-directed approach in the context of a F.IX missense mutation, while expression in the context of a F.IX gene deletion/null mutation was limited by inhibitor formation. However, in animals of the same strain, sustained expression without inhibitor formation has been accomplished using liver-directed gene therapy. Thus, the immunological outcome of gene transfer is dependent on the combination of vector and target tissue. We found that AAV-mediated gene transfer to the liver can induce immunological unresponsiveness to F.IX, which may be explained by either a tolerance or a suppression mechanism. Anti-F.IX formation is dependent on CD4+ T helper cells. Therefore, we are proposing a gene transfer model based on mice transgenic for an ovalbumin CD4 about-restricted T cell receptor in order to define the events leading to antigen-specific immunity or unresponsiveness after AAV-mediated gene transfer of a secreted protein. We will investigate potential mechanisms of tolerance induction (clonal deletion, T cell anergy) or suppression/immune deviation (e.g. by activation of regulatory cells) in hepatic gene transfer as opposed to T cell priming associated with a neutralizing antibody response in lymph nodes of injected muscle. For both the ovalbumin and the F.IX system, we will perform adoptive lymphocyte transfer experiments to distinguish tolerance and suppression mechanisms in liver-directed gene
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transfer. In recently generated transgenic mice expressing liver-derived variants of human F.IX, the risk of inhibitor formation in liver-directed gene therapy can be directly compared to other treatment modalities after mice have been crossed with hemophilia B mice on the appropriate genetic background. Finally, the risk of inhibitor formation may be further reduced by a combination of liver-directed gene transfer and transient immune modulation. Taken together, these studies will provide a detailed analysis of transgene product-specific T cell responses following AAV-mediated hepatic gene transfer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOREGULATORY DEFECTS IN HEMOPHILIA Principal Investigator & Institution: Sullivan, John L.; Professor; Pediatrics; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2001; Project Start 01-SEP-1988; Project End 31-MAR-2002 Summary: The long term objectives of this project are to understand the role of virusspecific immunity in the pathogenesis of HIV-1 infection. The major hypothesis to be tested is that strong virus specific cytotoxic T lymphocyte (CTL)responses are important for limiting viral replication and disease progression. Our studies will focus on a cohort of 144 individuals with hemophilia, followed since 1983, 85% of whom have been infected with HIV-1. In this cohort we have identified HIV-1 infected long term nonprogressors (LTNP), slow progressors and progressors. Currently, in 1997, 72 individuals remain alive and continue to be followed in the cohort. Immunological and virological studies will be carried out on repository samples of sequential plasma and peripheral blood mononuclear cells collected prospectively since 1983-84 when the project began. We propose to perform the following during the next grant period: (1) a targeted analysis of Gag- and Nef- specific CTL activity as it relates to disease progression, (2) an evaluation of CTL reactivity to epitopes in Nef in individuals with non-progressive infection, (3) an analysis of Nef- specific reactivity in relation to the allelic variation of viral Nef over time in these long term non-progressors, (4) a characterization of the breadth of CTL activity as it relates to disease progression, and (5) Finally, to develop CTL assays which utilize target cells and viral isolates more relevant to in vivo infected cells. These studies should further our understanding of HIV-1 specific cell-mediated immunity and provide new information which will be useful in the development of an effective vaccine for the prevention of HIV-1 infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IN UTERO STEM CELL TRANSPLANTATION FOR HEMOPHILIA A Principal Investigator & Institution: Almeida-Porada, Graca; Associate Professor; Animal Biotechnology; University of Nevada Reno Reno, Nv 89557 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Hemophilia A is an X-linked recessive bleeding disorder caused by the deficiency/abnormality of Factor VIII. Currently, treatment of hemophilia involves factor replacement using fresh frozen plasma, cryoprecipitate, or Factor VIII concentrate. While this greatly improves the quality of life of hemophiliacs, it is less than ideal, since regular treatments are required throughout the life of the patient. Treating hemophilia in utero would enable correction prior to disease onset, thus allowing the birth of a healthy baby who requires no further treatment. Our laboratory has developed and optimized a unique sheep model for in utero stem cell transplantation (IUSCT) that allows the engraftment and differentiation of human stem
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cells in the absence of preconditioning, by virtue of the early gestational recipient's preimmune status. This model has proven to be an accurate and valuable pre-clinical system for evaluating approaches to IUSCT, and the data generated in this model was used to conduct the first successful clinical IUSCT in a patient with X-SCID. In addition to the durable hematopoietic engraftment, transplanted hematopoietic stem cells (HSC) and marrow-derived mesenchymal stem cells (MSC) also give rise to other tissues in this model, including significant numbers of functional hepatocytes. These results suggest that adult marrow-derived stem cells may be ideally suited for cellular therapy to correct disorders such as the hemophilias in which a liver-derived factor is defective or absent. In the present proposal we will test this hypothesis by utilizing cryopreserved semen to re-establish a line of sheep that exhibited spontaneous factor VIII deficiency with symptomology closely mimicking that of human hemophilia A, while simultaneously transplanting normal sheep fetuses with adult HSC and MSC to determine the optimal stem cell population(s) for generating functional hepatic cells in vivo. We will then transplant the affected fetuses in utero with the optimal stem cell population(s) and assess whether this in utero cell therapy approach produces therapeutic benefit in this clinically relevant large animal model of hemophilia A. We will also examine the liver and other tissues of the recipient hemophilic sheep to establish a correlation between the degree of clinical improvement and the levels of Factor VIII-producing cells generated by the transplanted adult human HSC and MSC. It is hoped that these studies using adult BM-derived stem cells will lead to the development of a successful stem cell-based therapeutic approach to treat hemophilia prior to birth, thus obviating the need for lifelong factor therapy with its inherent risks/shortcomings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INDUCTION OF TOLERANCE--FACTOR VIII IN HEMOPHILIC MICE Principal Investigator & Institution: Scott, David W.; Head of Immunology; American National Red Cross Rockville, Md 20855 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 30-JUN-2003 Summary: Human antibodies that inactivate blood coagulation factor VIII fVIII inhibitors, develop in 25 percent of repeatedly transfused patients with severe hemophilia A and rarely in patients with moderate or mild hemophilia. Although the effects of inhibitors are variable, they often contribute to frequent, significant bleeding and disability, and they can present a life threatening complication. In addition, they are responsible for a large proportion of the cost of hemophilia care. The only effective method for inhibitor eradication is high dose fVIII therapy, which decreases inhibitor titers to undetectable levels in about 70 percent of patients, but it is very costly due to the frequent, high fVIII doses required. Patients with low inhibitor titers at the beginning of therapy are more rapidly and successfully tolerized, and tolerance is often long lived (up to 5 yrs.). It is not clear why 30 percent of patients are not tolerized and why it requires longer times in some patients. In 1995, hemophilia A mice were generated by targeted disruption of the murine fVIII gene in exons 16 or 17. We demonstrated that the mice respond to multiple fVIII intravenous injections of doses commonly used in humans by producing anti-fVIII antibodies. Moreover, others showed that splenic T cells from such mice can be stimulated by fVIII to proliferate in vitro. As human fVIII specific T and B cells are difficult to isolate from the peripheral blood, the hemophilic mice present a useful alternative for determining how immunological responses develop and how they can be eliminated. While the fVIII T
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and B cell epitopes may differ in humans and mice, the fundamental principles of immune recognition and tolerance should be similar. In this proposal we will use the hemophilic mice as a model to test high dose antigen stimulation for tolerance induction. We will determine if additional, simultaneous blocking of T and B cell costimulation by APCs with CTLA4Ig and T-B cell collaboration with anti-CD40L can further downregulate the immune response and whether this is more effective than using high antigen doses alone. Fusion of immunogenic polypeptides to IgG and expression in a retroviral vector introduced into bone marrow cells, leads to tolerance in both the primary and the secondary immune response. This method will also be tested in mice for tolerance induction to fVIII. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITOR FORMATION IN GENE THERAPY FOR HEMOPHILIA Principal Investigator & Institution: High, Katherine A.; Professor of Pediatrics; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2002 Summary: Our laboratory has had a longstanding interest in gene therapy as an approach to treating hemophilia B. Recently we have developed promising data in animal models of hemophilia using AAV-mediated gene transfer into muscle and liver. AAV is particularly attractive as a gene transfer vehicle because it is not associated with a strong immune response to the vector itself. In an engineered mouse model of hemophilia B in which the F.IX gene is deleted, however, successful gene transfer and expression have been accompanied by development of antibodies to the transgene product. In dogs with hemophilia B resulting from a missense mutation in the F.IX gene, antibody formation following AAV-mediated muscle-directed gene transfer has been either absent or transient and low-level. Based on our studies thus far, we hypothesize that the antibody response to the transgene product in AAV- mediated gene transfer will be influenced by the underlying mutation, and that this effect is based on whether or not the mutation allows the development of T cell tolerance. In the proposed studies we will use murine and canine models of hemophilia B to 1) define the role of T helper cells in the immune response to a transgene administered via intramuscular injection of an AAV vector; 2) characterize more fully the immune response to the transgene product in dogs with hemophilia B; and 3) determine whether any of several straightforward clinically feasible maneuvers can be used to modulate the immune response to the transgene product. These studies will involve a collaboration between the P.I.'s lab and the laboratory of Dr. Hildegund Ertl, an immunologist with experience in characterizing immune responses in the setting of viral vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INTRAPULMONARY GENE TRANSFER USING COMPACTED DNA Principal Investigator & Institution: Cooper, Mark J.; Assistant Professor; Copernicus Therapeutics, Inc. 11000 Cedar Ave, Ste 145 Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 30-AUG-2002 Summary: To develop a non-intravenous, needle-less gene transfer platform for systemic deficiency disorders, including hemophilia and alpha (1)- antitrypsin deficiency, Copernicus Therapeutics has evaluated intratracheal delivery of proprietary formulations of compacted DNA (PLASmin complexes). Our gene transfer system compacts single molecules of plasmid DNA into 15-25 nm particles, and this formulation is capable of efficiently transfecting non-dividing cells. In preliminary
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studies, intratracheal administration of non-targeted PLASmin complexes generated over 1,000-fold higher levels of transgene expression than naked DNA. Significant levels of human factor IX (-300 ng/ml) in lung epithelial lining fluid were measured following a single intratracheal dose of PLASmin complexes targeted with a ligand for the serpin enzyme complex receptor (SECR), a receptor expressed at the lumenal surface of bronchial epithelium. To advance this technology toward human trials, we propose to: i) identify the cell type transfected following intrapulmonary delivery of non-targeted PLASmin complexes; ii) evaluate SECR-targeted PLASmin complexes for intrapulmonary gene delivery; and iii) determine plasma and bronchoalveolar lavage fluid levels of human factor IX and alpha(1)-antitrypsin after intrapulmonary administration of non-targeted and SECR-targeted PLASmin complexes. Our promising results suggest that patients with systemic genetic deficiency states could be treated with aerosolized PLASmin complexes administered daily or several times per week. PROPOSED COMMERCIAL APPLICATIONS: Although gene therapy holds great promise for treating human disease, limitations in safety and efficacy have restricted its commercial development. Our non-toxic formulation of condensed DNA, termed PLASmin complexes, are stable in physiologic fluids, transfect post- mitotic cells, and generate high level gene expression in lung following an intrapulmonary dose. Delivered as an aerosol via a hand-held inhaler, PLASmin complexes may provide an effective and simple therapy for genetic deficiency states, including hemophilia and alpha(1)-antitrypsin deficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LENTIVIRAL VECTOR BASED GENE THERAPY FOR LIVER DISEASES Principal Investigator & Institution: Kafri, Tal; Assistant Professor; Microbiology and Immunology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Copied from Applicant Abstract): The overall goal of this study is to validate our hypothesis that lentivirus vectors can serve as an efficient and safe platform for therapeutic gene delivery to the liver tissue. The ability of HIV-1 and other lentiviruses to transduce non-dividing cells prompt the development of an HIV-l based gene delivery system. The novel lentivirus vectors proved efficient at transducing various tissues in vivo (brain, liver, muscle, retina, and hematopoietic stem cells) without any detectable pathology. Recently, we showed that a single intraperitoneal injection of hemophilic mice with lentivirus vectors resulted in long term expression of therapeutic levels of canine factor IX. The treated mice demonstrated aPTT values equivalent to those obtained from heterozygous littermates. In addition our preliminary results indicated that cis-regulatory sequences in the lentivirus down-regulate transgene expression. These studies are most encouraging, however we believe that further improvements in: vector production, trsansgene expression, and regulation, and better characterization of the mechanism responsible for the development of inhibitory antibodies are required before we can consider the use of the lentiviral system as a safe and efficient viral vector for liver gene therapy. To facilitate safe vector production we propose to generate a novel third generation packaging cell line, which will be devoid of the Tat and all HIV-l accessory proteins. As an additional measurement of safety, we will separate the new packaging system into four stably integrated plasmids (vector, envelope, packaging, and rev). To improve transgene expression from the lentivirus vector cassette we will attempt to identify and delete inhibitory sequences from the
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lentivirus vector genome. To improve regulation of transgene expression we will generate an improved new inducible lentivirus vector which will exhibit minimal basal inducible promoter activity. Testing the proposed improvements in hemophilic mouse and canine animal models will allow us to characterize potential immune response against the newly synthesized factor IX. We believe that the ability to maintain therapeutic levels of factor IX in these animal models will determine the feasibility of using lentivirus vector based gene therapy to cure hemophilia B and other hepatic metabolic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LENTIVIRAL VECTORS FOR GENE DELIVERY Principal Investigator & Institution: Olsen, John C.; Associate Professor; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The overall goal of this project is to advance lentiviral gene delivery systems to a point where they can serve as safe and efficient therapeutic gene delivery systems for human clinical trials. Lentiviral vectors based upon human immunodeficiency virus type I (HIV-1) and equine infectious anemia virus (EIAV) will be studied. Specifically, we are interested in improving the production and bio-safety of lentiviral vectors so that they can be used in treatments for diseases such as hemophilia B and cystic fibrosis. Thus our studies will focus on vector development and testing aspects of gene delivery to the liver and airway epithelium. It is clear that the ability of lentiviruses to transduce non-dividing cells is the main reason for development of lentivirus based gene delivery systems. Lentivirus vectors have proved efficient at transducing various tissues in vivo (brain, liver, muscle, retina, and hematopoietic stem cells). Recently, we showed that a single intraperitoneal injection of hemophilic mice with lentivirus vectors resulted in long term expression of therapeutic levels of canine factor IX. The treated mice demonstrated corrected blood clotting indices equivalent to those obtained from heterozygous litter mates. However, we believe that further improvement in vector production, vector safety, and in vivo transduction efficiencies of non-dividing cells can be made. The ability to study different lentivirus vectors in parallel will allow us to identify and to solve basic biological problems common to all lentivirus vectors. This approach permits us to investigate the effects of vector origin on the ability to efficiently transduce and express transgenes in tissues and cells from different species. To facilitate generation of cell lines for vector production, we will optimize the incorporation of Self-Inactivating (SIN) vector cassettes into stable packaging cell lines. To improve the safety of lentivirus vectors we propose to generate novel non-integrating lentiviral vectors that exhibit high levels of transgene expression in vivo. To investigate the effects of vector origin on the ability to transduce non-dividing cells, we will compare vectors derived from primate and non-primate lentiviruses on the ability to transduce non-dividing cells in model systems relevant for treatment of hemophilia B and cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: LENTIVIRAL VECTORS FOR GENE THERAPY FOR BETATHALASSEMIA Principal Investigator & Institution: Malik, Punam; Assistant Professor of Pediatrics and Pa; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2002; Project Start 08-MAY-2002; Project End 31-MAR-2007
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Summary: (provided by applicant): The B-thalassemias are the most common single gene defect in humans and result from absent or decreased B-globin synthesis, leading to severe anemia. Patients with B-thalassemia major are treated with life-long transfusions. Bone marrow transplantation can be curative, but is limited to a few with matched donors, and has potentially serious complications. Replacement of a normal Bglobin gene into hematopoietic stem cells (HSCs) can potentially correct the disorder permanently, avoiding the complications associated with a transplant. With the advent of better vectors, improved gene transfer techniques and a better understanding of stem cell and vector biology, gene therapy is going from the bench to the bedside, in diseases like SCID and hemophilia B. 'Globin' gene therapy has suffered from problems of vector instability, low titers and variable expression. The recently developed lentiviral vectors transduce the non-dividing HSCs and stably export large genomic fragments by unique RNA export mechanisms, imparting stability to globin vectors. Self-inactivating (SIN) lentiviral vectors are even more advantageous: the viral LTR is deleted upon integration into cells, completely inactivating viral transcription. This feature is ideal for the expression of a highly lineage-restricted gene such as globin, and additionally improves their bio-safety. We have recently shown remarkably lineage-specific and long-term expression of GFP and gamma-globin from SIN lentiviral vectors in mouse erythroleukemia (MEL) cells, primary murine and human cells. We propose to capitalize on these findings by examining the capabilities of SIN lentiviral vectors to carry the human B-globin gene and erythroid regulatory elements for gene transfer into HSCs that results in stable, lineage-specific and sustained expression of B-globin in RBCs. The aims of the study are to: 1) Develop SIN-lentiviral vectors carrying the human B-globin gene under control of erythroid regulatory elements, and screen them in MEL cells for stable transmission and high level expression. 2) Determine the efficacy, lineage specificity and long term expression of B-globin SIN lentiviral vectors in vivo, in thalassemic mice. 3) Determine the gene transfer capacity and efficacy of B-globin SIN lentiviral vectors in the RBC progeny of human thalassemia progenitor cells, using a unique model of human RBC production developed in our laboratory from hematopoietic progenitor cells. Together, these aims comprise a focussed research program to produce therapeutic and sustained levels of B-globin in human thalassemia RBCs, and form the basis for future preclinical studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EXPRESSION
LENTIVIRAL
VECTORS
FOR
POSITION-INDEPENDENT
Principal Investigator & Institution: Hawley, Robert G.; Head; American National Red Cross Rockville, Md 20855 Timing: Fiscal Year 2001; Project Start 15-JUN-2001; Project End 30-MAY-2005 Summary: (Investigator's abstract) Gene therapy using hematopoietic stem cells (HSCs) as the target cell population has great potential to improve treatment of a wide range of inherited and acquired blood diseases. Replication-defective retroviruses have been the vehicles of choice for gene delivery and expression in HSCs because of their ability to stably integrate into the genome of target cells. For more than a decade, our laboratory has been designing and optimizing retroviral vectors for gene transfer studies of HSC biology. In particular, our MSCV (murine stem cell virus) retroviral vector has proven to be highly efficient at delivering functional genes to the murine hematopoietic system. For this reason, the MSCV platform was chosen for use in two HSC gene therapy trials currently underway in the United States. To date, however, the outcomes of most clinical trials with retroviral vectors have been disappointing. This is believed to be due
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in part to low surface density of the amphotropic envelope receptor and the fact that retroviral vectors such as MSCV, which are derived from oncoretroviruses, can only integrate into cells undergoing mitosis. Thus it has been proposed that pantropic vectors developed from the lentivirus, human immunodeficiency virus (HJV), which can readily transfer genes into various types of stationary cells, may be more suitable for gene delivery to HSCs, which reside almost exclusively in the G0/G1 phase of the cell cycle. Even if efficient lentivirus-based gene transfer in HSCs is achieved, accumulated data indicate that in vivo transgene expression is frequently subject to transcriptional silencing and position effects. We propose therefore to develop next-generation HIVbased lentiviral vectors expressly for human HSC gene transfer applications. Our hypothesis is that utilization of transcriptional regulatory elements permissive for expression in HSCs in conjunction with chromatin insulator sequences and scaffold/matrix attachment regions will lead to maintenance of high-level transgene expression in HSCs and their differentiated progeny. To this end, the performance of next-generation lentiviral vectors utilizing the MSCV long terminal repeat as an internal promoter and harboring the chicken b-globin 5' constitutive hypersensitive site (5' HS4) insulator and/or the human interferon-b scaffold attachment region (IFN-SAR) will be assessed in human hematopoietic repopulating cells using a surrogate non-obese diabetic/severe combined immunodeficient (NOD/SCID) xenograft assay and in a murine hemophilia A model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LOW ANTIGENICITY FACTOR VIII Principal Investigator & Institution: Bergman, Garrett E.; Octagen Corporation 1 Bala Ave, Ste 300 Bala Cynwyd, Pa 19004 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2003 Summary: (Applicant's Description Verbatim): Our goal is to obtain registration of a low antigenicity recombinant fVIII product for the treatment of patients with neutralizing antibodies against human fVIII. Such inhibitor patients include those with hemophilia A who develop alloantibodies when treated with replacement human fVIII, as well as patients with "acquired hemophilia" who develop autoantibodies against endogenous fVIII. The development of an inhibitor to Will is a serious, potentially life threatening condition. Current treatment options are limited to so-called "bypassing" agents" and plasma derived porcine fVIII (Hyate:C). Bypassing agents are nonphysiologic and occasionally cause overdrive of the coagulation cascade. This may result in severe complications, such as disseminated intravascular thrombosis or myocardial infarction. Use of Hyate:C is currently limited by regulatory, treater and patient concerns arising from the plasma source of the product and side effects attributable to the relative impurity of the product. Applicant has exclusive access to recombinant porcine fVIII. Applicant has obtained substantial in vitro and in vivo data that supports the suitability of recombinant porcine Will for development as a low antigenicity fVIII product. Phase II of applicant's SBIR project shall include: completion of the preclinical development of the product, submission of an IND to the FDA, and initial safety and efficacy studies of the product in hemophilia A patients. In the preclinical stage, the safety and immunogenicity of the product will be studied in mice and cynomolgus monkeys. Pharmacokinetic data will be obtained in a highly predictive dog model of hemophilia A. After an ND is filed, the safety and pharmacokinetics of the product will be studied in a clinical trial in which approximately twelve inhibitor patients shall receive the product. PROPOSED COMMERCIAL APPLICATION: Approximately 26% of all hemophilia A patients develop antibodies. A significant portion cannot successfully be
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treated with human fVIII. A recombinant, low antigenicity fVIII product would compete well in the fVIII inhibitor patient market and be a first line therapy for "acquired hemophilia." Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MAINTENANCE OF ANIMAL MODELS OF HUMAN HEMOPHILIA AND VWD Principal Investigator & Institution: Nichols, Timothy C.; Pathology and Lab Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 30-JUN-2003 Summary: Disorders of blood coagulation and thrombosis complicating atherosclerosis are major causes of death and disability. Our objectives in this Resource Grant are: 1) To maintain a breeding colony of well- characterized dogs with genetically-determined bleeding disorders at the Francisco Owen Blood Research Laboratory (FOBRL), University of North Carolina, Chapel Hill; 2) To produce purpose bred-research animals with these bleeding disorders; and 3) To provide specialized support services for research projects using these dogs including canine blood banking and coagulation analyses. These dogs model human hemophilia A, hemophilia B, and von Willebrand disease (vWD) and have been maintained for over 50 years in Chapel Hill largely through support from the NIH. A well-trained support staff at the FOBRL has several years experience in managing these special dogs, maintaining a canine blood bank, developing and performing canine coagulation assays, conducting investigations, and collaborating successfully with investigators worldwide. As a result, research using the dugs from the FOBRL has lead to discoveries that have revolutionized treatment of inherited and acquired bleeding and thrombotic disorders. Many therapeutic agents have moved successfully from the research bench to clinical practice after being conceived of and tested in these dogs. Current research with these large animal models addresses several unmet national needs including the development of new methods of treatment for bleeding and thrombosis, and determination of the acute and chronic sequelae of these new treatments on genetic diseases. As such, these dogs constitute a unique national resource that have been regarded by many investigators as essential for pre-clinical testing of new treatments for the hemophilias, vWD, arterial thrombotic disorders, and hemorrhage. The demand for and use of these hemophilic dogs has nearly doubled during the past two decades. Beginning March 1999, there will be no NIH grant support for the maintenance of this colony making new research using these priceless bleeder drugs very difficult and extensive to initiate. The survival of the FOBRL colony will be jeopardized. The cost of establishing a colony at each investigator's institution is prohibitive. The primary benefit of this grant will be to maintain breeding stock for producing affordable, purpose-bred research animals in a cost-effective manner for the research community. The research animals will be supported by mechanisms that will separate from this Resource Grant. This Resource Grant is essential to ensue the survival of the colony in an established, successful environment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MODELING GENE THERAPY OF HEMOPHILIA A VIA LIVER DIRECTED GENE EXPRESSION Principal Investigator & Institution: Kazazian, Haig H.; Seymour Gray Professor; Stanford University Stanford, Ca 94305
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Timing: Fiscal Year 2001 Summary: A major problem in liver-directed gene therapy is the development of an immune response to the therapeutic transgene. Previously, we have found that mouse CMV-driven factor VIII cDNA delivered in a first-generation adenovirus to hemophilia A mice provokes a substantial immune response to both factor VIII and adenoviral proteins. This response can be blunted by suppression of T-cell with anti-CD4. Over the past year, it has become clear that adeno-associated virus (AAV) is a safety and perhaps more effective delivery vehicle than adenovirus. In this project, we aim to carry out long-term correction of hemophilic mice and dogs by delivery of FVIII cDNA to liver in an AAV vector. Our goal is to devise the means to deliver the FVII cDNA to liver in an AAV vector. Our goal is to devise the mans to deliver the FVIII cDNA without encountering an immune response. We have recently cloned a short SQ version of the mouse FVIII cDNA driven by a small liver-specific promoter (human alpha-anti-trypsin promoter) is an AAV vector. This and other vectors will be tested for preliminary for therapeutic effect in vitro and in vivo; then in immunosuppressed, FVIII-deficient mice; and finally in immunocompetent hemophilic mice. The total size of immunosuppressed, FVIII-deficient mice; and finally in immunocompetent hemophilic mice. The total size of the mouse FVIII-SQ cDNA in this year is under 4.4 kb, leaving roughly 380 bp for promoter/enhancer combinations. In immunocompetent mice, we will measure FVIII activity, FVIII antigen, and both cellular and humoral immune responses to FVIII. Using the information gained from mice expectations, we will attempt correction of hemophilia A dogs using canine FVIII-SQ cDNA via liver directed expression. We hope to overcome any immune response to FVIII and provide successful long-term treatment of these animal models. The studies are critical to clinical trials of liver-directed therapy of hemophilia A using AAV vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR AND CELLULAR CHARACTERIZATION OF AAV1 VECTOR Principal Investigator & Institution: Xiao, Weidong; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2005 Summary: Adeno-associated virus (AAV) has been studied extensively as a gene therapy vector. Results from both preclinical studies and clinical trials using recombinant AAV (rAAV) vector suggest that this vector would be safe and effective for muscle gene delivery. Currently, the most widely used rAAV vector is based on AAV serotype 2 because it is the most extensively characterized serotype. Recently, characterization of AAV serotype 1 demonstrated that AAV1 based vectors are approximately 10 to 20-fold more effective than AAV2 for delivery into muscle. Such dramatic differences suggest that AAV1 vector is not merely an alternative vector for AAV2 but has distinctive advantages over the AAV2 vector. Scientifically, AAV1 offers an excellent tool to study the biology and vectorology of AAV. As a continuation of my previous work, the following studies are proposed to characterize AAV1 as a gene therapy vector using hemophilia B as a disease model. 1). To identify the tissue tropism determinants of AAV1 for muscle. The hypothesis to be tested in this specific aim is that some dissimilar amino acid clusters between AAV1 and AAV2 account for the differences in affinity for muscle. Such dramatic differences in transducing muscle provide a reliable assay for the tissue tropism determinants. 2). To characterize the biological properties of AAV1/2 hybrid helpers, and to identify the cellular receptors for AAV1 virus. 3). To explore the effectiveness of AAV 1 and its hybrid derivative vectors
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in correcting the phenotype in hemophilic mice, and to administer these vectors to animals with neutralizing antibodies against AAV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR AND CELLULAR CONSEQUENCES OF VWF ALTERATION Principal Investigator & Institution: Montgomery, Robert R.; Director of Research; Blood Center of Southeastern Wisconsin Milwaukee, Wi 532012178 Timing: Fiscal Year 2001 Summary: This project explores the functional and structural alterations of von Willebrand factor with respect to intracellular processing and trafficking and elucidates its role as an intracellular chaperone for factor VIII. While FVIII and vWF have been known to associate extracellularly for years, recently, we have demonstrated the importance of this interaction in intracellular processing as well. Using chimeric molecules comprised of human and canine vWF, the signals for cell sorting, multimerization, and interaction(s) individually with factor VIII and platelets will be determined and explored in vitro and ex vivo. We will explore the interaction between vWF and FVIII in vivo using a number of specific techniques in mice. The cDNA for FVIII will be used to transduce murine CD34+ cells to demonstrate the co-localization of FVII together with vWF in the alpha-granules of platelets. Since there is some ambiguity about the cell that normally synthesizes FVIII, we will study murine tissues to determine the cells that produce FVIII using in situ hybridization, in situ PCR, and FVIII specific RT-PCR amplification of mRNA from microvascular endothelial cells from multiple tissue beds. In other experiments, the murine promoter elements for FVIII if differential expression of FVIIII is identified through in situ hybridization analysis. The final aim will employ knockout models of hemophilia A to further study tissue expression of FVIII and vWF. In order to validate the importance of endothelial expression of FVIII, a conditional knockout of FVIII will be developed where FVIII expression by endothelial cells is eliminated. These studies will define the critical elements for the intracellular trafficking of vWF and FVIII and impact on the approach to gene therapy of hemophilia A and vWD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEW THERAPIES FOR HEMOPHILIA Principal Investigator & Institution: Key, Nigel S.; Associate Professor; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 05-SEP-2000; Project End 31-JUL-2005 Summary: The theme of this Program Project proposal is to develop novel therapies for hemophilia. In particular, the focus will be on the most significant complication of the disease, namely the occurrence of inhibitory antibodies to the clotting factors that are normally used to treat bleeding episodes. The development of an inhibitory is a devastating event, which leads inevitably to increased morbidity, and cost of therapy (which is already exceptionally high for patients without this complication). Furthermore, development of inhibitors remains one of the principal concerns surrounding gene therapy for hemophilia. We will adopt a multi- disciplinary approach to this problem, concentrating on bio-engineered clotting factors (mutants of factor VIIa with enhanced pro-coagulant activity, and human-porcine factor VIII hybrid molecules with reduced immunogenicity and antigenicity. Although not part of this proposal, clinical trials involving these proteins can be realistically anticipated as a longer term
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Hemophilia
goal. In Project 1 ("The Role of Tissue trials involving these proteins can be realistically anticipated as a longer term goal. In Project 1 ("The Role of Tissue Factor in Hemophilia"), we will examine the biochemical basis for tissue factor encryption in vitro, and develop methods to measure expression of both the encrypted and procoagulant forms of tissue factor in vivo. In Project ("Enhanced Vitamin K- dependent Proteins in Hemophilia"), recombinant factor VII molecules that have been mutated at specific residues in the membrane contact region will be characterized with respect to their pro-coagulant activity. The anti-hemorrhagic efficacy (and potential undesirable thrombogenicity) of selected mutants will be tested in animal models of hemophilia. In Project 3 ("CD4+ T Cell Response to Porcine Factor VIII"), CD4+ T cell responses to human-porcine hybrid FVIII molecules will be examined, primarily in the murine model of hemophilia A with a FVIII inhibitor. It is our hypotheses that these hybrid molecules may be less immunogenic than human FVIII. Finally, in Project 4 ("Chimeraplasty for Factor IX and Factor VII Gene Expression"), we will use chimeric RNA/DNA constructs to "repair" the point mutation in the factor IX gene in canine hemophilia, and deliberately induce a selected point mutation in the factor VII gene to promote expression of high activity FVII(a) in vivo that will "by-pass" the need for factor VIII (or IX) in patients with inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW VECTORS FOR GENE THERAPY OF HEMOPHILIA A AND ALPHA-1 ANTITRYPSIN DEFICIENCY Principal Investigator & Institution: Lieber, Andre M.; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001 Summary: The overall goal of this proposal is to achieve long-term expression of human factor VIII (FVIII) and human alpha1-anti-trypsin (hAAT) at therapeutic levels in mice. Towards this goal, we will utilize hybrid deltaAd.AAV vectors, which are devoid of all adenoviral genes and accommodate transgene cassettes with a maximal size of AAV vectors. Transient expression of AAV rep78 from non-integrating adenoviral vectors stimulates site-specific integration of deltaAd.AAV vectors. We will use two principal gene transfer approaches: (A) transduction of hepatocytes in vivo after systemic vector application and (B) in vitro transduction of bone marrow derived stem cells with subsequent transplantation and liver repopulation. In the in vivo transduction studies (A), we will test i) whether the use of deltaAd.AAV vectors retargeted to hepatocytes will minimize vector related toxic and immunological side effects; ii) whether modified deltaAd.AAV vectors in combination with transient rep78 expression will allow for sitespecific integration in hepatocytes; and ii) whether integrated transgenes will provide sustained FVIII and hAAT expression at therapeutic levels. In the in vitro transduction studies with bone marrow derived stem cells (B), we will test i) whether bone marrow cells with liver repopulation capacity can be stably transduced with retargeted deltaAd.AAV vectors; ii) whether transduced cells will engraft in normal or diseased mouse livers, differentiate into hepatocytes, and provide lifelong transgene expression; and iii) whether this approach will circumvent the production of neutralizing antibodies to FVIII or hAAT. For both strategies, we will assess whether transduced cells can be expanded in vivo by dimerizer- drug dependent induction of cell proliferation. In vitro transduction and integration studies will be performed with murine and human hepatocytes. Vector toxicity tests and preliminary in vivo transduction studies will be done in normal mice to select the optimal vector/s and doses for subsequent studies in
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murine disease models including hemophilic, FVIII knockout mice and hAAT transgenic mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NON-PRIMATE FIV VECTORS FOR TREATMENT OF HEMOPHILIA A Principal Investigator & Institution: Sauter, Sybille; Genstar Therapeutics 10865 Altman Row, Ste 200 San Diego, Ca 92121 Timing: Fiscal Year 2002; Project Start 21-JAN-2002; Project End 20-JUL-2002 Summary: (provided by applicant): We propose to optimize non-primate Feline Immunodeficiency Virus (FIV) vectors for the treatment of hemophilia A to address the need for constitutive, long-term expression of the therapeutic protein, factor VIII. Lentiviral vectors offer multiple advantages over other gene delivery vehicles for gene therapy and FIV has particular advantages over other lentiviral vectors. Importantly, FIV is non-pathogenic in humans. FIV vectors have been shown to efficiently express transgenes in a variety of tissues and species, including primates. The long-term objective is to develop a commercially feasible FIV vector system. For that purpose, we propose to optimize the FIV vector technology in vitro and in vivo to increase the overall efficiency of this gene delivery system. The specific goals are to generate the next generation FIV-based vectors optimized for safety, high titer and efficacy for delivery of human FVIII and to evaluate the in vivo efficacy of the optimized FIVIFVIII vectors in mouse models for hemophilia A. The combined optimization of the FIV vector system itself in vitro and the identification of the best mode delivery in vivo are expected to increase the overall potency of FIV vectors for hemophilia A. Increased vector potency translates into lower doses and thus fewer risks. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NON-VIRAL GENE MEDICINE FOR THE TREATMENT OF HEMOPHILA Principal Investigator & Institution: Miao, Carol H.; Pediatrics; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): The goal of this study is to utilize animal models of hemophilia to develop improved, clinically relevant nonviral gene transfer methodologies. While viral gene transfer has recently shown promise for therapy of several diseases including hemophilia, many obstacles remain including: (1) difficulty of large scale virus production; (2) the host immune responses to viral vectors; (3) the potential toxicity of encapsulated viral vectors; and (4) the potential for mutagenic events initiated by random integration into the host genome. Nonviral gene transfer approaches could provide an alternative and possibly safer gene delivery strategy that may avoid some of these potential harmful effects. Our previous data clearly demonstrate the complete and sustained phenotypic correction of hemophilia B in mice following hepatic gene transfer of a high-expressing factor IX (FIX) plasmid. Furthermore, we have shown that using a combination of optimal cis-regulatory elements in FVIII gene expression cassettes, high-level expression of FVIII in the liver of hemophilia A mice was achieved. While clearly successful for plasmid delivery and expression, the rapid, high-volume tail-vein injection technique utilized in these studies, will not be suitable for direct clinical applications. Furthermore, a robust immune
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response against the FVIII led to complete inhibition of circulating FVIII activity despite maintenance of high level sustained FVIII expression in treated hemophilia A mice. Development of an effective method to induce tolerance will be essential for the successful application of all forms of FVIII of gene therapy including those utilizing nonviral protocols. We hypothesize that: 1.) Alternative delivery methods can be established (Transferrin-DNA conjugates, and ultrasound stimulation) that will allow efficient and clinically feasible plasmid DNA transfer into liver; 2) These combined approaches will lead to correction of disease in a hemophilia A murine model; and finally, 3) This model will also permit evaluation of the host immune response to the "neo-antigen" factor VIII, including elucidation of the mechanism of immune activation, and strategies for successful immuno-modulation. Aim I. To evaluate alternative clinically feasible methods for nonviral gene delivery of plasmid DNA into mouse livers. Aim II. To evaluate immune response against FVIII following non-viral gene transfer, and evelop strategies to prevent and modulate alloimmunization in hemophilia A mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL HEPATITIS C DRUGS Principal Investigator & Institution: Iadonato, Shawn P.; Vice President & Cheif Scientific Office; Illumigen Biosciences, Inc. 2203 Airport Wy S, Ste 450 Seattle, Wa 98134 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-JAN-2004 Summary: (provided by applicant): Illumigen is pursuing an alternative genetics-driven approach to drug discovery that relies on the identification of mutations associated with health rather than disease. Beneficial or health-inducing mutations, like most diseasecausing mutations, are expected to negatively impact gene function in a way that can be mimicked by an inhibitory drug. This Phase I application encompasses the first part of our program to identify genetic mutations that confer resistance to hepatitis C infection and to develop new drugs that mimic the beneficial effects of these mutations. We describe in this Phase I proposal a candidate gene based allele association study to investigate the genetic determinants of HCV resistance. Case and control subjects are being selected from two high-risk populations (hemophiliacs and injecting drug users). Cases are defined as those subjects with significant documented exposure to HCV who remain uninfected. A prioritized list of candidate genes will be interrogated in the case and control populations using targeted DNA sequencing. Polymorphism discovery will focus on the exons, exon/intron boundaries, and untranslated regions of each candidate gene. Nine million phred Q about 20 bases of data will be generated during Phase I. Methods for data analysis and control of population substructure are described. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL THERAPIES IN HEMOSTASIS AND TRANSFUSION MEDICINE Principal Investigator & Institution: Bussel, James B.; Associate Professor of Pediatrics; Pediatrics; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): This application is in response to RFA HL-02-001 entitled Transfusion Medicine/Hemostasis Clinical Network and is a consortium of the New York Presbyterian Hospital - Weill Cornell College of Medicine-Columbia College of Physicians and Surgeons. It provides health care to > 20% of the New York City metropolitan area and has access to > 20 million people within 2 hours. It is an amalgam
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of physicians and scientists involved in clinical research in Hemostasis and Transfusion Medicine with expertise in Pediatrics, Internal Medicine, Pathology, and Surgery. The group has both the patient population and the clinical expertise required to participate in clinical trials proposed by other centers in the Network. Specific Aim 1 is a clinical trial of refractory ITP, defined as children and adults with ITP who have failed to respond to splenectomy. It intends to focus on the pathophysiology of refractory ITP by comparing two novel treatments. One, rituximab, is an anti-CD20 which depletes the recipient of B cells and should be an effective immunosuppressant in a "pure" autoantibody disease like ITP. There is preliminary data describing its effectiveness which should optimize its use. The other arm intends to use thrombopoietin or mimetic (TPO) to increase the platelet count by stimulating platelet production. This arm hypothesizes that a critical element in refractory ITP is a decreased production of platelets which can be rectified by stimulation with TPO. A registry of splenectomy will be included to facilitate enrollment of eligible patients. Specific Aim 2 intends to optimize granulocytes for transfusion. This would be of great potential benefit to patients with prolonged, severe neutropenia who suffer considerable morbidity and occasional mortality from infection. There is also the high cost of prolonged hospitalizations. In the past, studies of granulocyte transfusion showed little benefit and significant toxicity. The current study will explore different methods of preparation of granulocytes and also novel techniques for evaluation of their efficacy. Specific Aim 3 demonstrates that the consortium is able to participate in protocols for a wide variety of disorders of hemostasis and transfusion medicine. The consortium includes Dr. Grima of the NY Blood Center who annually phereses approximately 20 TTP patients; a leading center, Cornell, for management of patients with alloimmune thrombocytopenia;and a large hemophilia center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL VECTOR FOR GENE TRANSFER FOR HEMOPHILIA B Principal Investigator & Institution: Manno, Catherine S.; Director, Transfusion Service; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001 Summary: Hemophilia B (HB) is an inherited bleed diathesis due to absence of functional coagulation F. IX. Gene transfer is an appealing approach to HB since small increases in plasma F.IX. Gene transfer is an appealing approach to HB since small increases in plasma F.IX improve the clinical course and tight control of transgene expression is unnecessary for clinical benefit. Efficacy and dose-finding can be extrapolated from experiments in animal models. A human trial assessing the safety of intramuscular (IM) administration of adeno-associated virus (AAV) vector with a CMV promoter encoding F.IX was developed 2-3 years ago, but new tools are now available that will likely improve the current vector. We propose three strategies for enhanced transgene expression and improved patient safety in the clinical trial. First, we will make a vector with a muscle-specific promoter to reduce the risk of immune response against the monocyte derived F.IX. Second, we will assess if vector injection into muscles rich in slow fibers ( soleus of the leg) results in enhanced murine transgene expression Third, since AAV-1 capsid provides superior gene transfer compared to the AAV-2 capsid in the current vector, we will test whether an AAV-1 vector produces better gene transfer than the AAV-2 in RAG-1 mice. Those modifications that result in enhanced transgene expression will be used to create a novel vector for a new trial of AAV-F.IX for IM administration. We will enroll 9 adult males with severe HB in a dose escalation safety trial. Three subjects will be enrolled in each of 3 dose cohorts. We will
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monitor subjects for local and systemic toxicity, antibody formation against the viral capsid Ag and F.IX and body fluids for the presence of vector sequences. Clinical endpoints will include changes in aPTTs, F.IX levels and patterns of factor concentrate use. After safety is demonstrated, we will establish if re-treatment with an AAV vector is useful, by injecting the new vector into subjects previously treated with AAV-CMVhF.IX who have demonstrated low transgene expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOGENESIS OF HIV AND HCV IN HEMOPHILIA: HGDS Principal Investigator & Institution: Gomperts, Edward; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2001; Project Start 25-SEP-2001; Project End 31-AUG-2005 Summary: (provided by the applicant) This study will define host and immune factors that influence HCV and HIV-1 infection. Understanding the immunopathogenesis of HIV-1 is vital to vaccine development and the establishment of new treatment strategies. In addition, HCV infection is recognized as a major worldwide threat with significant implications for HIV-1-coinfected individuals. The specific aims of this application are: 1) to investigate the role of viral specific immunologic responses in controlling HIV-1 and HCV infection, 2) to investigate the relationship between CD4+ and CD8+ cellular activation with HIV-1 viral load, HCV viral load, and HIV-1 clinical progression, 3) to investigate how host genetic factors that modulate the expression of intracellular cytokines affect the levels of HCV RNA, HIV-1 RNA and HIV-1 clinical progression, and 4) to investigate the mechanism by which HCV infection affects HIV-1 clinical progression. This study will utilize biologic specimens stored from participants in the Hemophilia Growth and Development Study (HGDS), a U.S. multi-center natural history study that enrolled subjects between 1989 and 1990 with 7-8 years of follow-up. The HGDS included those who were HCV infected (n=126) and those HIV-1/HCV coinfected (n=207). The first aim will utilize tetramer and ELlSPOT assays on longitudinally collected specimens to determine the relationship between HIV-1 specific responses and the control of viral replication and clinical progression. Similar studies will be performed to test the relationship between HCV-specific responses and HCV viral load in both cohorts. The second aim will determine if cellular activation, as measured by expression of activation markers on longitudinally collected CD4+ and CD8+ cells, is associated with HIV-1 and HCV RNA levels, as well as HIV-1 clinical progression. The third aim will determine if genetic polymorphisms in the promoter region of various Th1 and Th2 cytokines predicts HIV-1 clinical progression, and/or the quantity of inducible intracellular cytokines. The final aim of this study will explore the mechanism underlying recent observations that HCV infection and viral load adversely affect HIV-1 clinical progression. Two potential explanations for these observations will be tested. First, to determine if systemic cellular activation, that may occur in the setting of chronic HCV replication, accounts for the enhanced risk of HIV-1 progression, after controlling for CD4+ cell number and HIV viral load. Second, to explore the possibility that chronic HCV infection, previously shown to occur in the setting of waning HCVspecific immune responses, is associated with down-regulation of HIV-1 specific cellular responses and clinical progression. This study will utilize state-of-the-art technology in a well-characterized cohort to expand the current understanding of host and immune factors that influence viral replication and clinical disease progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Mckinney, Ross E.; Associate Professor, Pediatrics; Pediatrics; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 01-JUN-1989; Project End 28-FEB-2002 Summary: The Duke Pediatric AIDS Clinical Trials Unit is a multicenter program which provides ACTG protocol care to HIV infected and exposed children throughout North Carolina, southern Virginia, and northern South Carolina. To provide these services in a cost-effective, regional approach, the North Carolina Children's AIDS Network (NCCAN) was created. The core of the network is at Duke, where the largest number of patients are seen, data entry and quality assurance activities are based, and interface occurs with several large basic science programs. There is a full sub-unit at the University of North Carolina at Chapel Hill, which began with a focus on adolescents (because of a large hemophilia center), but has evolved to emphasize perinatal prophylaxis and primary therapy trials. The NC-CAN has two Outreach Clinics, at the Carolinas Medical Center in Charlotte, NC, and the Brenner Children's Hospital at Bowman Gray School of Medicine in Winston-Salem, NC. To serve these clinics, a physician-nurse team from Duke travels to Charlotte and Winston-Salem on a regularly scheduled basis (every 2 to 4 weeks for each site). In the Outreach Clinics, patients are seen by their local pediatric infectious diseases specialist for care, and by the Duke Travel Team for ACTG protocol related issues. Thus, patients can participate in ACTG protocols closer to their local community, making access to cutting edge medical care more easily available for this generally poor and disadvantaged population. The Travel Team also participates in Screening Clinics in Greenville, NC (East Carolina University School of Medicine) and Roanoke, VA (Community Hospital of the Roanoke Valley) where patients are seen and evaluated regarding their suitability for ACTG protocols, again in coordination with their local pediatric infectious diseases specialists. In addition to providing medical care closer to the patients' homes, the NC-CAN model as a whole allows the Duke PACTU to maintain tight quality assurance, since the forms are completed by Duke staff, and to provide Optimum laboratory specimen delivery, since clinical specimens from the Outreach and Screening Clinics are hand delivered to ACTG certified retrovirology and cytometry labs at UNC and Duke (respectively). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHILADELPHIA PEDIATRIC AIDS CLINICAL TRIALS UNIT Principal Investigator & Institution: Starr, Stuart E.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-MAR-1992; Project End 28-FEB-2002 Summary: This is a competitive renewal application for The Philadelphia Pediatric AIDS Clinical Trials Unit (PACTU), a consortium consisting of The Children's Hospital of Philadelphia (CHOP) as the main unit and a site for pediatric studies, St. Christopher's Hospital for Children (SCHC) as a pediatric subunit, and the Hospital of the University of Pennsylvania (HUP) and Temple University Hospital (TUH) as perinatal subunits. The Philadelphia PACTU has achieved a strong performance record over the past four years, with enrollments into Pediatric AIDS Clinical Trials Group (PACTG) clinical trials increasing from 24 during the first year of operation to 63 during year 4. The Philadelphia PACTU has had excellent success in entering patients into primary therapy, opportunistic infection, perinatal transmission, adolescent, quality- of-life, and immune-based therapy protocols, including many Phase I studies. In the past two years, an aggressive effort to promote participation in perinatal studies has resulted in a
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dramatic increase in the number of subjects enrolled into perinatal protocols. The Philadelphia PACTU has an outstanding record of administrative performance and compliance with regulatory and data management procedures. Several members of the Philadelphia PACTU hold leadership positions in the PACTG and are making major contributions to the scientific agenda, particularly with regard to immune-based prevention and treatment of HIV-infection in children. It is anticipated that, over the next four years, the Philadelphia PACTU will continue to: 1) enroll subjects into high priority protocols; 2) enroll an increased number of subjects into pediatric and perinatal protocols, including Phase I studies; 3) maintain its excellent record of compliance with regulatory and data management procedures; and 4) contribute in a major way to the scientific agenda of the PACTG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHOSPHOLIPID BINDING SPECIFICITY OF FACTOR IX Principal Investigator & Institution: Falls, Lisa A.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JUL-2001 Summary: The overall goal of this proposal is to characterize the phospholipid binding specificity of factor IX. Factor IXa cleaves factor X to produce Xa in a vitamin Kdependent reaction. The absence of factor Ix causes hemophilia B. The factor IXa reaction is one of many in the coagulation cascade requiring a membrane surface for assembly of the enzyme, substrate, and cofactor. The central hypothesis of this proposal is that phospholipid composition affects the binding of factor IX and the factor IXa catalyzed conversion of factor X to factor Xa. The effect of phospholipid composition on the enzymatic function of factor IXa will be examined by measuring factor Xa generation in the presence of phospholipid vesicles and soluble phospholipids of varying compositions. In addition, the binding specificity of factor DC for phospholipid vesicles will be determined using light scattering. Identification of the portions of the phospholipids important in the binding will be discovered by using soluble phospholipids to compete with phospholipid vesicles for the binding of fluorescently labeled factor IX in flow cytometry experiments. These studies will be complemented by 1H NMR spectroscopy experiments examining molecular contacts between factor IX( 147) and l ,2-dihexanoic-sn-glycero~3 phospho-L-serine. Ultimately, the structure of the factor IX(l47)-phosphatidylserine complex will be determined by two- dimensional NMR analysis. The results of this proposal will lead to new information about how phospholipid membranes contribute to the vitamin K-dependent coagulation reactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: POLYMER-BASED CONTROLLED RELEASE SYSTEMS: GENE DELIVERY Principal Investigator & Institution: Wang, Chun; Chemical Engineering; Massachusetts Institute of Technology Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-FEB-2002 Summary: Advancement of gene therapy to the clinic is hampered by the lack of efficient and reliable means of gene delivery. Efficiency of gene transfer mediated by non-viral gene delivery diseases such as hemophilia, it is highly important to maintain prolonged steady release of therapeutic genes. It is hypothesized that controlled and efficient long-term delivery of genes could be achieved by combining polymer-based controlled release devices with non-viral vectors. A very important issue to be
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addressed in developing clinically useful gene delivery systems is DNA stability. Inactivation of DNA due to physical and chemical degradation during preparation of controlled release systems, long-term storage, and following administration, severely compromises the efficacy of gene therapy. Understanding the degradation pathways of DNA should lead to rational design of effective strategies for DNA stabilization. The specific aims of this proposal are (1) to prepare and characterize biodegradable poly(lactic) acid co-glycolic acid) (PLGA) microsphere encapsulating plasmid DNA complexed with selected non-viral vectors including cationic polymers and peptides, (2) to evaluate the release of complexed plasmid DNA from PLGA microspheres and transfection efficiency in vitro, (3) to identify the non-enzymatic pathways involved in the degradation of plasmid DNA complexed with selected cationic vectors in dry and hydrated PLGA PLGA microspheres using robust analytical techniques, and (4) to design and test methods of plasmid DNA stabilization based on the knowledge gained from polymer-based controlled delivery systems for gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RECOMBINANT FACTOR VIII SQ IN PREVIOUSLY TREATED HEMOPHILIA A Principal Investigator & Institution: White, Gilbert C.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGIONAL PRIMATE RESEARCH CENTER Principal Investigator & Institution: Whelton, Paul K.; Senior Vice President for Health Science; None; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2001; Project Start 01-JUN-1978; Project End 30-APR-2003 Summary: This application is a request for the support of the operation of the Tulane Regional Primate Research Center for the next five year period. The research will be done utilizing non-human primates most of which are produced at the Center from breeding colonies. The score of the research projects, although primarily in the area of infectious diseases, covers a range of biomedical disciplines. The proposed AIDS research will include studies of vaccines, the interaction of the IDS virus with other infectious agents, the pathogenesis of disease in the monkey including the transfer of virus form the mother to the fetus, the role of alcohol in the infectious process, and the role of the mucosal immune response. Gene therapy studies will test strategies for correcting globoid cell leukodystrophy, hemophilia B, cystic fibrosis, liver disease, and as a treatment for AIDS. Other infectious disease research will be done on Lyme borreliosis (antibiotic treatment and autoimmunity), malaria (severe cerebral disease and disease during pregnancy)< lymphatic filariasis, and pyelonephritis in diabetics. Other, non-infectious disease research projects will be done on neuropeptides, aging, opioids, and vascular injury with balloon catheters. In addition to the research junction of the Center, this grant will support breeding colonies of macaques. It will also provide support for this Center to serve as a resource for investigators from other institutions who have need to conduct research in non-human primates. The performance site of these activities will be at the Tulane Regional Primate Research Center in Covington, Louisiana. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF FACTOR VIII SECRETION Principal Investigator & Institution: Kaufman, Randal J.; Professor/ Hhmi Investigator; Biological Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 30-NOV-2005 Summary: (provided by applicant): FVIII (FVIII) is the plasma protein deficient or functionally defective in hemophilia A, an X-chromosome linked bleeding disorder affecting 1/5,000 males. Affected patients experience significant morbidity and mortality related to repeated and/or life-threatening bleeding events. Protein replacement therapy with recombinant-derived FVIII is presently the preferred therapy. However, the cost of recombinant FVIII and the continued problem ofimmunogenicity remain significant problems. The long term goal of the proposed research is to provide fundamental insight into the regulation of FVIII synthesis and secretion with the ultimate goal of developing improved therapies for hemophilia A. The specific aims of this proposal are to test the following three hypotheses: FVIII secretion is limited by transient aggregation immediately after its translation. We will characterize the requirements for ATP-dependent dissociation of FVIII aggregates. FVIII expression is toxic to cells by activation or ER stress-response signaling kinases. We will determine whether accumulation of FVIII within the ER activates protein kinases to inhibit protein synthesis and induce transcription of genes encoding ER stress proteins. ERGIC-53 is a molecular chaperone that interacts with the B domains or FV (FV) and F VIII and facilitates their transport to the Golgi compartment. We will elucidate the requirement of ERGIC-53 in the transport of FV and FVIII to the Golgi compartment. These studies will identify folding pathways of FVIII, improve FVIII secretion efficiency and limit toxicity associated with FVIII expression. In addition, these studies will identify how deficiency in ERGIC-53 causes combined deficiency of FV and FVIII. They will provide fundamental new insights into FVIII protein synthesis and secretion. The information will be vital to the future development of improved gene therapy protocols for hemophilia A. The ER provides an essential function to promote folding of proteins destined for the cell surface. Elucidating the mechanisms of protein folding, retention, and transport through the ER will have impact on the ability to therapeutically intervene in disease states that are associated with defective protein folding in the ER. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF LIVER SPECIFIC GENE EXPRESSION Principal Investigator & Institution: Sladek, Frances M.; Associate Professor; Entomology; University of California Riverside 900 University Ave Riverside, Ca 92521 Timing: Fiscal Year 2001; Project Start 16-JUN-1998; Project End 31-MAY-2002 Summary: (Adapted from the investigator's abstract). The liver is the primary organ responsible for producing plasma and other proteins essential for basic metabolism and detoxification of chemical compounds. Whereas research during the past decade has shown that these liver proteins are produced largely as a result of liver-specific gene expression mediated by liver-enriched transcription factors, it is not known exactly how liver-specific transcription is achieved. For example, many questions remain about the mechanism of action of hepatocyte nuclear factor 4 (HNF-4), one of the most important transcription factors for determining the hepatic phenotype and regulator of over 40 target genes, including those involved in glucose, fatty acid, and cholesterol metabolism, blood coagulation, and chemical detoxification. The goal of this proposal, therefore, is to elucidate the mechanism of liver-specific gene expression by studying three important
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aspects of HNF-4: (1) The applicants recently showed that due to its strong and exclusive homodimerization activity and exclusive nuclear localization, HNF-4 defines a new subgroup in the nuclear receptor superfamily. They propose to investigate the specific amino acids that determine homo- vs. heterodimerization as well as the role of protein dimerization in receptor function. This will be achieved by rationally based sitedirected mutagenesis studies derived from what is already known about other receptors as well as from a naturally occurring mutation in HNF-4 that was recently found in patients with maturity-onset diabetes of the young (MODY1); (2) The applicants will examine the mechanism of transcriptional activation by HNF-4 by analyzing the interaction between HNF-4, co-activators, co-repressors, and the basal transcription machinery by in vivo and in vitro assays; and (3) The applicants will establish an in vitro system to investigate the transcriptional synergy between HNF-4 and another liverenriched transcription factor, C/EBP alpha, on the apolipoprotein B gene promoter. Synergy between tow liver-enriched transcription factors could explain liver-specific gene expression for this and other genes. Since HNF-4 has been directly or indirectly linked to several human diseases, including atherosclerosis, hepatitis, hemophilia, hepatocarcinogenesis, and, most recently, diabetes, detailed mechanistic knowledge of HNF-4 function will not only shed light on liver-specific gene expression and the action of nuclear receptors but also provide a basis for the possible future development of therapeutic reagents for a wide variety of diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REPAIR OF FACTOR VIII BY TARGETED RNA TRANS SPLICING Principal Investigator & Institution: Mansfield, S Gary.; Intronn, Llc 9700 Great Seneca Hwy, Ste 264 Rockville, Md 20850 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 14-APR-2004 Summary: (provided by applicant): Successful gene therapy will revolutionize the treatment of the inherited bleeding disorders hemophilia A and B. Hemophilia A is caused by deficiency of coagulation factor VIII (FVIII) and is a prime disorder for genetic correction. The disease constitutes 80% of all hemophilia patients and is the focus of this proposal. The requirements for successful FVIII gene transfer include: the persistent expression of therapeutic levels of FVIII, the lack of significant toxicity to the gene transfer vehicle (vector), the lack of host immune response to the normal factor VIII protein and to the vector, and reduced ectopic expression of the normal product. Gene therapy through the use of Intronn's platform technology, spliceosome mediated RNA trans-splicing (SMART), can potentially circumvent some of these problems. Intronn has developed and patented constructs called pre-trans-splicing molecules (PTMs) that are capable of modifying mRNA in vivo. PTMs work by promoting trans-splicing reactions between the PTM and a targeted pre-messenger RNA. The product of a SMART reaction is a novel chimeric or composite RNA that can encode virtually any desired gene product. The product of a SMART reaction contains one or more exons of the target endogenous pre-mRNA and an exonic or cDNA sequence delivered by the PTM. We propose studies to target mutant factor VIII in cell and animal models of hemophilia A with PTMs that can perform repair of endogenous transcripts to generate full length functional FVIII. This Phase I application proposes to optimize the splice elements and binding domain of PTMs using a LacZ based repair model in 293 cells, and to subclone lead sequences into factor VIII based PTMs and to test these in a characterized mouse model of hemophilia A. Lead PTMs identified in Phase I will be further optimized in Phase II of this application using cell based medium to high throughput screens. Fully optimized PTMs in Phase II will be transferred to an AAV delivery system and tested in
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mouse and canine models of hemophilia A for long term correction of factor VIII. This work will be performed in collaboration with a key university site (UNC-Chapel Hill) with extensive experience in hemophilia A biology, gene transfer and experimentation with murine and canine models of hemophilia A. The research proposed in Phase I and II of this application will form the groundwork for future clinical trials in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF N-GLYCAN CHAIN IN FACTOR VIII--C BIOLOGICAL ACTIVITY Principal Investigator & Institution: Katiyar, Vishwa N.; Inter American University of Puerto Rico Box 3255 San Juan, Pr 00936 Timing: Fiscal Year 2001 Summary: Description (Applicant Abstract): Factor VIII:C is a component of the blood coagulation cascade and its deficiency leads to hemophilia A. It is a bleeding disorder that affects 10-20 per 100,000 males. The disease is transmitted by X-chromosomal inheritance and causes the blood to clot slowly. Prothrombin is converted to thrombin at an abnormally slow rate and a re-bleeding phenomena is frequently seen. Cloning and expression of human Factor VIII:C has suggested the presence of 25 asparagine-linked (N-linked) glycosylation sites in a 270 kDa protein. The N-glycan structure of the recombinant Factor VIII:C expressed in baby hamster kidney (BHK) cells revealed mainly high mannose-type and bi-, tri-, and tetra-antennary complex-type sugar chains. In addition, it contains Gal alpha1-3Gal group as 3 percent of the total sugar chain, and Gal alpha1-4(Fuc alpha1-3) GlcNAc beta1-4(gal alpha1-4 GlcNAc beta1-2)Man group. The presence of high levels of Gal alpha 1 -3Gal group makes the recombinant Factor VIII:C highly antigenic, and as such, is unfit for use as a drug. Our long-term objective is to develop Factor VIII:C from a naturally occurring cell type that is free from side effects and that can be used to combat hemophilia A. The specific aim of our proposal is to test the hypothesis that N-glycosylation is essential for a naturally expressed Factor VIII:C blood clotting activity, and discrete changes in its N-glycan structure affects the ability to activate Factor X. Using a capillary endothelial cell line as a source for naturally occurring active Factor VIII:C, we propose to (i) identification and determination the sequence of N-glycan chains by the FACE OLIGO Profiling and Sequencing systems; (ii) determine the N-glycan structure by Electrospray Ionization Mass Spectrometry; and (iii) develop Factor VIII:C variants defective in N-glycan chain using exo- and endoglycosidases in vitro as well as using glycosylation and/or oligosaccharide processing inhibitors in vivo to study its biological activity. At the conclusion of the project we expect to have the complete N-glycan structure of endothelial cells expressed Factor VIII:C. In addition, we will also obtain critical information on the role of N-glycans in the Factor VIII:C biological activity, i.e. its ability to convert Factor X to Factor Xa. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SAFETY AND IMMUNOGENICITY OF HEPATITIS A VACCINE IN HEMOPHILIA Principal Investigator & Institution: Koerper, Marion A.; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SEQUENTIAL PRE AND POSTNATAL GENE THERAPY OF HEMOPHILIA Principal Investigator & Institution: Gaensler, Karin L.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SLEEPING HEMOPHILIA A
BEAUTY-MEDIATED
GENE
THERAPY
FOR
Principal Investigator & Institution: Hackett, Perry B.; Professor; Discovery Genomics, Inc. 614 Mckinley Pl Ne Minneapolis, Mn 55413 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-OCT-2003 Summary: (provided by applicant): Hemophilia A is a bleeding disorder caused by the absence of clotting factor VIII (FVIII). This disease is inherited in an X-linked recessive manner and it is estimated that there are 15,000 affected individuals in the U.S. Treatment of Hemophilia A has been greatly improved over the last 10 years with the availability of recombinant FVIII (recombinate). However, the high expense of this treatment (as much as $100,000 per year in severe cases) and variable levels of FVIII maintained in the circulation compromise the effectiveness of this therapy. FVIII gene therapy presents a therapeutic alternative for hemophilia A, which would provide more consistent levels of circulating FVIII and thus more efficacious and cost-effective treatment of the disease. Here the investigators propose development of the Sleeping Beauty (SB) transposon system for non-viral FVIII gene transfer and expression in the liver as a therapeutic approach for hemophilia A. The approach is based on the studies that demonstrate long-term, SB transposon-mediated gene expression in the liver and lung. It is hypothesized that the FVIII gene can similarly be delivered to the liver of experimental animals, providing long-term and curative expression of human FVIII. Two Specific Aims are proposed to address this prediction. In SPECIFIC AIM 1, several SB transposons will be assembled which are designed to introduce and express the human FVIII gene under transcriptional regulation of several different strong promoters. Constructs that contain both transposon and transposase functions on the same plasmid will be made. FVlll transposition and expression functions will first be tested in cultured human cells (HEK 293 and Huh7 hepatoma). In SPECIFIC AIM 2, the FVIII transposon constructs tested in Aim 1 will be introduced into the livers of FVIIIdeficient knock-out mice by intravenous administration, subsequently testing these animals for long-term expression of FVIII in the circulation with improved clotting of tested blood and decreased bleeding. Results from these experiments will support subsequent scale-up and translation of the Sleeping Beauty transposase system for treatment of hemophilia A, to be proposed as part of a phase II SBIR study. Technological Innovation: Sleeping Beauty is a novel gene transfer system with potential application in gene therapy. The market size for the inherited-diseases market niche, to which this technology applies, is about to $5.8 billion Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SPECIFICITY OF PROPEPTIDE CONVERTING ENZYMES Principal Investigator & Institution: Mackin, Robert B.; Biomedical Sciences; Creighton University 2500 California St Omaha, Ne 68178
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Timing: Fiscal Year 2001; Project Start 01-JAN-1997; Project End 31-DEC-2003 Summary: This proposal focuses on using proinsulin as a model substrate to address two fundamental questions regarding peptide-converting enzymes (PCE)-mediated processing. First, is the processing specificity determined by structural elements within the PCEs? Second, what specific structural elements of the PCEs are involved in the precise recognition of propeptide cleavage sites? The inial goal of this project is to obtain sufficient proinsulin for use in an in vitro enzyme assay. Products of the in vitro assay will be subjected to structural characterization to conclusively define the sites of PCEmediated cleavage. This assay will then be used to test the effects of microdomain swapping between PC1 and PC2 in an attempt to define which structural regions of an individual furin/PC member is responsible for substrate recognition. Finally the proinsulin substrate will be manipulated to determine whether its three dimensional structure affects processing specificity. Results from these studies should provide valuable information regarding the tertiary structural interactions between the PCEs and their propeptide substrates. A number of cases of hyperproinsulinemia, hyperproglucanemia, insulin resistance and at least two cases of hemophilia have been shown to be caused by mutations affecting the endoproteolytic cleavage site in propeptides. These observations raise the possibility that patients could be treated by administering a modified version of the PCE via gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELL GENE THERAPY FOR CANINE HEMOPHILIA Principal Investigator & Institution: Schuening, Friedrich G.; Professor of Medicine; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 19-SEP-2004 Summary: (provided by applicant): Hemophilia can potentially be cured by ex vivo retrovirus-mediated transfer of the factor VIII or factor IX gene into autologous hematopoietic stem cells followed by infusion of the genetically corrected cells into the stem cell donor. Transduction efficiency into hematopoietic stem cells of large animals and humans using Moloney murine leukemia virus (MoMLV) vectors has been too low so far to achieve a therapeutic effect. One of the reasons is that hematopoietic stem cells are considered to be predominantly quiescent and MoMLV vectors are not able to transduce non-dividing target cells. In contrast, human immunodeficiency virus type 1 (HIV-1) based vectors have been shown to infect nondividing cells. We, therefore, wish to compare the efficiency of HIV-1 vectors containing the canine B-domain deleted factor VIII gene with corresponding MoMLV vectors to transduce stem cells of normal dogs. Using the most efficient vector system, we then wish to evaluate strategies with low toxicity to increase engraftment of transduced hematopoietic stem cells by partial marrow ablation with: a) cyclophosphamide, b) busulfan, or c) 100 cGy total body irradiation (TBI). We wish to compare these strategies with 200 cGy total body irradiation, shown to be most effective in enhancing engraftment of transduced marrow cells in our past studies. Another hurdle towards gene therapy is the possible induction of host immune responses to transduced cells and transgene encoded proteins. We propose to characterize in normal beagles the immune response to autologous marrow cells transduced with the "foreign" human factor VIII gene and to prevent or decrease this immune response by immunosuppressive treatment after transplantation. The most efficient vector system, the least toxic strategy to increase engraftment of transduced marrow cells and the most effective method to prevent a host immune response against factor VIII will then be used to investigate in hemophilia A dogs whether long-term correction of canine hemophilia can be achieved by retrovirus-mediated transfer of the
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canine factor VIII cDNA into hematopoietic stem cells. The outlined studies will address important problems of current gene transfer efforts and, if successful, will facilitate future gene therapy of hemophilia and other diseases in man. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEM CELL THERAPY FOR HEMOPHILIA A Principal Investigator & Institution: Verfaillie, Catherine M.; Professor; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (provided by applicant): Hemophilia-A is an X-linked genetic disorder caused by a deficiency in coagulation factor VIII. Current therapy consists of factor VIII replacement when bleeding occurs. However, this therapy cannot prevent bleeding. Because hemophilia is caused by a single gene defect, it is an excellent disorder for gene therapy. However, current methods for ex vivo gene therapy have been unsuccessful because of lack of suitable target cells, and poor long-term production of factor VIII following transplantation of target cells due in part to poor target cell engraftment and problems with gene transfer and gene expression. We have recently characterized human post natal bone marrow cells that differentiate into most cells of mesodermal origin, including myocytes and endothelium, as well as neuroectodermal cells and cytokeratin-8,18,l9 and cMET positive epithelial cells, termed Multipotent Adult Stem Cells, or MAPC. MAPC can undergo >70 cell doublings in an undifferentiated state, can readily be transduced with retroviral vectors and can be detected, in multiple organs following transplantation in xenogeneic animals. MAPC are therefore ideal target cells for gene therapy of hemophilia-A. Several groups, including our won, have shown that immune recognition of the "neoprotein" may lead to the production of antibodies against fVIIl. We have extensive experience ion characterizing the immune response against fVIII which will allow us to test in murine models how we may circumvent immune rejection of transgenically produced fVIII. We propose the following specific aims: Spedfic Aim 1. We will test the transduction efficiency in MAPC and long-term expression of factor VIII in by undifferentiated MAPC and their differentiated progeny following transduction with a B-domain deleted human fVIII (hfVIII) containing vector. Specific Aim 2. We will transplant hfVIII transduced human MAPC in NOD-SCID mice and test (1) engraftment of the undifferentiated cells in vivo, (2) organ specific differentiation of MAPC in vivo, (3) longevity of MAPC or differentiated progeny in vivo and (4) production of factor VIII in vivo. Specific Aim 3. We will transplant hfVIll transduced murine MAPC (mMAPC) in syngeneic murine recipients which should allow us to determine long-term engraftment of MAPC and long-term expression of fVIII in vivo. Specific Aim 4: We will characterize the immune rejection fVIII following transplantation hfVIII transduced mMAPC in hemophilic mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURAL DETERMINATION OF FACTOR IXA: BLOOD COAGULATION Principal Investigator & Institution: Lanzo, Cheryl; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001 Summary: Bleeding disorders can be characterized by excessive blood clotting known as thrombosis, or by the inability to form blood clots termed hemophilia. Blood clotting is a tightly regulated process involving exquisite control of the many proteins in the blood
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clotting cascade including factor IXa, factor VIIIa, factor Xa, and factor VIIa. We are working to understand the structural determinants of the regulation of factor IXa, a central protein in the clotting cascade. The activation of factor IXa results in clotting whereas the inhibition prevents clotting. Better understanding of the structure of factor IXa will lead to the design of small protein mimetics to treat blood clotting disorders. The catalytic activity of factor IXa is dependent on a cofactor called factor VIIIa. We are working on determining the structure of factor IXa with factor VIIIa in order to elucidate the structural determinants leading to the activation of factor IXa. Further, ecotin, a serine protease inhibitor, will be derivatized to specifically inhibit factor IXa. Inhibition of factor IXa is expected to protect against thrombosis without resulting bleeding complications which is expected from inhibiting factor Xa or factor VIIa. The crystallographic analysis of factor IXa-ecotin derivatives will facilitate our understanding of the region(s) of ecotin which are important for the inhibition of factor IXa. I am using the Computer Graphics Laboratory and MidasPlus to structurally model factor IXa with factor VIIIa and ecotin derivatives. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURAL STUDIES OF BLOOD COAGULATION PROTEINS Principal Investigator & Institution: Stoddard, Barry L.; Full Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 01-APR-1999; Project End 30-APR-2007 Summary: (provided by applicant): Factor VIII (fVIII) is a serum protein that acts as a critical cofactor and regulator of the intrinsic blood coagulation pathway. Factor VIII acts by nucleating the assembly of a membrane-bound proteolytic complex that contains the factor IXa protease on the surface of activated platelets. This complex activates factor X as part of a proteolytic cascade that generates fibrin polymers. Prior to its own activation, factor VIII circulates in a tight, stable complex with von Willebrand Factor. A wide variety of inheritable coagulation deficiencies are associated with mutations in factor VIII (hemophilia A), factor IX (hemophilia B) and von Willebrand Factor (von Willebrand Disease). Recent studies have reported the high resolution structure of the C2 membrane-binding domain of factor VIII, the structural characterization of hemophilia-associated missense mutations found in the fVIII C domains, the structure of a complex between fVIII and a hemophilia patient-derived antibody inhibitor, and a detailed analysis of the structural genomic relationships throughout the discoidin fold superfamily (of which the fV and fVIII C domains are members). The first specific aim for this project renewal is to characterize the effects of hemophilia-associated point mutations throughout the solvent-exposed surface of the factor VIII C2 domain on its stability, its membrane binding affinity and its association with von Willebrand Factor. These experiments will test the hypothesis that a specific subset of these mutations cause deficiencies in factor VIII membrane binding or vWF association. The second specific aim for this project is to determine the three-dimensional structure of full-length fVIII heterodimer. This structure will be used to study the role of domain motions involved in membrane binding by fVIII, to perform detailed analyses of the structural epidemiology of hemophilia-associated point mutations across the entire structure of the fVIII heterodimer, and to provide a high quality structural model for future crystallographic studies of protein complexes with factor VIII. The third specific aim for this project is to determine the structure of the N-terminal, D'-D3 domain from von Willebrand Factor, alone and/or in complex with factor VIII heterodimer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURE AND FUNCTION OF THE FACTOR VIII-VWF COMPLEX Principal Investigator & Institution: Lollar, John S.; Professor; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JUL-1988; Project End 30-JUN-2006 Summary: (provided by applicant): Factor VIII (fVIII) participates in the intrinsic pathway of blood coagulation and is essential for normal hemostasis. The sites of hemostatically significant fVIII expression remain unknown and the control of fVIII expression is poorly understood. The problem is relevant to the basic biology of the hemostatic mechanism and to the development of better treatments for hemophilia A. Additionally, there is a clear association between elevated fVIII levels and thrombotic disease, which further underscores the need to understand the regulation of fVIII expression.This project has two specific aims. In Aim 1, we will study the endogenous synthesis of fVIII in vivo. We will identify cellular sites of murine fVIII synthesis by immunolocalization. Additionally, we will study the tissue distribution of fVIII using eGFP-fVIII transgenic mice. Human fulminant hepatic failure is associated with increased fVIII, which is surprising because the liver is considered the dominant site of fVIII synthesis. Understanding this phenomenon may be a key to identifying mechanisms of fVIII regulation. Therefore, we will study the tissue distribution of fVIII and fVIII mRNA in a murine model of fulminant hepatic failure. Transplantation studies have suggested that the spleen synthesizes hemostatically significant amounts of fVIII, but conflicting results have been obtained. Therefore, we will determine whether transplantation of normal donor spleen corrects the hemostatic defect in hemophilia A mice.In Aim 2, we will characterize the regulation of fVIII expression in heterologous systems. These systems are important models for the study of the regulation of fVIII synthesis. Additionally, heterologous expression is used in the commercial manufacture of fVIII. There is a worldwide shortage of fVIII that is due in part to low-level expression, in the last project period, we observed that expression of porcine Bdomainless fVIII is approximately ten-fold higher than any level previously reported. We will identify sequences responsible for high-level expression of porcine fVIII. Additionally, we will identify the mechanism of differential expression of porcine versus human fVIII by using cell-free translation and co-translational processing systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURE AND REGULATION OF HUMAN FACTOR VIII Principal Investigator & Institution: Fay, Phillip J.; Professor of Medicine and Biochemistry; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2006 Summary: (provided by applicant): Hemophilia A, the most common of the severe, inherited bleeding disorders, results from a deficiency or defect in the plasma protein, factor VIII. There is no cure for hemophilia A and treatment consists of replacement using (purified) factor VIII preparations. During the last funding period we have made significant strides in characterizing sequences and ligands, and determining mechanisms important for factor VIIL/factor Villa subunit structure and function. We will use this information as a platform to identify fine point structural details of intraprotein interactions that will define mechanisms for the regulation of this critical protein. The first aim will study inter-factor Villa subunit interactions related to the
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retention and stimulation of A2 subunit. This subunit is critical as demonstrated by the limited cofactor activity observed for isolated A2. Further, the relatively weak affinity interaction of A2 subunit in factor VIIIa governs the subunit structure and function of the active protein. Goals are to identify and determine the roles of residues in A1 and A2 that serve in the inter-subunit interaction and are responsible for the stimulation of A2dependent cofactor activity. Specific aims include: (i) elucidation of salt bridging between basic residues in A2 and the acidic C-terminus of Al and (ii) examination of interactive sites in Al that are independent of this C-terminal tail. Methods will employ peptide analysis and molecular biology/cell culture techniques to generate novel factor VIII/subunit molecules. Alterations in activity will be correlated with changes in structure using a variety of physical methods amenable to low levels of protein. The second aim studies metal ion-dependent and -independent interactions in factor VIII involved in association of heavy and light chains. The goal of this aim is to define and model the association of these two chains in the active conformation. Our studies will: (i) examine the role of Cu in the high affinity inter-chain interaction following characterization of factor VIH molecules possessing altered consensus type 1 and type 2 Cu binding Sites, (ii) determine the role of Ca2+ in yielding the active cofactor conformation following quantitation of Ca sites and physical analyses of the conversion of inactive to active cofactor conformation, and (iii) assess metal ion-independent interactions including the role of exposed hydrophobic sites in heavy and light chains, and contribution of the A2 domain to the inter-factor VIII interaction. Definition of these issues will yield valuable insights into the biochemistry of the native as well as dysfunctional factor VIII molecules, and provide information for the design of superior therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURE FUNCTION STUDIES ON NORMAL AND MUTATED FACTOR IX Principal Investigator & Institution: Roberts, Harold R.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002 Summary: The overall aim of this proposal is to assign functional significance to specific structural regions of the coagulation factor IX. These studies have arisen as an outgrowth of work done in the last cycle of this program project grant. Using the same techniques that successfully identified the endothelial cell factor IX receptor as collagen type IV, we have identified a chimeric factor IX molecular that does not bind to the platelet factor IX binding site. We hypothesize that even if factor IX is otherwise fully active, factor IX that does not bind to platelets will be ineffective in a physiologic setting. We propose studies to understand the role of the platelet factor IX binding site by using this chimera in both in vitro studies and in vivo studies in hemophilic dogs and in a hemophilia B mouse strain developed in the last cycle of this program studies in hemophilic dogs and in hemophilia B mouse strain developed in the last cycle of this program project grant. We are also planning to examine the physiologic consequence of mutating Arg338 in factor IX to Leu. This mutation increases factor IXa activity at least 3 fold. This residue is coded for by a CG mutational hot spot, yet not mutations have been reported at this site. This is especially remarkable since 16 hot spots in factor IX account for 40% of all reported mutations. We hypothesize that mutations have been reported because mutation at that site do not cause hemophilia but rather are thrombogenic. We will test this hypothesis in hemophilia B dogs and mice. We are proposed studies to understand the residues of factor IX that are involved in substrate recognition and
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cleavage. In the last cycle of this grant, we established that, in the absence of factor VIIIa, porcine factor IXa has higher activity toward human factor X than does wild type factor IXa. We will isolate the residues responsible for this higher activity using a humanporcine chimera and point mutations. Also, we will examine the interactions of the Kunitz inhibitor protease nexin II with factor IXa to define residues involved in the extended binding site of factor IXa. Finally, we plan to define a binding site for factor VIIIa using a peptide from factor VIII that we have shown to bind to factor IXa and inhibit its activity. We will crosslink this peptide to factor IXa and isolate peptides of factor IXa to which it is bound. Overall, these studies will allow us to define specific structural regions of factor IX that are involved in a number of important physiologic functions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGETABLE VECTORS FOR GENE THERAPY Principal Investigator & Institution: Meruelo, Daniel; Professor; Pathology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2001; Project Start 30-SEP-1995; Project End 28-FEB-2005 Summary: (Applicant's Abstract) Both acquired disorders, like AIDS and cancer, as well as inherited disorders like hemophilia, cystic fibrosis, mental retardation, and many others will prove amenable to treatment by gene therapy. The approach is both rational and highly likely to achieve dramatic results. The human genome project and the work of many groups across various disciplines are helping to rapidly identify and clone the required genes for such an approach. However, the promise of gene therapy for the treatment of human inherited and acquired disorders will not be fully realized until the issue of delivery is satisfactorily resolved. Thus, there is an urgent need for safe, efficient and targetable vectors to permit the delivery of genes being discovered in the course of studying the human genome. In this grant we document the generation of the first truly targetable vector system for gene delivery. Our studies today have established a method for production of targetable high-titered virus vectors capable of achieving complete tumor regression in an animal model. This system embodies all the attributes of safety, high efficiency of transduction and expression, and ease of engineering and production that are necessary for successful gene therapy. Through this application we seek funding to perfect the system, to resolve some issues of fundamental importance not only to our vector system but also for the field of apoptosis in general. We also seek to develop vectors and therapeutic approaches that have a high probability of helping to treat a broad variety of diseases and disorders. Our specific aims are: 1. To develop at least three highly apoptotic Sindbis-virus based vectors that would be able to target growing human tumor cells. 2. To test the above vectors in experimental animal protocols to establish safety, pharmacokinetics, biodistribution, and optimal dosing schedules for successful therapy of tumors. 3. To identify and study the mechanism of action of a major gene conferring resistance/susceptibility to apoptosis. The approach is based on the observation that mammalian cells are fully susceptible to Sindbis virus mediated apoptosis, while insect cells are completely resistant. These novel studies, in combination with ongoing efforts to investigate viral-induced apoptosis, will expand the range of diseases that can be approached with Sindbis and other viral vectors, as well as contribute important new knowledge to the field of apoptosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETED GENE THERAPY FOR HEMOPHILIA A Principal Investigator & Institution: Bahou, Wadie F.; Chief; Medicine; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 30-JUN-2004 Summary: Hemophilia A (congenital deficiency of coagulation factor VIII) is the most common (serious) congenital bleeding disorder worldwide. Hemophilia A is a model system for definitive genetic therapy for the following reasons: (I) it is caused by a single- gene defect, (ii) its biological processing and synthesis have been extensively studied, (iii) therapeutic levels of plasmatic clotting factors ameliorate hemorrhagic episodes, and (iv) physiologic levels in human are low (100 - 200 ng/mL), with clinical manifestations closely paralleling circulating fVIII levels such that therapeutic benefit can be reached with 5 percent fVIII activity (5 - 10 ng/mL). As a definitive means of genetic treatment, this laboratory has focused on adeno- associated virus (AAV) for fVIII gene therapy strategies, as AAV infection is not associated with human diseases, and cells carrying proviruses fail to express novel cell-surface antigens, thereby failing to serve as immunological targets. If a helper virus is not present during an AAV infection, the AAV genome integrates in a site-specific region (AAVS1) on human chromosome 19q, a property that is dependent on AAV rep68/78 and inverted terminal repeats (TR's). By virtue of being produced primarily in the liver, the hepatocyte is the logical site for gene replacement strategies for hemophilia A, although vascular endothelial cells remain an attractive target as a means of regulated delivery by co-expression with Von Willebrand factor. In this proposal, we will continue to develop novel viral vectors for hemophilia A gene therapy, viruses which collectively share the unique integrating properties of the AAV terminal repeats, as a means of definitive treatment for hemophilia A. To date, we have been the only laboratory that has successfully generated a fVIII/rAAV virus, serving as proof-of-principle for further research in this direction. Three viruses will be characterized for their ability to deliver B-domaindeleted factor VIII recombinant AAV, adeno/adeno-associated hybrid (Ad/AAV) virus, and mini-adenovirus (mAD) containing the AAV TR's, generated as a unique transcriptional byproduct of parental Ad/AAV hybrid viruses. Additional aims will be directed at establishing the utility of vascular endothelial cells as targets for fVIII delivery, using both in vitro and in vivo models for targeted delivery into these cellular types. Optimal viral vectors will be studied in murine and canine models of hemophilia A. The proposed work is designed to lay the foundation for anticipated trials in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE UW/FHCRC PROGRAM OF EXCELLENCE IN GENE THERAPY Principal Investigator & Institution: Stamatoyannopoulos, George; Professor of Medicine and Genetics; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 28-SEP-2000; Project End 31-AUG-2005 Summary: The UW/FHCRC Program of Excellence in Gene Therapy. The goal of this application from a Program of Excellence in Gene Therapy is to combine the resources of two Institutions, the University of Washington (UW) and the Fred Hutchinson Cancer Research Center (FHCRC), to advance gene therapy in two areas of interest of NHLBIstem cell gene therapy of hematological disorders and gene therapy of two common inherited lung diseases. The program puts together an outstanding group of gene therapy investigators and utilizes several resources of the two Institutions. The PEGT is composed of six projects, four core units, a training program and a Coordinating and Date Core Unit. Two projects propose preclinical studies on new therapy strategies.
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Four projects plan critical trials. Project 1 focuses on the development of new gene therapy approaches for hemophilia A and alpha-1 anti-trypsin deficiency. The objective of Project 2 is to develop gene targeting methods that can be used to correct genes in cells capable of reconstituting the hemopoietic system. Project 3 is a clinical project on gene therapy of Cystic Fibrosis Project 4 clinical studies on a novel inducible suicide gene based on the induction of apoptosis through oligimerization of the human Fas protein. Project 5 proposes preclinical and clinical studies of gene therapy of sickle cell disease and beta thalassemia. Project 6 is a clinical trial in patients with Fanconi anemia. Four core units support the research of the projects. Core A is a clinical core. Core B is a hemopoietic Cell Procurement and Processing Resource. Core Unit C is a primate stem cell transplantation core. Core D is the administrative core unit of the PEGT. The Hemopoietic Cell Procurement and Processing Core Unit and the Primate Transplantation Core Unit are proposed as core facilities for all the PEGT and NHLBI investigators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSFERRING INTEGRASE TECHNOLOGY TO ANIMALS Principal Investigator & Institution: Calos, Michele P.; Associate Professor; Genetics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: (provide by applicant): We have developed new technology for site-specific integration in mammalian cells. The technology involves use of novel phage integrases that mediate efficient integration at compact recognition sites. Sites recognized by the enzymes occur at low frequency in mammalian genomes and can be used to target integration. We have validated this technology in mammalian tissue culture cells, and it is ready for transfer to animals. In vivo experiments are now essential for application of the technology to improve existing methodologies for gene therapy and for construction of transgenic animals. The proposed experiments include the generation of transgenic mice that carry recognition sites for the integrases. These animals will be used for gene therapy studies and to improve basic technology for creation of transgenic mammals. We will carry out gene therapy studies in wild-type, transgenic, and disease model mice by introducing plasmid DNA to the liver by the hydrodynamic tail vein injection method. We will deliver a plasmid carrying the gene for a phage integrase along with a plasmid carrying the therapeutic gene and a recognition site for the integrase. The enzyme will mediate site-specific integration of the therapeutic gene into the genome at sites recognized by the enzyme. We will use this technology to develop effective permanent gene therapy treatments for emphysema and hemophilia B by introducing the a1-antitrypsin and factor IX genes. Success in these experiments will lead to application of this innovative technology to other gene therapy settings and progress toward clinical trials in patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSFUSION MEDICINE/HEMOSTASIS CLINICAL RESEARCH Principal Investigator & Institution: Neufeld, Ellis J.; Associate Professor of Pediatrics; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The focus of this grant is randomized clinical trials for hematologic disorders, which require a multi-center approach in the NHLBI Transfusion Medicine/Hemostasis Clinical Research Network. Three Harvard teaching
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hospitals form a consortium for this Core Clinical Center application. Key linkages among the institutions are in place, including the Joint Program in Transfusion Medicine, and the Boston Hemophilia Center. Adult and pediatric hematology and transfusion medicine services are represented, as well as collaboration with the high-risk obstetrics services at our institutions. The first proposed study has a pediatric focus and two-year time frame. The aim of this randomized phase II trial is to assess the efficacy of rituximab (anti-CD20 monoclonal antibody) vs. azathioprine, in children and adolescents with severe or refractor chronic idiopathic thrombocytopenic purpura. The primary efficacy outcome will be platelet counts at study day 90. Secondary outcomes include bleeding score trend, platelet counts at one year, side effects of medication, and requirement for 'salvage' regimens during either course of therapy. Our proposed longterm study will focus on randomized treatment strategies in thrombotic thrombocytopenic purpura (TTP). The aim is to determine whether rituximab therapy in addition to prednisone and plasmapheresis will facilitate remission induction, compared to standard therapy of plasmapheresis/ prednisone alone. Primary efficacy outcomes include the fraction of patients alive with no more than 9 plasma exchange procedures at 30 days from diagnosis (early responders) and the fraction of patients alive and relapse-free at 24 months. Secondary endpoints will include the death rate, the fraction of patients in remission at 30 days, the time to first remission in each treatment group, the number of plasma exchange procedures per patients, the number of relapses per group, and the time to remission and relapse rate, in each group, stratified for the presence of absence of VWV metalloprotease inhibitors and quantification of VW protease activity. Third, we propose a multicenter consortium for a phase III randomized study comparing two different dosage regimens of intravenous gamma globulin during pregnancies at risk for neonatal alloimmune thrombocytopenia. A repository for sera, plasma, and DNA from patients in each of the transfusion network studies is proposed, to facilitate further biological studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSFUSION MEDICINE/HEMOSTASIS CLINICAL RESEARCH NETWO* Principal Investigator & Institution: Triulzi, Darrell J.; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Core Center Program Objectives: The Pittsburgh Transfusion Medicine/Hemostasis Research Network (PTN) seeks to contribute to important multicenter clinical trials in transfusion medicine and hemostasis by capitalizing on our three strengths: 1) The integrated delivery of transfusion medicine and coagulation services to all the major University of Pittsburgh Medical Center Health System (UPMCHS) hospitals by the University of Pittsburgh faculty at the Institute For Transfusion Medicine (ITxM);2) The extraordinary patient base afforded by the UPMCHS hospitals including a Pittsburgh Cancer Institute (PCI), adult and pediatric level I trauma centers, a largest organ transplant program, a children's hospital, a women's hospital and outpatient facilities including the Hemophilia Center of Western PA and PCI; and3) The extensive experience and extertice of all three core center investigators in running and/or participating in multicenter clinical trials in transfusion medicine and hemostasis. Specific Aims: We propose two protocols to accomplish these objectives:1) Prospective Randomized Trial of Activase in the Prevention of Central Venous Access Device Infection in Hemophilia" (Project 1); and2) Multi-center, Randomized, Controlled Clinical Trial of Plasma Exchange Therapy vs Standard of Care
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in Children with Thrombocytopenia Associated Multi-Organ Failure (Project 2)The Core Center will provide the infrastructure and oversight necessary for the successful implementation and execution of these trials including: management of the budget for each protocol, timely establishment of program network office, coordinate resources for the operation of each protocol (e.g., research nurse, data clerk), assure timely implementation and operation of new protocols (e.g., accrural, timely data reporting, patient follow up) through biweekly research meetings with protocol investigators, establish a local DSMB for each protocol, assist protocol investigators with data analysis, interpretation, and publication, establish a Community Advisory Group to educate the community and to discuss and disseminate study results, and work with other network sites to select and revise study protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSFUSION MEDICINE/HEMOSTASIS TRIAL SITE AT PSBC Principal Investigator & Institution: Slichter, Sherrill J.; Executive Vice President of Research; Puget Sound Blood Center 921 Terry Ave Seattle, Wa 98104 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): A Transfusion Medicine/Hemostasis Clinical Trial Site to be located at the Puget Sound Blood Center (PSBC) is proposed. PSBC is a regional blood program that distributes all blood and blood products to patients in Seattle and surrounding counties. It is anticipated that network clinical trials will be conducted at any of 6 Seattle hospitals that have a total of 2,193 beds, and, during 2001, 20,996 patients in these hospitals received over 150,000 blood products. Four University of Washington medical school faculty, based at PSBC, with extensive experience in clinical trials will participate with other trial sites in the network clinical trials. These physician scientists are all recognized experts in their areas of research interest; i.e., platelet and granulocyte transfusion therapy, apheresis procedures and their indications, disorders of hemostasis and thrombosis, and patients with ITP. These physicians supervise a hemostasis clinic at PSBC that specializes in hemophilia care, a coagulation laboratory, a platelet antibody laboratory, and an apheresis facility. Through these clinical activities, they are aware of patients with a variety of disorders besides those in area hospitals - who might be candidates for participation in network clinical trials. Two network clinical trials are proposed: 1) "Evaluate The Hemostatic Efficacy And Platelet Utilization Rates Of Low Versus Standard Dose Platelet Therapy;" and 2) A Multicenter Randomized Controlled Trial On The Efficacy Of Transfusion Of G-CSF Mobilized Granulocytes To Neutropenic Patients With Infection." The first trial seeks to determine whether low dose compared to standard dose platelet transfusions are able to maintain adequate hemostasis while decreasing the total number of platelets required to support thrombocytopenic patients. The primary endpoint will be hemostasis; i.e., to demonstrate non-inferiority of patients randomized to the low dose arm compared to those in the standard close arm in the percentage of patients that develop WHO Grade 2 bleeding. The second trial will evaluate the effectiveness of granulocyte transfusion therapy to determine the clinical efficacy of G-CSF mobilized granulocyte transfusions for neutropenic patients with bacteria or fungal infections. Patients will be randomized to receive daily granulocyte transfusions along with standard care or standard care alone. The primary endpoint will be the proportion of patients in each arm who demonstrate both a microbial response to their infection and who also survive at least 28 days from study entry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSLATIONAL BYPASS IN PATIENTS WITH HEMOPHILIA Principal Investigator & Institution: Sommer, Steve S.; City of Hope National Medical Center Duarte, Ca 91010 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): We hypothesize that small molecules that readily enter cells can induce nonsense suppression by the protein synthetic apparatus such, that nonsense mutations are translationally bypassed at levels up to 20 percent. Evaluation of efficacy will be performed with the prototype drug gentamicin, an aminoglycoside antibiotic. If successful, translational bypass therapy could be beneficial for a significant minority of patients with severe genetic disease. Hemophilia is chosen as the model disease. Major effects of severe hemophilia A)B can be eliminated with only a slight increase in factor level. The hemophilias are an advantageous system to determine directly the efficacy of gentamicin gene therapy because many patients with nonsense mutations are available, the protein product can be measured readily and the kinetics of accumulation and decay can be determined over a short period since the proteins turn over rapidly. The proposed study has four specific aims: 1.Assess gentamicin suppression of nonsense mutations in an initial set of ten patients with severe hemophilia B. 2.Determine if there is a correlation between gentamicin-induced nonsense suppression and gene (factor VIII or IX), stop codon type, and sequence context. 3.Determine whether gentainicin suppresses frameshift mutations in five patients with hemophilia A or B and missense mutations in five patients with hemophilia A or B. 4.Determine whether the effect of gentamicin can be maintained with regular administration of gentamicin for up to twelve weeks. Nonsense suppressors could revolutionize therapy for hemophilia in underdeveloped countries where factor replacement is not readily available and carries risks of blood-borne pathogens. An efficacious nonsense suppressor should be effective in nonsense mutations in any of the 30,000 -40,000 human genes. Nonsense suppressors also may be beneficial in the treatment of cancers that result from nonsense mutation in tumor suppressor genes. 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 “hemophilia” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for hemophilia in the PubMed Central database:
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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 factor IX-deficient mouse model for hemophilia B gene therapy. by Wang L, Zoppe M, Hackeng TM, Griffin JH, Lee KF, Verma IM.; 1997 Oct 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23538
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Antibody against human immunodeficiency virus type 1 (HIV-1) Tat protein may have influenced the progression of AIDS in HIV-1-infected hemophiliac patients. by Re MC, Furlini G, Vignoli M, Ramazzotti E, Zauli G, La Placa M.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170285
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Disruption of a Binding Site for Hepatocyte Nuclear Factor 4 Results in Hemophilia B Leyden. by Reijnen MJ, Sladek FM, Bertina RM, Reitsma PH.; 1992 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49488
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Expression of Human Factor IX in Rabbit Hepatocytes by Retrovirus-Mediated Gene Transfer: Potential for Gene Therapy of Hemophilia B. by Armentano D, Thompson AR, Darlington G, Woo SL.; 1990 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54488
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Expression of Human Factor IX in Rat Capillary Endothelial Cells: Toward Somatic Gene Therapy for Hemophilia B. by Yao S, Wilson JM, Nabel EG, Kurachi S, Hachiya HL, Kurachi K.; 1991 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52454
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Expression of von Willebrand Factor "Normandy": An Autosomal Mutation that Mimics Hemophilia A. by Tuley EA, Gaucher C, Jorieux S, Worrall NK, Sadler JE, Mazurier C.; 1991 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52086
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Gene Therapy for Hemophilia A: Production of Therapeutic Levels of Human Factor VIII in vivo in Mice. by Dwarki VJ, Belloni P, Nijjar T, Smith J, Couto L, Rabier M, Clift S, Berns A, Cohen LK.; 1995 Feb 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42629
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Gene therapy for the hemophilias. by Kay MA, High K.; 1999 Aug 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33717
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Genetic induction of immune tolerance to human clotting factor VIII in a mouse model for hemophilia A. by Evans GL, Morgan RA.; 1998 May 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20448
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Hemophilia A Due to Mutations that Create New N-Glycosylation Sites. by Aly AM, Higuchi M, Kasper CK, Kazazian HH Jr, Antonarakis SE, Hoyer LW.; 1992 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49202
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Hemophilia and Hemophiliacs. by Quick AJ.; 1955 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=199934
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Hemophilia as a Defect of the Tissue Factor Pathway of Blood Coagulation: Effect of Factors VIII and IX on Factor X Activation in a Continuous-Flow Reactor. by Repke D, Gemmell CH, Guha A, Turitto VT, Broze GJ Jr, Nemerson Y.; 1990 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54800
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In vivo Hepatic Gene Therapy: Complete Albeit Transient Correction of Factor IX Deficiency in Hemophilia B Dogs. by Kay MA, Landen CN, Rothenberg SR, Taylor LA, Leland F, Wiehle S, Fang B, Bellinger D, Finegold M, Thompson AR, Read M, Brinkhous KM, Woo SL.; 1994 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43369
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Long-term expression of human coagulation factor VIII and correction of hemophilia A after in vivo retroviral gene transfer in factor VIII-deficient mice. by VandenDriessche T, Vanslembrouck V, Goovaerts I, Zwinnen H, Vanderhaeghen ML, Collen D, Chuah MK.; 1999 Aug 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17896
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Molecular Characterization of Mild-to-Moderate Hemophilia A: Detection of the Mutation in 25 of 29 Patients by Denaturing Gradient Gel Electrophoresis. by Higuchi M, Antonarakis SE, Kasch L, Oldenburg J, Economou-Petersen E, Olek K, Arai M, Inaba H, Kazazian HH Jr.; 1991 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52497
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Molecular Characterization of Severe Hemophilia A Suggests that about Half the Mutations are not within the Coding Regions and Splice Junctions of the Factor VIII Gene. by Higuchi M, Kazazian HH Jr, Kasch L, Warren TC, McGinniss MJ, Phillips JA III, Kasper C, Janco R, Antonarakis SE.; 1991 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52304
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Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero. by Lipshutz GS, Sarkar R, Flebbe-Rehwaldt L, Kazazian H, Gaensler KM.; 1999 Nov 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23946
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Single Nucleotide Primer Extension to Detect Genetic Diseases: Experimental Application to Hemophilia B (Factor IX) and Cystic Fibrosis Genes. by Kuppuswamy MN, Hoffman JW, Kasper CK, Spitzer SG, Groce SL, Bajaj SP.; 1991 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50973
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Somatic Mosaicism and Female-to-Female Transmission in a Kindred with Hemophilia B (Factor IX Deficiency). by Taylor SA, Deugau KV, Lillicrap DP.; 1991 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50743
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Spinal subdural hematoma revealing hemophilia A in a child: A case report. by Eftekhar B, Ghodsi M, Ketabchi E, Bakhtiari A, Mostajabi P.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194670
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Sustained correction of bleeding disorder in hemophilia B mice by gene therapy. by Wang L, Takabe K, Bidlingmaier SM, Ill CR, Verma IM.; 1999 Mar 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22393
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The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion. by Lozier JN, Dutra A, Pak E, Zhou N, Zheng Z, Nichols TC, Bellinger DA, Read M, Morgan RA.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130574
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Traumatic Hemarthrosis of the Knee Secondary to Hemophilia A in a Collegiate Soccer Player: A Case Report. by Fiala KA, Hoffmann SJ, Ritenour DM.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164362
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X-Ray Structure of Clotting Factor IXa: Active Site and Module Structure Related to Xase Activity and Hemophilia B. by Brandstetter H, Bauer M, Huber R, Lollar P, Bode W.; 1995 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40889
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 hemophilia, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “hemophilia” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for hemophilia (hyperlinks lead to article summaries): •
A 6-month versus a 12-month surveillance for hepatocellular carcinoma in 559 hemophiliacs infected with the hepatitis C virus. Author(s): Santagostino E, Colombo M, Rivi M, Rumi MG, Rocino A, Linari S, Mannucci PM; Study Group of the Association of Italian Hemophilia Centers. Source: Blood. 2003 July 1; 102(1): 78-82. Epub 2003 March 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12649165&dopt=Abstract
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A founder factor VIII mutation, valine 2016 to alanine, in a population with an extraordinarily high prevalence of mild hemophilia A. Author(s): Xie YG, Zheng H, Leggo J, Scully MF, Lillicrap D. Source: Thrombosis and Haemostasis. 2002 January; 87(1): 178-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11848452&dopt=Abstract
6 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.
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A quantitative measure of the efficacy of factor VIII in hemophilia A mice. Author(s): Parker ET, Lollar P. Source: Thrombosis and Haemostasis. 2003 March; 89(3): 480-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624631&dopt=Abstract
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A traumatic spinal epidural hematoma in an infant with hemophilia A. Author(s): Irwin SL, Attia MW. Source: Pediatric Emergency Care. 2001 February; 17(1): 40-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11265907&dopt=Abstract
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AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Author(s): Manno CS, Chew AJ, Hutchison S, Larson PJ, Herzog RW, Arruda VR, Tai SJ, Ragni MV, Thompson A, Ozelo M, Couto LB, Leonard DG, Johnson FA, McClelland A, Scallan C, Skarsgard E, Flake AW, Kay MA, High KA, Glader B. Source: Blood. 2003 April 15; 101(8): 2963-72. Epub 2002 December 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515715&dopt=Abstract
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AAV-mediated gene transfer for hemophilia. Author(s): High K. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 November-December; 4(6 Suppl): 56S-61S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544490&dopt=Abstract
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AAV-mediated gene transfer for hemophilia. Author(s): High KA. Source: Annals of the New York Academy of Sciences. 2001 December; 953: 64-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11795424&dopt=Abstract
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Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia A: similarities with the intron 22 inversion mutation in human hemophilia. Author(s): Hough C, Kamisue S, Cameron C, Notley C, Tinlin S, Giles A, Lillicrap D. Source: Thrombosis and Haemostasis. 2002 April; 87(4): 659-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12008949&dopt=Abstract
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Absence of anti-human herpesvirus 8 antibody in 32 Japanese hemophiliacs with advanced HIV infection. Author(s): Shimizu S, Katano H, Sata T, Chen KR, Tagami H, Hanabusa H, Shimizu H. Source: Archives of Dermatological Research. 2001 July; 293(7): 380-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11550814&dopt=Abstract
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Acquired hemophilia A in a patient with systemic lupus erythematosus. Author(s): Ishikawa T, Tsukamoto N, Suto M, Uchiumi H, Mitsuhashi H, Yokohama A, Maesawa A, Nojima Y, Naruse T. Source: Intern Med. 2001 June; 40(6): 541-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11446683&dopt=Abstract
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Acquired hemophilia a presenting as a bleeding diathesis in a postpartum patient: diagnosis and management. Author(s): Scully MF, Shublaq W, Oliver GD. Source: J Obstet Gynaecol Can. 2002 May; 24(5): 430-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196864&dopt=Abstract
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Acquired hemophilia successfully treated with oral immunosuppressive therapy. Author(s): Lee JJ, Chung IJ, Park MR, Yang DH, Cho SH, Ryang DW, Kim HJ. Source: Korean J Intern Med. 2000 July; 15(2): 135-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10992727&dopt=Abstract
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Acquired hemophilia. Author(s): Boggio LN, Green D. Source: Reviews in Clinical and Experimental Hematology. 2001 December; 5(4): 389404; Quiz Following 431. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11844135&dopt=Abstract
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Acquired hemophilia: a single-center survey with emphasis on immunotherapy and treatment-related side-effects. Author(s): Delgado J, Villar A, Jimenez-Yuste V, Gago J, Quintana M, HernandezNavarro F. Source: European Journal of Haematology. 2002 September; 69(3): 158-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406009&dopt=Abstract
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Acquired hemophilia: diagnosis and management. Author(s): Zakarija A, Green D. Source: Curr Hematol Rep. 2002 September; 1(1): 27-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901122&dopt=Abstract
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Adeno-associated virus-mediated gene transfer for hemophilia B. Author(s): High KA. Source: International Journal of Hematology. 2002 November; 76(4): 310-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12463593&dopt=Abstract
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Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion. Author(s): Bristol JA, Gallo-Penn A, Andrews J, Idamakanti N, Kaleko M, Connelly S. Source: Human Gene Therapy. 2001 September 1; 12(13): 1651-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11535168&dopt=Abstract
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Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Author(s): van der Bom JG, Mauser-Bunschoten EP, Fischer K, van den Berg HM. Source: Thrombosis and Haemostasis. 2003 March; 89(3): 475-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624630&dopt=Abstract
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Alternative methods for anticoagulation monitoring in pediatric patients with applicability to a patient with severe hemophilia A and circulating inhibitor. Author(s): McNamara JL, Lombardi JP, Ferguson R, Manning PB, Gruppo RA. Source: J Extra Corpor Technol. 2001 December; 33(4): 239-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11806436&dopt=Abstract
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An Alu insert as the cause of a severe form of hemophilia A. Author(s): Sukarova E, Dimovski AJ, Tchacarova P, Petkov GH, Efremov GD. Source: Acta Haematologica. 2001; 106(3): 126-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713379&dopt=Abstract
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An ELISA system to detect anti-factor VIII antibodies without interference by lupus anticoagulants. Preliminary data in hemophilia A patients. Author(s): Blanco AN, Peirano AA, Grosso SH, Gennari LC, Bianco RP, Lazzari MA. Source: Haematologica. 2000 October; 85(10): 1045-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11025595&dopt=Abstract
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An open letter to the hemophilia community from the Community Advocacy Working Group. Author(s): Dubin C, Hamilton J, Kuhn D, Niederman R, Ray C, Ray L, Valdez D, Wadleigh J. Source: Common Factor. 1995 April; (No 10): 24-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11362348&dopt=Abstract
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Analysis of large structural changes of the factor VIII gene, involving intron 1 and 22, in severe hemophilia A. Author(s): Andrikovics H, Klein I, Bors A, Nemes L, Marosi A, Varadi A, Tordai A. Source: Haematologica. 2003 July; 88(7): 778-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857556&dopt=Abstract
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Antibodies to factor VIII in hemophilia A patients. Author(s): Brackmann HH, Schwaab R, Effenberger W, Hess L, Hanfland P, Oldenburg J. Source: Vox Sanguinis. 2000; 78 Suppl 2: 187-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10938950&dopt=Abstract
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Antibodies to heterologous proteins in hemophilia A patients receiving recombinant factor VIII (Recombinate). Author(s): Ingerslev J, Christiansen K, Ravn HB, Bray GL, Gomperts ED; Recombinate Study Group. Source: Thrombosis and Haemostasis. 2002 April; 87(4): 626-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12008945&dopt=Abstract
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Antibodies with hydrolytic activity towards factor VIII in patients with hemophilia A. Author(s): Lacroix-Desmazes S, Misra N, Bayry J, Villard S, Kazatchkine MD, Kaveri SV. Source: Journal of Immunological Methods. 2002 November 1; 269(1-2): 251-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379365&dopt=Abstract
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Apathetic Graves' disease and acquired hemophilia due to factor VIIIc antibody. Author(s): Marongiu F, Cauli C, Mameli G, Usai B, Mariotti S. Source: J Endocrinol Invest. 2002 March; 25(3): 246-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11936467&dopt=Abstract
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Arthroscopic synovectomy in children and adolescents with hemophilia. Author(s): Journeycake JM, Miller KL, Anderson AM, Buchanan GR, Finnegan M. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 September; 25(9): 726-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12972809&dopt=Abstract
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Assaying the circulating factor VIII activity in hemophilia A patients treated with recombinant factor VIII products. Author(s): Mikaelsson M, Oswaldsson U. Source: Seminars in Thrombosis and Hemostasis. 2002 June; 28(3): 257-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12098085&dopt=Abstract
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Association of immune complexes and plasma viral load with CD4+ cell depletion, CD8+ DR+ and CD16+ cell counts in HIV+ hemophilia patients. Implications for the immunopathogenesis of HIV-induced CD4+ lymphocyte depletion. Author(s): Daniel V, Susal C, Weimer R, Zimmermann R, Huth-Kuhne A, Opelz G. Source: Immunology Letters. 2001 March 1; 76(2): 69-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11274723&dopt=Abstract
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Blood-induced joint damage in hemophilia. Author(s): Roosendaal G, Lafeber FP. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 37-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640563&dopt=Abstract
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Can costs of hemophilia products be curtailed? Not as we do business today! Author(s): Aledort LM. Source: Thrombosis and Haemostasis. 2002 October; 88(4): 541. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362221&dopt=Abstract
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Carrier detection and prenatal diagnosis of hemophilia A. Author(s): Xuefeng W, Yuanfang L, Zhiguang L, Haiyan C, Xiaojie S, Yishi F, Hongli W. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2001 December; 39(12): 1204-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11798076&dopt=Abstract
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Carrier detection and prenatal diagnosis of hemophilia Alpha. Author(s): Liu Y, Wang X, Chu H, Li Z, Wang H, Wang Z. Source: Chinese Medical Journal. 2002 July; 115(7): 991-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150727&dopt=Abstract
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Carrier detection by DNA linkage analysis in eighty Thai hemophilia A families. Author(s): Mahasandana C, Pung-Amritt P, Treesucon A, Petrarat S, Veerakul G, Visudhiphan S, Yenchitsomanus PT. Source: J Med Assoc Thai. 2002 August; 85 Suppl 2: S513-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12403227&dopt=Abstract
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Catheter-related deep venous thrombosis in children with hemophilia. Author(s): Journeycake JM, Quinn CT, Miller KL, Zajac JL, Buchanan GR. Source: Blood. 2001 September 15; 98(6): 1727-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11535504&dopt=Abstract
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Catheter-related thrombosis in children with hemophilia A: evidence of a multifactorial disease. Author(s): Ettingshausen CE, Kurnik K, Schobess R, Kreuz WD, Halimeh S, Pollman H, Nowak-Gottl U. Source: Blood. 2002 February 15; 99(4): 1499-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11852883&dopt=Abstract
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CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A. Author(s): Jacquemin M, Vantomme V, Buhot C, Lavend'homme R, Burny W, Demotte N, Chaux P, Peerlinck K, Vermylen J, Maillere B, van der Bruggen P, Saint-Remy JM. Source: Blood. 2003 February 15; 101(4): 1351-8. Epub 2002 October 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393451&dopt=Abstract
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CDC/hemophilia study targets blood safety and joint disease. Centers for Disease Control and Prevention. Author(s): Colvin R. Source: Common Factor. 1997 November; (No 11): 7, 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11364846&dopt=Abstract
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Changes in the occurrence of and risk factors for hemophilia-associated intracranial hemorrhage. Author(s): Nuss R, Soucie JM, Evatt B; Hemophilia Surveillance System Project Investigators. Source: American Journal of Hematology. 2001 September; 68(1): 37-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11559935&dopt=Abstract
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Characterization of antibodies induced by human factor VIII in a murine knockout model of hemophilia A. Author(s): Reipert BM, Ahmad RU, Turecek PL, Schwarz HP. Source: Thrombosis and Haemostasis. 2000 November; 84(5): 826-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11127864&dopt=Abstract
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Characterization of antibodies to factor VIII in hemophilia A patients treated by immune tolerance therapy. Author(s): Scandella D, Reyes H, Felch M, Sakurai Y. Source: Haematologica. 2000 October; 85(10 Suppl): 86-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11187882&dopt=Abstract
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Characterization of high-risk HIV-1 seronegative hemophiliacs. Author(s): Salkowitz JR, Purvis SF, Meyerson H, Zimmerman P, O'Brien TR, Aledort L, Eyster ME, Hilgartner M, Kessler C, Konkle BA, White GC 2nd, Goedert JJ, Lederman MM. Source: Clinical Immunology (Orlando, Fla.). 2001 February; 98(2): 200-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11161976&dopt=Abstract
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Characterization of the immune response to factor VIII using hemophilia A* mice. Author(s): Hoyer LW, Qian J. Source: Haematologica. 2000 October; 85(10 Suppl): 100-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11187859&dopt=Abstract
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Choice of replacement therapy for hemophilia: recombinant products only? Author(s): Mannucci PM, Giangrande PL. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2000; 1(2): 72-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11920173&dopt=Abstract
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Circulating factor VIII immune complexes in patients with type 2 acquired hemophilia A and protection from activated protein C-mediated proteolysis. Author(s): Nogami K, Shima M, Giddings JC, Hosokawa K, Nagata M, Kamisue S, Suzuki H, Shibata M, Saenko EL, Tanaka I, Yoshioka A. Source: Blood. 2001 February 1; 97(3): 669-77. Erratum In: Blood 2001 March 15; 97(6): 1542. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11157483&dopt=Abstract
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Circumcision, hemophilia, and being healthy in developing countries. Author(s): Kavakli K, Nisli G. Source: Pediatric Hematology and Oncology. 2001 September; 18(6): 419-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11554238&dopt=Abstract
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Clinical efficacy of recombinant activated factor VII (rFVIIa) during acute bleeding episode and surgery in a patient with acquired hemophilia A with high inhibitor titer. Author(s): Franchini M, Capra F, Capelli C, de Maria E, Lippi G, Gandini G. Source: Haematologica. 2001 April; 86(4): E12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11325664&dopt=Abstract
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Clinical observation on hemophilia A treatment by cadaveric spleen transplantation. Author(s): Xiang WZ, Jie ZW, Sheng XS. Source: Transplantation Proceedings. 2002 August; 34(5): 1929-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12176633&dopt=Abstract
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Clinical trial to investigate the pharmacokinetics, pharmacodynamics, safety, and efficacy of recombinant factor VIIa in Japanese patients with hemophilia with inhibitors. Author(s): Shirahata A, Kamiya T, Takamatsu J, Kojima T, Fukutake K, Arai M, Hanabusa H, Tagami H, Yoshioka A, Shima GM, Naka GH, Fujita GS, Minamoto Y, Kamizono J, Saito H. Source: International Journal of Hematology. 2001 June; 73(4): 517-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11503968&dopt=Abstract
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Coincidence of cytomegalovirus retinitis and central retinal vein occlusion in a patient with hemophilia B and AIDS. Author(s): Schiemann U, Steins M, Knospe V, Riedasch M, Domschke W, Stoll R. Source: Aids Patient Care and Stds. 1999 January; 13(1): 7-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11362097&dopt=Abstract
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Combined hemophilia A and type 2 von Willebrand's disease: defect of both factor VIII level and factor VIII binding capacity of von Willebrand factor. Author(s): Casonato A, Pontara E, Sartorello F, Gemmati D, Cattini MG, Girolami A. Source: Haematologica. 2001 October; 86(10): 1110-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11602423&dopt=Abstract
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Complete and sustained phenotypic correction of hemophilia B in mice following hepatic gene transfer of a high-expressing human factor IX plasmid. Author(s): Ye X, Loeb KR, Stafford DW, Thompson AR, Miao CH. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 January; 1(1): 103-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871546&dopt=Abstract
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Comprehensive care for hemophilia and related inherited bleeding disorders: why it matters. Author(s): Hoots WK. Source: Curr Hematol Rep. 2003 September; 2(5): 395-401. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12932311&dopt=Abstract
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Concomitant compression of median and ulnar nerves in a hemophiliac patient: a case report. Author(s): Kaymak B, Ozcakar L, Cetin A, Erol K, Birsin Ozcakar Z. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2002 December; 69(6): 611-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12537271&dopt=Abstract
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Considerations for the hemophiliac patient with inhibitors to factor VIII. Author(s): Chaney JD, Nielsen VG. Source: Anesthesia and Analgesia. 2001 March; 92(3): 785-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11226120&dopt=Abstract
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Continuous axillary brachial plexus analgesia in a patient with severe hemophilia. Author(s): Kang SB, Rumball KM, Ettinger RS. Source: Journal of Clinical Anesthesia. 2003 February; 15(1): 38-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693408&dopt=Abstract
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Coping strategies, pain, and disability in patients with hemophilia and related disorders. Author(s): Santavirta N, Bjorvell H, Solovieva S, Alaranta H, Hurskainen K, Konttinen YT. Source: Arthritis and Rheumatism. 2001 February; 45(1): 48-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11308061&dopt=Abstract
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Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Author(s): Gringeri A, Mantovani LG, Scalone L, Mannucci PM; COCIS Study Group. Source: Blood. 2003 October 1; 102(7): 2358-63. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816859&dopt=Abstract
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Cost trends in the treatment for hemophilia: another view. Author(s): Kletter SD, Rankin PJ. Source: Thrombosis and Haemostasis. 2002 October; 88(4): 542-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362222&dopt=Abstract
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Current status of gene therapy for hemophilia. Author(s): Nathwani AC, Nienhuis AW, Davidoff AM. Source: Curr Hematol Rep. 2003 July; 2(4): 319-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901329&dopt=Abstract
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Dallas, police surveillance and the NHF. National Hemophilia Foundation. Author(s): Dubin CS. Source: Common Factor. 1995 April; (No 10): 3, 31-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11362351&dopt=Abstract
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Declining immune function in children and adolescents with hemophilia and HIV infection: effects on neuropsychological performance. Hemophilia Growth and Development Study. Author(s): Loveland KA, Stehbens JA, Mahoney EM, Sirois PA, Nichols S, Bordeaux JD, Watkins JM, Amodei N, Hill SD, Donfield S. Source: Journal of Pediatric Psychology. 2000 July-August; 25(5): 309-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10880061&dopt=Abstract
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Defining the impact of hemophilia: the Academic Achievement in Children with Hemophilia Study. Author(s): Shapiro AD, Donfield SM, Lynn HS, Cool VA, Stehbens JA, Hunsberger SL, Tonetta S, Gomperts ED; Academic Achievement in Children with Hemophilia Study Group. Source: Pediatrics. 2001 December; 108(6): E105. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731632&dopt=Abstract
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Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Author(s): White GC 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J; Factor VIII and Factor IX Subcommittee. Source: Thrombosis and Haemostasis. 2001 March; 85(3): 560. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11307831&dopt=Abstract
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Desire and need: understanding hemophiliacs' participation in gene therapy trials. Author(s): Faust SP. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2001 July; 4(1): 2-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11472098&dopt=Abstract
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Desmopressin in mild hemophilia A: indications, limitations, efficacy, and safety. Author(s): Lethagen S. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 101-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640572&dopt=Abstract
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Detailed characterization of an anti-factor IX monoclonal antibody that neutralizes the prolonged ox brain prothrombin time of hemophilia B(M) by synthetic peptides. Author(s): Takahashi I, Kojima T, Sano M, Watanabe T, Kamiya T, Saito H. Source: Peptides. 2000 May; 21(5): 603-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10876041&dopt=Abstract
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Development of improved factor VIII molecules and new gene transfer approaches for hemophilia A. Author(s): Saenko EL, Ananyeva NM, Moayeri M, Ramezani A, Hawley RG. Source: Current Gene Therapy. 2003 February; 3(1): 27-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553533&dopt=Abstract
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Diagnosis of hemophilia made after intraoperative bleeding during attempted penetrating keratoplasty in an elderly patient. Author(s): Choi DM, Goldstein MH, Driebe WT Jr. Source: The Clao Journal : Official Publication of the Contact Lens Association of Ophthalmologists, Inc. 2001 January; 27(1): 53-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11215607&dopt=Abstract
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Disappearance of FVIII inhibitors in a severe hemophilia A neonate after steroid treatment correlated with a cytokine shift toward a T-helper 2 pattern. Author(s): Vianello F, Zanon E, Zerbinati P, Innella B, Girolami A. Source: Haematologica. 2000 October; 85(10): 1114-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11025617&dopt=Abstract
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Distal deep venous thrombosis in a hemophilia A patient with inhibitor and severe infectious disease, 18 days after recombinant activated factor VII transfusion. Author(s): Van der Planken MG, Schroyens W, Vertessen F, Michiels JJ, Berneman ZN. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 2002 June; 13(4): 367-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032404&dopt=Abstract
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Distribution of Th1- and Th2-induced anti-factor VIII IgG subclasses in congenital and acquired hemophilia patients. Author(s): Reding MT, Lei S, Lei H, Green D, Gill J, Conti-Fine BM. Source: Thrombosis and Haemostasis. 2002 October; 88(4): 568-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362225&dopt=Abstract
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Do hemophilia A and von Willebrand disease protect against carotid atherosclerosis? A comparative study between coagulopathics and normal subjects by means of carotid echo-color Doppler scan. Author(s): Bilora F, Dei Rossi C, Girolami B, Casonato A, Zanon E, Bertomoro A, Girolami A. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 1999 October; 5(4): 232-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10726019&dopt=Abstract
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Dual vectors expressing murine factor VIII result in sustained correction of hemophilia A mice. Author(s): Mah C, Sarkar R, Zolotukhin I, Schleissing M, Xiao X, Kazazian HH, Byrne BJ. Source: Human Gene Therapy. 2003 January 20; 14(2): 143-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614565&dopt=Abstract
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Economics of hemophilia care. Author(s): Aledort LM. Source: Haemostasis. 2000 November-December; 30(6): 333-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11357002&dopt=Abstract
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ED visits by males with hemophilia. Author(s): Nuss R, Hoffman R, Hammond L. Source: The American Journal of Emergency Medicine. 2002 March; 20(2): 74-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880866&dopt=Abstract
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Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia. Multicenter Hemophilia Cohort Study. Author(s): Yeo AE, Matsumoto A, Hisada M, Shih JW, Alter HJ, Goedert JJ. Source: Annals of Internal Medicine. 2000 June 20; 132(12): 959-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10858179&dopt=Abstract
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Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Author(s): Lee DH, Walker IR, Teitel J, Poon MC, Ritchie B, Akabutu J, Sinclair GD, Pai M, Wu JW, Reddy S, Carter C, Growe G, Lillicrap D, Lam M, Blajchman MA. Source: Thrombosis and Haemostasis. 2000 March; 83(3): 387-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10744141&dopt=Abstract
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Effects of HIV infection on age and cause of death for persons with hemophilia A in the United States. Author(s): Chorba TL, Holman RC, Clarke MJ, Evatt BL. Source: American Journal of Hematology. 2001 April; 66(4): 229-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11279632&dopt=Abstract
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Efficacy of 2-chlorodeoxyadenosine in refractory factor VIII inhibitors in persons without hemophilia. Author(s): Sallah S, Wan JY. Source: Blood. 2003 February 1; 101(3): 943-5. Epub 2002 September 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393474&dopt=Abstract
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Efficacy of induction therapy with high-dose interferon for patients with hemophilia and human immunodeficiency virus-hepatitis C virus coinfection. Author(s): Hanabusa H. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 December 15; 35(12): 1527-33. Epub 2002 Dec 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471573&dopt=Abstract
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Elbow arthropathy in hemophilia. Author(s): Malhotra R, Gulati MS, Bhan S. Source: Archives of Orthopaedic and Trauma Surgery. 2001; 121(3): 152-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11262781&dopt=Abstract
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End-stage liver disease in persons with hemophilia and transfusion-associated infections. Author(s): Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC 2nd, Angiolillo AL, Luban NL, Sherman KE, Manco-Johnson M, Preiss L, Leissinger C, Kessler CM, Cohen AR, DiMichele D, Hilgartner MW, Aledort LM, Kroner BL, Rosenberg PS, Hatzakis A. Source: Blood. 2002 September 1; 100(5): 1584-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12176875&dopt=Abstract
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ESWL in hemophiliac patients. Author(s): Czaplicki M, Jakubczyk T, Judycki J, Borkowski A, Jaskowiak W, Ziemski JM, Scharf R, Misiak A, Szalecki P. Source: European Urology. 2000 September; 38(3): 302-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10940704&dopt=Abstract
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Ethical dilemmas in the pediatric hemophilia community. Author(s): Schaefer J. Source: Pediatric Nursing. 1999 September-October; 25(5): 537-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12024403&dopt=Abstract
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Evaluation of DHPLC in the analysis of hemophilia A. Author(s): Oldenburg J, Ivaskevicius V, Rost S, Fregin A, White K, Holinski-Feder E, Muller CR, Weber BH. Source: Journal of Biochemical and Biophysical Methods. 2001 January 30; 47(1-2): 39-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11179760&dopt=Abstract
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Evaluation of high concentration intranasal and intravenous desmopressin in pediatric patients with mild hemophilia A or mild-to-moderate type 1 von Willebrand disease. Author(s): Gill JC, Ottum M, Schwartz B. Source: The Journal of Pediatrics. 2002 May; 140(5): 595-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032528&dopt=Abstract
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Evaluation of the putative role of C-C chemokines as protective factors of HIV-1 infection in seronegative hemophiliacs exposed to contaminated hemoderivatives. Author(s): Barretina J, Blanco J, Gutierrez A, Puig L, Altisent C, Espanol T, Caragol I, Clotet B, Este JA. Source: Transfusion. 2000 April; 40(4): 461-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10773060&dopt=Abstract
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Evidence of porcine endogenous retroviruses in porcine factor VIII and evaluation of transmission to recipients with hemophilia. Author(s): Heneine W, Switzer WM, Soucie JM, Evatt BL, Shanmugam V, Rosales GV, Matthews A, Sandstrom P, Folks TM. Source: The Journal of Infectious Diseases. 2001 February 15; 183(4): 648-52. Epub 2001 January 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11170992&dopt=Abstract
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Exon skipping caused by an intronic insertion of a young Alu Yb9 element leads to severe hemophilia A. Author(s): Ganguly A, Dunbar T, Chen P, Godmilow L, Ganguly T. Source: Human Genetics. 2003 September; 113(4): 348-52. Epub 2003 July 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884004&dopt=Abstract
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Experience of a single Italian center in genetic counseling for hemophilia: from linkage analysis to molecular diagnosis. Author(s): Tagariello G, Belvini D, Salviato R, Are A, De Biasi E, Goodeve A, Davoli P. Source: Haematologica. 2000 May; 85(5): 525-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10800171&dopt=Abstract
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Extracorporeal membrane oxygenation as a bridge to cardiac transplantation in a patient with cardiomyopathy and hemophilia A. Author(s): Thiagarajan RR, Roth SJ, Margossian S, Mackie AS, Neufeld EJ, Laussen PC, Forbess JM, Blume ED. Source: Intensive Care Medicine. 2003 June; 29(6): 985-8. Epub 2003 April 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12719805&dopt=Abstract
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Factor concentrate usage in persons with hemophilia in New York State. Author(s): Linden JV, Kolakoski MH, Lima JE, Du P, Lipton RA. Source: Transfusion. 2003 April; 43(4): 470-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12662279&dopt=Abstract
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Factor replacement and outcomes in hemophiliacs undergoing total knee arthroplasty. Author(s): Atilla B. Source: The Journal of Bone and Joint Surgery. American Volume. 2003 May; 85-A(5): 965; Author Reply 965. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12728053&dopt=Abstract
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Factor X deficiency and hemophilia A : occurrence of two different coagulation defects in a family. Author(s): Parmar RC, Bavdekar SB, Sahu DR, Kamat JR. Source: Indian Pediatrics. 2001 February; 38(2): 183-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11224586&dopt=Abstract
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Factor XI deficiency in Iranians: its clinical manifestations in comparison with those of classic hemophilia. Author(s): Peyvandi F, Lak M, Mannucci PM. Source: Haematologica. 2002 May; 87(5): 512-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12010665&dopt=Abstract
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Failure of recombinant FVIIa as treatment for abdominal bleeding in acquired hemophilia. Author(s): Makris M, Hampton KK, Preston EE. Source: American Journal of Hematology. 2001 January; 66(1): 67-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11426500&dopt=Abstract
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Female hemophilia. Author(s): Wandroo FA, Wani JI, Qaudri MI, Laway BA, Bhat FA. Source: J Assoc Physicians India. 1997 April; 45(4): 326. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12521096&dopt=Abstract
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First and next generation native rFVIII in the treatment of hemophilia A. What has been achieved? Can patients be switched safely? Author(s): Suiter TM. Source: Seminars in Thrombosis and Hemostasis. 2002 June; 28(3): 277-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12098089&dopt=Abstract
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First molecular characterization of an unequal homologous alu-mediated recombination event responsible for hemophilia. Author(s): Vidal F, Farssac E, Tusell J, Puig L, Gallardo D. Source: Thrombosis and Haemostasis. 2002 July; 88(1): 12-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12154809&dopt=Abstract
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Floating thrombus on an ASD occluder device in a patient with hemophilia A. Author(s): Fabricius AM, Krueger M, Falk V, Hanke M, Mohr FW. Source: The Thoracic and Cardiovascular Surgeon. 2001 October; 49(5): 312-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11605146&dopt=Abstract
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Frequency of factor VIII intron 1 inversion in a cohort of severe hemophilia A Italian patients. Author(s): Acquila M, Pasino M, Lanza T, Bottini F, Boeri E, Bicocchi MP. Source: Haematologica. 2003 May; 88(5): Elt17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745291&dopt=Abstract
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Functional analysis of the EGF-like domain mutations Pro55Ser and Pro55Leu, which cause mild hemophilia B. Author(s): Knobe KE, Persson KE, Sjorin E, Villoutreix BO, Stenflo J, Ljung RC. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 April; 1(4): 782-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871416&dopt=Abstract
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Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B. Author(s): Christophe OD, Lenting PJ, Cherel G, Boon-Spijker M, Lavergne JM, Boertjes R, Briquel ME, de Goede-Bolder A, Goudemand J, Gaillard S, d'Oiron R, Meyer D, Mertens K. Source: Blood. 2001 September 1; 98(5): 1416-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11520790&dopt=Abstract
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Gallbladder hematoma in a patient with hemophilia B, report of a case. Author(s): Shimura T, Kojima T, Tsutsumi S, Yoshida T, Uchiumi H, Kuwano H. Source: Hepatogastroenterology. 2000 July-August; 47(34): 939-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11020853&dopt=Abstract
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Gene therapies for the hemophilias. Author(s): Thompson AR. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2000 July; 2(1): 5-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10899822&dopt=Abstract
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Gene therapy for hemophilia B: AAV-mediated transfer of the gene for coagulation factor IX to human muscle. Author(s): Larson PJ, High KA. Source: Advances in Experimental Medicine and Biology. 2001; 489: 45-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11554590&dopt=Abstract
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Gene therapy for hemophilia. Author(s): Miller DG, Stamatoyannopoulos G. Source: The New England Journal of Medicine. 2001 June 7; 344(23): 1782-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11396447&dopt=Abstract
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Gene therapy for hemophilia. Author(s): Lynch CM. Source: Curr Opin Mol Ther. 1999 August; 1(4): 493-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713765&dopt=Abstract
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Gene therapy for hemophilia. Author(s): Chuah MK, Collen D, VandenDriessche T. Source: The Journal of Gene Medicine. 2001 January-February; 3(1): 3-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11269333&dopt=Abstract
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Gene therapy for hemophilia: a step closer to reality. Author(s): White GC 2nd, Roberts HR. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2000 March; 1(3): 207-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10933934&dopt=Abstract
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Gene therapy for hemophilia: are viral vectors really feasible? Author(s): Walsh C. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 February; 1(2): 218-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871491&dopt=Abstract
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Gene therapy for the hemophilias. Author(s): VandenDriessche T, Collen D, Chuah MK. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 July; 1(7): 1550-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871290&dopt=Abstract
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Gene therapy for the hemophilias. Author(s): Walsh CE. Source: Current Opinion in Pediatrics. 2002 February; 14(1): 12-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880728&dopt=Abstract
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Gene therapy for the treatment of hemophilia B using PINC-formulated plasmid delivered to muscle with electroporation. Author(s): Fewell JG, MacLaughlin F, Mehta V, Gondo M, Nicol F, Wilson E, Smith LC. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2001 April; 3(4): 574-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11319920&dopt=Abstract
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Gene therapy in hemophilia: clinical trials update. Author(s): White GC 2nd. Source: Thrombosis and Haemostasis. 2001 July; 86(1): 172-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11487005&dopt=Abstract
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Gene therapy of hemophilia. Author(s): Schwaab R, Oldenburg J. Source: Seminars in Thrombosis and Hemostasis. 2001 August; 27(4): 417-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11547364&dopt=Abstract
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Gene therapy progress and prospects: gene therapy for the hemophilias. Author(s): Walsh CE. Source: Gene Therapy. 2003 June; 10(12): 999-1003. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12776156&dopt=Abstract
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Gene transfer as an approach to treating hemophilia. Author(s): High KA. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 107-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640573&dopt=Abstract
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Gene transfer as an approach to treating hemophilia. Author(s): High KA. Source: Circulation Research. 2001 February 2; 88(2): 137-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11157664&dopt=Abstract
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Generalized additive models with interval-censored data and time-varying covariates: application to human immunodeficiency virus infection in hemophiliacs. Author(s): Bacchetti P, Quale C. Source: Biometrics. 2002 June; 58(2): 443-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12071419&dopt=Abstract
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Genetic counseling of hemophilia carriers. Author(s): Ljung R, Tedgard U. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 31-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640562&dopt=Abstract
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Genetic variants of hemophilia B: detection by means of a specific PTC inhibitor. Author(s): Roberts HR, Grizzle JE, McLester WD, Penick GD. Source: The Journal of Clinical Investigation. 1968 February; 47(2): 360-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12066779&dopt=Abstract
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Genotype analysis of hepatitis C virus in Brazilian hemophiliacs and blood donors. Author(s): Martins RM, Barbosa AP, Oliveira JM, Vanderborght B, Yoshida CF. Source: Vox Sanguinis. 2000; 78(4): 255. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10895102&dopt=Abstract
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Health status and health-related quality of life associated with hemophilia. Author(s): Barr RD, Saleh M, Furlong W, Horsman J, Sek J, Pai M, Walker I. Source: American Journal of Hematology. 2002 November; 71(3): 152-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410568&dopt=Abstract
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Hemophilia A and B are associated with abnormal spatial dynamics of clot growth. Author(s): Ovanesov MV, Krasotkina JV, Ul'yanova LI, Abushinova KV, Plyushch OP, Domogatskii SP, Vorob'ev AI, Ataullakhanov FI. Source: Biochimica Et Biophysica Acta. 2002 August 15; 1572(1): 45-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12204332&dopt=Abstract
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Hemophilia A mutations within the factor VIII A2-A3 subunit interface destabilize factor VIIIa and cause one-stage/two-stage activity discrepancy. Author(s): Hakeos WH, Miao H, Sirachainan N, Kemball-Cook G, Saenko EL, Kaufman RJ, Pipe SW. Source: Thrombosis and Haemostasis. 2002 November; 88(5): 781-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12428094&dopt=Abstract
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Hemophilia A, von Willebrand disease, and atherosclerosis of abdominal aorta and leg arteries: factor VIII and von Willebrand factor defects appear to protect abdominal aorta and leg arteries from atherosclerosis. Author(s): Bilora F, Boccioletti V, Zanon E, Petrobelli F, Girolami A. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2001 October; 7(4): 311-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11697715&dopt=Abstract
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Hemophilia A--from basic science to clinical practice. Author(s): Klinge J, Ananyeva NM, Hauser CA, Saenko EL. Source: Seminars in Thrombosis and Hemostasis. 2002 June; 28(3): 309-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12098093&dopt=Abstract
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Hemophilia and HIV standard of care. Author(s): Colvin R. Source: Common Factor. 1997 November; (No 11): 10-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11364844&dopt=Abstract
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Hemophilia and related bleeding disorders: a story of dismay and success. Author(s): Mannucci PM. Source: Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2002; : 1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12446416&dopt=Abstract
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Hemophilia B in a female. Author(s): Shetty S, Ghosh K, Mohanty D. Source: Acta Haematologica. 2001; 106(3): 115-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713376&dopt=Abstract
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Hemophilia care in the state of Rio de Janeiro, Brazil. Author(s): Fontes EM, Amorim L, Carvalho SM, Farah MB. Source: Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 2003 February-March; 13(2-3): 124-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12744788&dopt=Abstract
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Hemophilia centre twinning with Nanfang Hospital, Guangzhou, China. Challenges and opportunities. Author(s): Luke KH. Source: Transfusion and Apheresis Science : Official Journal of the World Apheresis Association : Official Journal of the European Society for Haemapheresis. 2001 October; 25(2): 83-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11761278&dopt=Abstract
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Hemophilia factor VIII therapy. B- and T-cell tolerance: from basic concepts to clinical practice. Author(s): Saint-Remy JM. Source: Haematologica. 2000 October; 85(10 Suppl): 93-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11187884&dopt=Abstract
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Hemophilia gene therapy: novel rAAV vectors and RNA repair strategy. Author(s): Chao H, Walsh CE. Source: Curr Opin Mol Ther. 2002 October; 4(5): 499-504. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435052&dopt=Abstract
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Hemophilia gene therapy: update. Author(s): Monahan PE, White GC 2nd. Source: Current Opinion in Hematology. 2002 September; 9(5): 430-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172462&dopt=Abstract
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Hemophilia Growth and Development Study: caregiver report of youth and family adjustment to HIV disease and immunologic compromise. Author(s): Bordeaux JD, Loveland KA, Lachar D, Stehbens J, Bell TS, Nichols S, Amodei N, Adkins KB; Hemophilia Growth and Development Study. Source: Journal of Pediatric Psychology. 2003 April-May; 28(3): 175-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654942&dopt=Abstract
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Hemophilia treatment. Immune tolerance induction: treatment duration analysis and economic considerations. Author(s): Aledort LM, Kroner B, Mariani G. Source: Haematologica. 2000 October; 85(10 Suppl): 83-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11187881&dopt=Abstract
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Hemophilia. Author(s): Mariani G, Kroner BL, Brackmann HH. Source: The New England Journal of Medicine. 2001 October 4; 345(14): 1066; Author Reply 1067. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11586969&dopt=Abstract
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Hemophilia. Author(s): Aledort LM. Source: The New England Journal of Medicine. 2001 October 4; 345(14): 1066; Author Reply 1067. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11586968&dopt=Abstract
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Hemophilia. Author(s): Punch JD, Merion RM, Turcotte JG. Source: The New England Journal of Medicine. 2001 October 4; 345(14): 1066-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11586967&dopt=Abstract
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Hemophilia. After a setback, gene therapy progresses.gingerly. Author(s): Gura T. Source: Science. 2001 March 2; 291(5509): 1692-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11253191&dopt=Abstract
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Hemophilia: treatment options in the twenty-first century. Author(s): Mannucci PM. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 July; 1(7): 1349-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871268&dopt=Abstract
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Hemorrhagic bullae after cryosurgery in a patient with hemophilia A. Author(s): Hancox JG, Graham GF, Yosipovitch G. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2003 October; 29(10): 1084-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974713&dopt=Abstract
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Hemorrhagic glaucoma in an infant with hemophilia, spontaneous hyphema, aniridia, and persistent iris vessels. Author(s): Theobald T, Davitt BV, Shields SR. Source: J Aapos. 2001 April; 5(2): 129-30. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11304824&dopt=Abstract
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Hepatitis C in adults and adolescents with hemophilia: a randomized, controlled trial of interferon alfa-2b and ribavirin. Author(s): Fried MW, Peter J, Hoots K, Gaglio PJ, Talbut D, Davis PC, Key NS, White GC, Lindblad L, Rickles FR, Abshire TC. Source: Hepatology (Baltimore, Md.). 2002 October; 36(4 Pt 1): 967-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297845&dopt=Abstract
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Hepatitis C virus infection among Brazilian hemophiliacs: a virological, clinical and epidemiological study. Author(s): Carmo RA, Oliveira GC, Guimaraes MD, Oliveira MS, Lima AA, Buzek SC, Correa-Oliveira R, Rocha MO. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 2002 May; 35(5): 589-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12011945&dopt=Abstract
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High frequency of CCR5-delta32 homozygosity in HCV-infected, HIV-1-uninfected hemophiliacs results from resistance to HIV-1. Author(s): Zhang M, Goedert JJ, O'brien TR. Source: Gastroenterology. 2003 March; 124(3): 867-8. Erratum In: Gastroenterology. 2003 May 12; 124(5): 1568. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12612937&dopt=Abstract
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High throughput mutation screening of the factor VIII gene (F8C) in hemophilia A: 37 novel mutations and genotype-phenotype correlation. Author(s): Citron M, Godmilow L, Ganguly T, Ganguly A. Source: Human Mutation. 2002 October; 20(4): 267-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12325022&dopt=Abstract
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Highlights from the XXV International Congress of the World Federation of Hemophilia. May 19-24, 2002, Seville, Spain. Author(s): Lusher JM; World Federation of Hemophilia. Source: Medgenmed [electronic Resource] : Medscape General Medicine. 2002 June 18; 4(3): 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466757&dopt=Abstract
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HIV-infected children with hemophilia: one- and two-year follow-up of neuropsychological functioning. Author(s): Hooper SR, Whitt JK, Tennison MB, Burchinal M, Gold SH, Hall CD. Source: Pediatr Aids Hiv Infect. 1997 April; 8(2): 91-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11361782&dopt=Abstract
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Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Author(s): Haase M. Source: Blood. 2002 December 1; 100(12): 4242; Author Reply 4242-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12433699&dopt=Abstract
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Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Author(s): Roth DA, Kessler CM, Pasi KJ, Rup B, Courter SG, Tubridy KL; Recombinant Factor IX Study Group. Source: Blood. 2001 December 15; 98(13): 3600-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11739163&dopt=Abstract
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Idiopathic intracranial hypertension and hemophilia A. Author(s): Jacome DE. Source: Headache. 2001 June; 41(6): 595-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11437898&dopt=Abstract
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Immune tolerance by intermittent factor VIII boluses in two high responder hemophilia A patients. Author(s): Landolfi R, de Cristofaro R, Lazzareschi I, Riccardi R, Mariani G. Source: Haematologica. 2000 October; 85(10 Suppl): 73-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11187877&dopt=Abstract
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Immune tolerance in hemophilia and treatment of hemophiliacs with an inhibitor. Author(s): Mariani G, Brackmann HH. Source: Haematologica. 2001 March; 86(3): 225-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11255267&dopt=Abstract
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Immune tolerance in hemophilia with factor VIII inhibitors: predictors of success. Author(s): Mariani G, Kroner B; Immune Tolerance Study Group (ITSG). Source: Haematologica. 2001 November; 86(11): 1186-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11694405&dopt=Abstract
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Immune tolerance induction and the treatment of hemophilia. Malmo protocol update. Author(s): Berntorp E, Astermark J, Carlborg E. Source: Haematologica. 2000 October; 85(10 Suppl): 48-50; Discussion 50-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11187871&dopt=Abstract
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Immune tolerance induction in hemophilia A: a review. Author(s): Mariani G, Siragusa S, Kroner BL. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 69-76. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640568&dopt=Abstract
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Immunobiology of inhibitor development in hemophilia A. Author(s): Fijnvandraat K, Bril WS, Voorberg J. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 61-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640567&dopt=Abstract
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Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy. Author(s): Yokozaki S, Takamatsu J, Nakano I, Katano Y, Toyoda H, Hayashi K, Hayakawa T, Fukuda Y. Source: Blood. 2000 December 15; 96(13): 4293-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11110704&dopt=Abstract
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Immunological characterization of factor VIII autoantibodies in patients with acquired hemophilia A in the presence or absence of underlying disease. Author(s): Matsumoto T, Shima M, Fukuda K, Nogami K, Giddings JC, Murakami T, Tanaka I, Yoshioka A. Source: Thrombosis Research. 2001 December 15; 104(6): 381-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11755947&dopt=Abstract
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Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C virus infection. Author(s): Ragni MV, Belle SH. Source: The Journal of Infectious Diseases. 2001 April 1; 183(7): 1112-5. Epub 2001 March 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11237838&dopt=Abstract
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Implications of gene sequencing in the direct diagnosis of hemophilia by PCR-RFLP. Author(s): Vidal F, Farssac E, Altisent C, Puig L, Gallardo D. Source: Haematologica. 2002 January; 87(1): 109-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11801473&dopt=Abstract
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In hemophilia A and autoantibody inhibitor patients: the factor VIII A2 domain and light chain are most immunogenic. Author(s): Scandella DH, Nakai H, Felch M, Mondorf W, Scharrer I, Hoyer LW, Saenko EL. Source: Thrombosis Research. 2001 March 1; 101(5): 377-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11297754&dopt=Abstract
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Incidence of focal white matter lesions in a population of hemophiliac children and their normal siblings. Hemophilia Growth and Development Study. Author(s): Nelson MD Jr, Wilson DA, Kisker CT, Evatt BL, Fenstermacher MJ, Lynn HS, Donfield SM, Maeder MA. Source: Pediatric Radiology. 2000 October; 30(10): 705-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11075607&dopt=Abstract
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Incidence of hepatitis C virus infection in children with hemophilia in Poland. Author(s): Januszkiewicz D, Wysocki J, Nowak J. Source: Acta Virol. 2000 June-August; 44(3): 227-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11155369&dopt=Abstract
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Incidence of infectious and noninfectious side effects in hemophilia patients in the new German Federal States during treatment with cryoprecipitate. Author(s): Lenk H, Schneider M. Source: Seminars in Thrombosis and Hemostasis. 2002 April; 28 Suppl 1: 51-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12016579&dopt=Abstract
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Increased soluble Fas in HIV-infected hemophilia patients with CD4+ and CD8+ cell count increases and viral load and immune complex decreases. Author(s): Daniel V, Susal C, Weimer R, Zimmermann R, Huth-Kuhne A, Opelz G. Source: Aids Research and Human Retroviruses. 2001 March 1; 17(4): 329-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11242519&dopt=Abstract
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Induction of acquired factor IX inhibitors in cynomolgus monkey (Macaca fascicularis): a new primate model of hemophilia B. Author(s): Tomokiyo K, Teshima K, Nakatomi Y, Watanabe T, Mizuguchi J, Nozaki C, Nakagaki T, Miyamoto S, Funatsu A, Iwanaga S. Source: Thrombosis Research. 2001 May 15; 102(4): 363-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11369429&dopt=Abstract
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Influence of factor VIIa and phospholipids on coagulation in “acquired” hemophilia. Author(s): Butenas S, Brummel KE, Paradis SG, Mann KG. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 January 1; 23(1): 123-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524235&dopt=Abstract
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Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Author(s): Lisman T, Mosnier LO, Lambert T, Mauser-Bunschoten EP, Meijers JC, Nieuwenhuis HK, de Groot PG. Source: Blood. 2002 January 1; 99(1): 175-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11756168&dopt=Abstract
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Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products. Author(s): Kreuz W, Ettingshausen CE, Zyschka A, Oldenburg J, Saguer IM, Ehrenforth S, Klingebiel T. Source: Seminars in Thrombosis and Hemostasis. 2002 June; 28(3): 285-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12098090&dopt=Abstract
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Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Author(s): Hrachovinova I, Cambien B, Hafezi-Moghadam A, Kappelmayer J, Camphausen RT, Widom A, Xia L, Kazazian HH Jr, Schaub RG, McEver RP, Wagner DD. Source: Nature Medicine. 2003 August; 9(8): 1020-5. Epub 2003 July 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858167&dopt=Abstract
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Interferon-alpha treatment of chronic hepatitis C in children with hemophilia. Author(s): Ko JS, Choe YH, Kim EJ, Lee EH, Jang JJ, Seo JK. Source: Journal of Pediatric Gastroenterology and Nutrition. 2001 January; 32(1): 41-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11176323&dopt=Abstract
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Intracranial hemorrhage in neonates with unrecognized hemophilia A: a persisting problem. Author(s): Myles LM, Massicotte P, Drake J. Source: Pediatric Neurosurgery. 2001 February; 34(2): 94-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11287809&dopt=Abstract
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Intraoral hemostasis using a recombinant activated factor VII preparation in a hemophilia a patient with inhibitor. Author(s): Morimoto Y, Yoshioka A, Shima M, Kirita T. Source: Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2003 September; 61(9): 1095-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12966487&dopt=Abstract
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Intratracheal administration of recombinant human factor IX (BeneFix) achieves therapeutic levels in hemophilia B dogs. Author(s): Russell KE, Read MS, Bellinger DA, Leitermann K, Rup BJ, McCarthy KP, Keith JC Jr, Khor SP, Schaub RG, Nichols TC. Source: Thrombosis and Haemostasis. 2001 March; 85(3): 445-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11307812&dopt=Abstract
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Intron factor VIII gene inversion in a population of Italian hemophilia A patients. Author(s): Riccardi F, Tagliaferri A, Manotti C, Pattacini C, Neri TM. Source: Blood. 2002 November 1; 100(9): 3432. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12412575&dopt=Abstract
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Inversion of intron 1 of the factor VIII gene for direct molecular diagnosis of hemophilia A. Author(s): Tizzano EF, Cornet M, Baiget M. Source: Haematologica. 2003 January; 88(1): 118-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12551839&dopt=Abstract
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Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate. Author(s): Soucie JM, Erdman DD, Evatt BL, Anderson LJ, Torok TJ, El-Jamil M, Barnhart E, Tepper M, Burrill HN, Pickett AM, Mengeling WL. Source: Transfusion. 2000 June; 40(6): 708-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10864993&dopt=Abstract
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Is Alu-mediated recombination an important cause of hemophilia? Author(s): Sommer SS, Scaringe WA, Hill KA. Source: Thrombosis and Haemostasis. 2002 July; 88(1): 3-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12152672&dopt=Abstract
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Issues of disclosure and condom use in adolescents with hemophilia and HIV. Hemophilia Behavioral Evaluative Intervention Project Staff. Author(s): Geary MK, King G, Forsberg AD, Delaronde SR, Parsons J. Source: Pediatr Aids Hiv Infect. 1996 December; 7(6): 418-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11361499&dopt=Abstract
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Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus. Author(s): Iversen AK, Christiansen CB, Attermann J, Eugen-Olsen J, Schulman S, Berntorp E, Ingerslev J, Fugger L, Scheibel E, Tengborn L, Gerstoft J, Dickmeiss E, Svejgaard A, Skinhoj P. Source: The Journal of Infectious Diseases. 2003 January 15; 187(2): 215-25. Epub 2003 Jan 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552446&dopt=Abstract
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Liver biopsies in adult hemophiliacs with hepatitis C: a United States center's experience. Author(s): Venkataramani A, Behling C, Rond R, Glass C, Lyche K. Source: The American Journal of Gastroenterology. 2000 September; 95(9): 2374-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11007246&dopt=Abstract
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Living-donor liver transplantation in an HIV-positive patient with hemophilia. Author(s): Sugawara Y, Ohkubo T, Makuuchi M, Kimura S, Morisawa Y, Tachikawa N, Oka S. Source: Transplantation. 2002 December 15; 74(11): 1655-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490807&dopt=Abstract
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Low cost locally prepared fibrin glue for clinical applications: reported of 145 cases. Committee of Bangkok International Hemophilia Training Center. Author(s): Isarangkura P, Chiewsilp P, Chuansumrit A, Suwannuraks M, Keorochana S, Attanawanich S, Tardtong P, Martinowitz U, Horoszowski H. Source: J Med Assoc Thai. 1999 November; 82 Suppl 1: S49-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10730518&dopt=Abstract
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Lyophilized cryoprecipitate for children with hemophilia A. Author(s): Nuchprayoon I, Sahasittiwat S, Kittikalayawong A, Chantanakajornfung A. Source: J Med Assoc Thai. 2002 June; 85 Suppl 1: S293-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12188426&dopt=Abstract
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Management of hemophilia in developing countries. Author(s): Kashyap R, Choudhry VP. Source: Indian J Pediatr. 2001 February; 68(2): 151-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11284184&dopt=Abstract
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Management of musculoskeletal complications of hemophilia. Author(s): Rodriguez-Merchan EC. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 87-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640570&dopt=Abstract
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Management of splenic trauma in the pediatric hemophiliac patient: Case series and review of the literature. Author(s): Koren JP, Klein RL, Kavic MS, Krill CE Jr. Source: Journal of Pediatric Surgery. 2002 April; 37(4): 568-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11912512&dopt=Abstract
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MANN: empowered and oppressed? Men's Advocacy Network of the National Hemophilia Foundation. Author(s): Kuhn D. Source: Common Factor. 1995 April; (No 10): 28-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11362350&dopt=Abstract
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Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Author(s): Butenas S, Brummel KE, Branda RF, Paradis SG, Mann KG. Source: Blood. 2002 February 1; 99(3): 923-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11806995&dopt=Abstract
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Mechanism of the immune response to human factor VIII in murine hemophilia A. Author(s): Wu H, Reding M, Qian J, Okita DK, Parker E, Lollar P, Hoyer LW, Conti-Fine BM. Source: Thrombosis and Haemostasis. 2001 January; 85(1): 125-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11204564&dopt=Abstract
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Medicine betrayed: hemophilia patients and HIV in the US. Author(s): Keshavjee S, Weiser S, Kleinman A. Source: Social Science & Medicine (1982). 2001 October; 53(8): 1081-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11556777&dopt=Abstract
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Modified Bentall operation in a patient with hemophilia A. Author(s): Kaminishi Y, Aizawa K, Saito T, Misawa Y, Madoiwa S, Sakata Y. Source: Jpn J Thorac Cardiovasc Surg. 2003 February; 51(2): 68-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12692936&dopt=Abstract
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Molecular analyses in hemophilia B families: identification of six new mutations in the factor IX gene. Author(s): Espinos C, Casana P, Haya S, Cid AR, Aznar JA. Source: Haematologica. 2003 February; 88(2): 235-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604421&dopt=Abstract
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Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Author(s): Soucie JM, Nuss R, Evatt B, Abdelhak A, Cowan L, Hill H, Kolakoski M, Wilber N. Source: Blood. 2000 July 15; 96(2): 437-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10887103&dopt=Abstract
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Moyamoya disease associated with hemophilia A. Case report. Author(s): Matsuda M, Enomoto T, Yanaka K, Nose T. Source: Pediatric Neurosurgery. 2002 March; 36(3): 157-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11919451&dopt=Abstract
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Mucocutaneous manifestations in Japanese HIV-positive hemophiliacs. Author(s): Shimizu S, Chen KR, Tagami H, Hanabusa H. Source: Dermatology (Basel, Switzerland). 2000; 201(4): 321-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11146342&dopt=Abstract
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Mutation detection in factor VIII cDNA from lymphocytes of hemophilia A patients by solid phase fluorescent chemical cleavage of mismatch. Author(s): Waseem NH, Bagnall R, Green PM, Giannelli F. Source: Methods in Molecular Biology (Clifton, N.J.). 2002; 187: 109-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12013738&dopt=Abstract
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Mutations associated with hemophilia A in the 558-565 loop of the factor VIIIa A2 subunit alter the catalytic activity of the factor Xase complex. Author(s): Jenkins PV, Freas J, Schmidt KM, Zhou Q, Fay PJ. Source: Blood. 2002 July 15; 100(2): 501-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091341&dopt=Abstract
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New protocol for immune tolerance induction in acquired hemophilia. Author(s): Nemes L, Pitlik E. Source: Haematologica. 2000 October; 85(10 Suppl): 64-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11187874&dopt=Abstract
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New therapies show promise for patients with leukemia, hemophilia, and heart disease. Author(s): Stephenson J. Source: Jama : the Journal of the American Medical Association. 2001 January 10; 285(2): 153-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11176790&dopt=Abstract
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Nondisclosure of human immunodeficiency virus and hepatitis C virus coinfection in a patient with hemophilia: medical and ethical considerations. Author(s): Kulkarni R, Scott-Emuakpor AB, Brody H, Weil WB, Ragni MV, Gera R. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2001 March-April; 23(3): 153-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11305718&dopt=Abstract
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Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses. Author(s): Liu ML, Nakaya S, Thompson AR. Source: Thrombosis and Haemostasis. 2002 February; 87(2): 273-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11858487&dopt=Abstract
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Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. Author(s): Roth DA, Tawa NE Jr, O'Brien JM, Treco DA, Selden RF; Factor VIII Transkaryotic Therapy Study Group. Source: The New England Journal of Medicine. 2001 June 7; 344(23): 1735-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11396439&dopt=Abstract
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Observed decline in the rate of death among Japanese hemophiliacs infected with HIV-1. Author(s): Tatsunami S, Fukutake K, Taki M, Shirahata A, Mimaya J, Takamatsu J, Ueda Y, Yoshioka A, Takata N, Yamada K. Source: International Journal of Hematology. 2000 August; 72(2): 256-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11039680&dopt=Abstract
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On the treatment of hemorrhage in patients with hemophilia and associated inhibitors. Author(s): Tarantino M, Aledort L. Source: Transfusion. 2001 December; 41(12): 1628-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11778084&dopt=Abstract
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PCR assay for the inversion causing severe Hemophilia A and its application. Author(s): Liu J, Liu Q, Liang Y, Wang L, Nozary G, Xiao B, Zhu Z, Zhou Y, Liu L, Guan Y, Zhang J, Sommer SS. Source: Chinese Medical Journal. 1999 May; 112(5): 419-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11593511&dopt=Abstract
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Peripheral nerve complications in hemophilia. Author(s): Saraf SK, Singh OP, Singh VP. Source: J Assoc Physicians India. 2003 February; 51: 167-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725260&dopt=Abstract
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Pharmacokinetic analysis of plasma-derived and recombinant F IX concentrates in previously treated patients with moderate or severe hemophilia B. Author(s): Ewenstein BM, Joist JH, Shapiro AD, Hofstra TC, Leissinger CA, Seremetis SV, Broder M, Mueller-Velten G, Schwartz BA; Mononine Comparison Study Group. Source: Transfusion. 2002 February; 42(2): 190-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11896334&dopt=Abstract
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Pharmacokinetics, prophylactic effects, and safety of a new recombinant FVIII formulated with sucrose (BAY 14-2222) in Japanese patients with hemophilia A. Author(s): Shirahata A, Fukutake K, Takamatsu J, Shima M, Yoshioka A. Source: International Journal of Hematology. 2000 July; 72(1): 101-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10979218&dopt=Abstract
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Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Author(s): Powell JS, Ragni MV, White GC 2nd, Lusher JM, Hillman-Wiseman C, Moon TE, Cole V, Ramanathan-Girish S, Roehl H, Sajjadi N, Jolly DJ, Hurst D. Source: Blood. 2003 September 15; 102(6): 2038-45. Epub 2003 May 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763932&dopt=Abstract
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Phenotype correction of hemophilia A mice by spliceosome-mediated RNA transsplicing. Author(s): Chao H, Mansfield SG, Bartel RC, Hiriyanna S, Mitchell LG, Garcia-Blanco MA, Walsh CE. Source: Nature Medicine. 2003 August; 9(8): 1015-9. Epub 2003 July 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847523&dopt=Abstract
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Phosphate-32 colloid radiosynovectomy in hemophilia: outcome of 125 procedures. Author(s): Siegel HJ, Luck JV Jr, Siegel ME, Quinones C. Source: Clinical Orthopaedics and Related Research. 2001 November; (392): 409-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11716416&dopt=Abstract
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Polymorphism of DXS102 locus in Chinese population and its application to gene diagnosis in hemophilia B family. Author(s): Bao Y, Lu D, Xu H, Shi Q, Qiu X, Xue J. Source: Chinese Medical Journal. 1998 June; 111(6): 527-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11245073&dopt=Abstract
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Possible linkage of amprenavir with intracranial bleeding in an HIV-infected hemophiliac. Author(s): Kodoth S, Bakshi S, Scimeca P, Black K, Pahwa S. Source: Aids Patient Care and Stds. 2001 July; 15(7): 347-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11483161&dopt=Abstract
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Possible synergy between recombinant factor VIIa and prothrombin complex concentrate in hemophilia therapy. Author(s): Key NS, Christie B, Henderson N, Nelsestuen GL. Source: Thrombosis and Haemostasis. 2002 July; 88(1): 60-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12152680&dopt=Abstract
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Postpartum acquired hemophilia (factor VIII inhibitors): a case report and review of the literature. Author(s): Shobeiri SA, West EC, Kahn MJ, Nolan TE. Source: Obstetrical & Gynecological Survey. 2000 December; 55(12): 729-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11128909&dopt=Abstract
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Pre- and perinatal relations of hemophilia A and B. Author(s): Beke A, Ban Z, Nagy B, Toth-Pal E, Papp C, Csaba A, Papp Z. Source: Fetal Diagnosis and Therapy. 2003 January-February; 18(1): 17-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566770&dopt=Abstract
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Predictors of retention among HIV/hemophilia health care professionals. Author(s): Brown LK, Schultz JR, Forsberg AD, King G, Kocik SM, Butler RB. Source: General Hospital Psychiatry. 2002 January-February; 24(1): 48-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11814534&dopt=Abstract
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Prenatal diagnosis in hemophilia A using factor VIII gene polymorphism--Indian experience. Author(s): Chowdhury MR, Tiwari M, Kabra M, Menon PS. Source: Annals of Hematology. 2003 July; 82(7): 427-30. Epub 2003 May 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12768323&dopt=Abstract
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Prevalence of hepatitis B and C seromarkers and abnormal liver function tests among hemophiliacs in Guilan (northern province of Iran). Author(s): Mansour-Ghanaei F, Fallah MS, Shafaghi A, Yousefi-Mashhoor M, Ramezani N, Farzaneh F, Nassiri R. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 December; 8(12): Cr797-800. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503038&dopt=Abstract
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Prevalence of hepatitis C Virus infection among hemophiliacs in Central Brazil. Author(s): Barbosa AP, Martins RM, Teles SA, Silva SA, Oliveira JM, Yoshida CF. Source: Memorias Do Instituto Oswaldo Cruz. 2002 July; 97(5): 643-4. Epub 2002 August 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12219127&dopt=Abstract
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Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A. Author(s): Bogdanova N, Markoff A, Pollmann H, Nowak-Gottl U, Eisert R, Dworniczak B, Eigel A, Horst J. Source: Human Mutation. 2002 September; 20(3): 236-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12204009&dopt=Abstract
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Progression to acquired immunodeficiency syndrome in 94 human immunodeficiency virus-positive hemophiliacs with long-term follow-up. Author(s): Lorenzo JI, Moscardo F, Lopez-Aldeguer J, Aznar JA. Source: Haematologica. 2001 March; 86(3): 291-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11357820&dopt=Abstract
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Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients. Author(s): Scandella DH. Source: Seminars in Thrombosis and Hemostasis. 2000; 26(2): 137-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10919405&dopt=Abstract
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Prophylaxis for severe hemophilia: experience from Europe and the United States. Author(s): van den Berg HM, Fischer K. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 49-54. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640565&dopt=Abstract
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Proteolytic antibodies against factor VIII in hemophilia A. Author(s): Stollar BD. Source: The New England Journal of Medicine. 2002 February 28; 346(9): 702-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11870249&dopt=Abstract
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Pseudotumor occurring in hemophilia. Author(s): van Ommeren JW, Mooren DW, Veth RP, Novakova IR, van de Kaa CA. Source: Archives of Orthopaedic and Trauma Surgery. 2000; 120(7-8): 476-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10968546&dopt=Abstract
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Quantifying practice effects in longitudinal research with the WISC-R and WAIS-R: a study of children and adolescents with hemophilia and male siblings without hemophilia. Author(s): Sirois PA, Posner M, Stehbens JA, Loveland KA, Nichols S, Donfield SM, Bell TS, Hill SD, Amodei N; Hemophilia Growth and Development Study. Source: Journal of Pediatric Psychology. 2002 March; 27(2): 121-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11821496&dopt=Abstract
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Radionuclide synovectomy (radiosynoviorthesis) in hemophilia: a very efficient and single procedure. Author(s): Rodriguez-Merchan EC. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 97-100. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640571&dopt=Abstract
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Rapid hemophilia A molecular diagnosis by a simple DNA sequencing procedure: identification of 14 novel mutations. Author(s): Vidal F, Farssac E, Altisent C, Puig L, Gallardo D. Source: Thrombosis and Haemostasis. 2001 April; 85(4): 580-3. Erratum In: Thromb Haemost 2001 August; 86(2): 727. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11341489&dopt=Abstract
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Recombinant coagulation factor VIIa: from the concept to clinical application in hemophilia treatment in 2000. Author(s): Hedner U. Source: Seminars in Thrombosis and Hemostasis. 2000; 26(4): 363-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11092209&dopt=Abstract
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Recombinant FVIIa in the treatment of bleeding in acquired hemophilia. Author(s): Guerin V, Chossat I, Dutronc H, Dubreuil M, Valentin F. Source: American Journal of Hematology. 2002 August; 70(4): 333. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210820&dopt=Abstract
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Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Author(s): Bagnall RD, Waseem N, Green PM, Giannelli F. Source: Blood. 2002 January 1; 99(1): 168-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11756167&dopt=Abstract
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Red Cross and federal government held liable for hemophiliacs' HIV infection. Author(s): Elliott R. Source: Can Hiv Aids Policy Law Rev. 2000; 5(4): 5-7. English, French. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11833171&dopt=Abstract
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Relation between HIV-1 and hepatitis C viral load in patients with hemophilia. Author(s): Daar ES, Lynn H, Donfield S, Gomperts E, Hilgartner MW, Hoots WK, Chernoff D, Arkin S, Wong WY, Winkler CA; Hemophilia Growth and Development Study. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2001 April 15; 26(5): 466-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11391167&dopt=Abstract
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Relationships among the detection of p24 antigen, human immunodeficiency virus (HIV) RNA level, CD4 cell count, and disease progression in HIV-infected individuals with hemophilia. Author(s): Sabin CA, Lepri AC, Devereux H, Phillips AN, Loveday C, Lee CA. Source: The Journal of Infectious Diseases. 2001 August 15; 184(4): 511-4. Epub 2001 July 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11471111&dopt=Abstract
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Replacement therapy with virus-inactivated clotting factor concentrates in patients with severe hemophilia in Heidelberg. Author(s): Zimmermann R, Uhle C, Huth-Kuhne A. Source: Seminars in Thrombosis and Hemostasis. 2002 April; 28 Suppl 1: 75-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12016582&dopt=Abstract
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Response to measles, mumps, and rubella revaccination among HIV-positive and HIV-negative children and adolescents with hemophilia. Hemophilia Growth and Development Study. Author(s): Hilgartner MW, Maeder MA, Mahoney EM, Donfield SM, Evatt BL, Hoots WK. Source: American Journal of Hematology. 2001 February; 66(2): 92-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11421305&dopt=Abstract
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Rheumatological management of patients with hemophilia. Part 1: joint manifestations. Author(s): Alcalay M, Deplas A. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2002 October; 69(5): 442-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477227&dopt=Abstract
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Rheumatological management of patients with hemophilia. Part II: Muscle hematomas and pseudotumors. Author(s): Alcalay M, Deplas A. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2002 December; 69(6): 556-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12537262&dopt=Abstract
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Ricky Ray Hemophilia Relief Fund Program. Adoption of interim final rule as final rule with amendments. Author(s): Health Resources and Services Administration, HHS. Source: Federal Register. 2001 November 23; 66(226): 58667-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11780623&dopt=Abstract
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Risk factors for infection with HBV and HCV in a largecohort of hemophiliac males. Author(s): Soucie JM, Richardson LC, Evatt BL, Linden JV, Ewenstein BM, Stein SF, Leissinger C, Manco-Johnson M, Sexauer CL; Hemophilia Surveillance System Project Investigators. Source: Transfusion. 2001 March; 41(3): 338-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11274587&dopt=Abstract
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Risk factors for inhibitor development in hemophilia A. Author(s): Oldenburg J, Brackmann HH, Schwaab R. Source: Haematologica. 2000 October; 85(10 Suppl): 7-13; Discussion 13-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11187876&dopt=Abstract
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Safe passage: a plea for safety in hemophilia gene therapy. Author(s): Ragni MV. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 October; 6(4): 436-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12377182&dopt=Abstract
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Safety issues affecting hemophilia products. Author(s): Hoots WK. Source: Transfus Med Rev. 2001 April; 15(2 Suppl 1): 11-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11441416&dopt=Abstract
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Sensitization of CD4+ T cells to coagulation factor VIII: response in congenital and acquired hemophilia patients and in healthy subjects. Author(s): Reding MT, Wu H, Krampf M, Okita DK, Diethelm-Okita BM, Christie BA, Key NS, Conti-Fine BM. Source: Thrombosis and Haemostasis. 2000 October; 84(4): 643-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11057864&dopt=Abstract
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Should gene therapy be used for newborns with hemophilia? Author(s): Ponder KP. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 January; 7(1): 7-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573611&dopt=Abstract
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Should treatment of hepatitis C in HIV-seropositive and HIV-seronegative patients with hemophilia include induction doses of interferon? Author(s): McGovern B, Bica I. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 August 1; 37(3): 463-4; Author Reply 464-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884180&dopt=Abstract
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Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A. Author(s): Valleix S, Vinciguerra C, Lavergne JM, Leuer M, Delpech M, Negrier C. Source: Blood. 2002 October 15; 100(8): 3034-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12351418&dopt=Abstract
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Solitary rectal ulcer: a rare cause of gastrointestinal bleeding in an adolescent with hemophilia A. Author(s): Bishop PR, Nowicki MJ, Subramony C, Parker PH. Source: Journal of Clinical Gastroenterology. 2001 July; 33(1): 72-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11418797&dopt=Abstract
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Somatic mosaicism and compound heterozygosity in female hemophilia B. Author(s): Costa JM, Vidaud D, Laurendeau I, Vidaud M, Fressinaud E, Moisan JP, David A, Meyer D, Lavergne JM. Source: Blood. 2000 August 15; 96(4): 1585-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10942410&dopt=Abstract
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Somatic mosaicism in hemophilia A: a fairly common event. Author(s): Leuer M, Oldenburg J, Lavergne JM, Ludwig M, Fregin A, Eigel A, Ljung R, Goodeve A, Peake I, Olek K. Source: American Journal of Human Genetics. 2001 July; 69(1): 75-87. Epub 2001 June 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11410838&dopt=Abstract
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Spontaneous subdural hematoma in a young adult with hemophilia. Author(s): Agrawal D, Mahapatra AK. Source: Neurology India. 2003 March; 51(1): 114-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865541&dopt=Abstract
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State of care for hemophilia in pediatric patients. Author(s): Santagostino E, Gringeri A, Mannucci PM. Source: Paediatric Drugs. 2002; 4(3): 149-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11909007&dopt=Abstract
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Status of infection in young hemophilia patients in Munster. Author(s): Pollmann H, Richter H. Source: Seminars in Thrombosis and Hemostasis. 2002 April; 28 Suppl 1: 47-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12016578&dopt=Abstract
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Successful treatment of high titer inhibitors in mild hemophilia A with avoidance of factor VIII and immunosuppressive therapy. Author(s): Robbins D, Kulkarni R, Gera R, Scott-Emuakpor AB, Bosma K, Penner JA. Source: American Journal of Hematology. 2001 November; 68(3): 184-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11754400&dopt=Abstract
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Successful use of recombinant factor VIIa for hemostasis during total knee replacement in a severe hemophiliac with high-titer factor VIII inhibitor. Author(s): Carr ME Jr, Loughran TP, Cardea JA, Smith WK, Kuhn JG, Dottore MV. Source: International Journal of Hematology. 2002 January; 75(1): 95-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11843300&dopt=Abstract
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Surgery-associated acquired hemophilia A. Author(s): Theodossiades G, Tsevrenis V, Nomikou E, Dadiotis L, Kontopoulou-Griva I. Source: Annals of Hematology. 2001 November; 80(11): 691-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11757731&dopt=Abstract
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Surgical management of intractable epilepsy in children with hemophilia. Author(s): Yeh DJ, Lee M, Park YD, Smith JR, Lightsey AL Jr. Source: Stereotactic and Functional Neurosurgery. 1999; 73(1-4): 88-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10853108&dopt=Abstract
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Survival and viral load in four groups of HIV-1 infected hemophiliacs compared by three-way data clustering. Author(s): Tatsunami S, Kuwabara R, Hiroi T, Matsui H, Fukutake K, Mimaya U, Yamada K, Sato M. Source: Medinfo. 2001; 10(Pt 1): 557-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11604802&dopt=Abstract
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Sustained human factor VIII expression in hemophilia A mice following systemic delivery of a gutless adenoviral vector. Author(s): Reddy PS, Sakhuja K, Ganesh S, Yang L, Kayda D, Brann T, Pattison S, Golightly D, Idamakanti N, Pinkstaff A, Kaloss M, Barjot C, Chamberlain JS, Kaleko M, Connelly S. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 January; 5(1): 63-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11786047&dopt=Abstract
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Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector. Author(s): Scallan CD, Lillicrap D, Jiang H, Qian X, Patarroyo-White SL, Parker AE, Liu T, Vargas J, Nagy D, Powell SK, Wright JF, Turner PV, Tinlin SJ, Webster SE, McClelland A, Couto LB. Source: Blood. 2003 September 15; 102(6): 2031-7. Epub 2003 May 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738670&dopt=Abstract
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Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. Author(s): Escuriola Ettingshausen C, Halimeh S, Kurnik K, Schobess R, Wermes C, Junker R, Kreuz W, Pollmann H, Nowak-Gottl U. Source: Thrombosis and Haemostasis. 2001 February; 85(2): 218-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11246535&dopt=Abstract
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The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion. Author(s): Lozier JN, Dutra A, Pak E, Zhou N, Zheng Z, Nichols TC, Bellinger DA, Read M, Morgan RA. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 October 1; 99(20): 12991-6. Epub 2002 September 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12242334&dopt=Abstract
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The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia. Author(s): Fischer K, van der Bom JG, Mauser-Bunschoten EP, Roosendaal G, Prejs R, de Kleijn P, Grobbee DE, van den Berg M. Source: Blood. 2002 April 1; 99(7): 2337-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11895765&dopt=Abstract
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The efficacy of functional foot orthoses in the control of pain in ankle joint disintegration in hemophilia. Author(s): Slattery M, Tinley P. Source: Journal of the American Podiatric Medical Association. 2001 May; 91(5): 240-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11359888&dopt=Abstract
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The Hemophilia Utilization Group Study (HUGS): determinants of costs of care in persons with haemophilia A. Author(s): Globe DR, Cunningham WE, Andersen R, Dietrich SL, Curtis RG, Parish KL, Miller RT, Sanders NL, Kominski G; Hemophilia Utilization Group Study. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. 2003 May; 9(3): 325-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694525&dopt=Abstract
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The hemophilias--from royal genes to gene therapy. Author(s): Mannucci PM, Tuddenham EG. Source: The New England Journal of Medicine. 2001 June 7; 344(23): 1773-9. Review. Erratum In: N Engl J Med 2001 August 2; 345(5): 384. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11396445&dopt=Abstract
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The incidence of inhibitors in hemophilia A and the induction of immune tolerance. Author(s): Briet E, Peters M. Source: Advances in Experimental Medicine and Biology. 2001; 489: 89-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11554594&dopt=Abstract
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The limitation of factor IX coagulant activity determination in the diagnosis of hemophilia B carriers. Author(s): Rurgkhum S, Sasanakul W, Chotsuppakarn S, Pintadit P, Chuansumrit A. Source: J Med Assoc Thai. 2002 November; 85 Suppl 4: S1071-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12549778&dopt=Abstract
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The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Author(s): Astermark J, Berntorp E, White GC, Kroner BL; MIBS Study Group. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. 2001 May; 7(3): 267-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11380630&dopt=Abstract
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The molecular basis of hemophilia A: genotype-phenotype relationships and inhibitor development. Author(s): Goodeve AC, Peake IR. Source: Seminars in Thrombosis and Hemostasis. 2003 February; 29(1): 23-30. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640561&dopt=Abstract
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The role of arthroscopic synovectomy in the management of hemarthrosis in hemophilia patients: financial perspectives. Author(s): Tamurian RM, Spencer EE, Wojtys EM. Source: Arthroscopy : the Journal of Arthroscopic & Related Surgery : Official Publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 2002 September; 18(7): 789-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12209438&dopt=Abstract
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The upward spiral of drug costs: a time series analysis of drugs used in the treatment of hemophilia. Author(s): Rogoff EG, Guirguis HS, Lipton RA, Seremetis SV, DiMichele DM, Agnew GM, Karpatkin M, Barish RJ, Jones RL, Bianco C, Knothe BD, Lee MS. Source: Thrombosis and Haemostasis. 2002 October; 88(4): 545-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362223&dopt=Abstract
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The use of recombinant factor VIII products in previously treated patients with hemophilia A: pharmacokinetics, efficacy, safety, and inhibitor development. Author(s): Lee C. Source: Seminars in Thrombosis and Hemostasis. 2002 June; 28(3): 241-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12098083&dopt=Abstract
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The utility of activated partial thromboplastin time (aPTT) clot waveform analysis in the investigation of hemophilia A patients with very low levels of factor VIII activity (FVIII:C). Author(s): Shima M, Matsumoto T, Fukuda K, Kubota Y, Tanaka I, Nishiya K, Giles AR, Yoshioka A. Source: Thrombosis and Haemostasis. 2002 March; 87(3): 436-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11916076&dopt=Abstract
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Theodore E. Woodward Award. AAV-mediated gene transfer for hemophilia. Author(s): High KA. Source: Trans Am Clin Climatol Assoc. 2003; 114: 337-51; Discussion 351-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12813929&dopt=Abstract
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Therapeutic choices for patients with hemophilia and high-titer inhibitors. Author(s): Kulkarni R, Aledort LM, Berntorp E, Brackman HH, Brown D, Cohen AR, Ewing NP, Gringeri A, Gruppo R, Hoots K, Leissenger C, Peerlinck K, Poon MC, Wong WY. Source: American Journal of Hematology. 2001 August; 67(4): 240-6. Review. Erratum In: Am J Hematol 2002 February; 69(2): 155-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11443636&dopt=Abstract
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Treatment of a patient with hemophilia A and hepatitis C virus-related cirrhosis by living-related liver transplantation from an obligate carrier donor. Author(s): Horita K, Matsunami H, Shimizu Y, Shimizu A, Kurimoto M, Suzuki K, Tsukadaira T, Arai M. Source: Transplantation. 2002 June 27; 73(12): 1909-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12131686&dopt=Abstract
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Treatment of hemophilia: recombinant factors only? No. Author(s): Mannucci PM. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 February; 1(2): 216-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871490&dopt=Abstract
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Treatment of hemophilia: recombinant factors only? Yes. Author(s): Giangrande PL. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 February; 1(2): 214-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871489&dopt=Abstract
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Treatment strategies in children with hemophilia. Author(s): Petrini P. Source: Paediatric Drugs. 2002; 4(7): 427-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12083971&dopt=Abstract
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Trends in human immunodeficiency virus type 1 (HIV-1) load among HIV-1-infected children with hemophilia. Author(s): Engels EA, Rosenberg PS, Katki H, Goedert JJ, Biggar RJ; Multicenter Hemophilia Cohort Study. Source: The Journal of Infectious Diseases. 2001 August 1; 184(3): 364-8. Epub 2001 June 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11443565&dopt=Abstract
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Unbalanced X-chromosome inactivation with a novel FVIII gene mutation resulting in severe hemophilia A in a female. Author(s): Favier R, Lavergne JM, Costa JM, Caron C, Mazurier C, Viemont M, Delpech M, Valleix S. Source: Blood. 2000 December 15; 96(13): 4373-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11110718&dopt=Abstract
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Unusual case of coronary artery disease in a patient with severe hemophilia B. Author(s): Mol Pathol. 2002 Apr;55(2):127-44 Source: American Journal of Hematology. 2002 February; 69(2): 152-3. /entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11950963
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Update on chronic hepatitis C in hemophiliacs. Author(s): Franchini M, Capra F, Tagliaferri A, Rossetti G, De Gironcoli M, Rocca P, Aprili G, Gandini G. Source: Haematologica. 2002 May; 87(5): 542-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12010670&dopt=Abstract
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Use of blood outgrowth endothelial cells for gene therapy for hemophilia A. Author(s): Lin Y, Chang L, Solovey A, Healey JF, Lollar P, Hebbel RP. Source: Blood. 2002 January 15; 99(2): 457-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11781225&dopt=Abstract
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Use of high dose factor VIIa in hemophilia patients. Author(s): Hedner U. Source: Advances in Experimental Medicine and Biology. 2001; 489: 75-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11554593&dopt=Abstract
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Use of intraligamentary anesthesia in a patient with severe hemophilia and factor VIII inhibitor. Author(s): Eigner TL. Source: Spec Care Dentist. 1990 July-August; 10(4): 121-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11100219&dopt=Abstract
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Use of prophylaxis to prevent complications of hemophilia. Author(s): Mannucci PM, Mendolicchio L, Gringeri A. Source: Advances in Experimental Medicine and Biology. 2001; 489: 59-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11554591&dopt=Abstract
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Use of recombinant factor vila to control bleeding in an adolescent male with severe hemophilia A, HIV thrombocytopenia, hepatitis C, and end-stage liver disease. Author(s): Puetz JJ, Bouhasin JD. Source: Am J Hosp Palliat Care. 2002 July-August; 19(4): 277-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12141793&dopt=Abstract
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Viral vector-mediated gene therapy for hemophilia. Author(s): VandenDriessche T, Collen D, Chuah MK. Source: Current Gene Therapy. 2001 September; 1(3): 301-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12109144&dopt=Abstract
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Virus load and risk of heterosexual transmission of human immunodeficiency virus and hepatitis C virus by men with hemophilia. The Multicenter Hemophilia Cohort Study. Author(s): Hisada M, O'Brien TR, Rosenberg PS, Goedert JJ. Source: The Journal of Infectious Diseases. 2000 April; 181(4): 1475-8. Epub 2000 April 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10753732&dopt=Abstract
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What can we learn from the immune response to human factor VIII in a mouse model of hemophilia A? Author(s): Reipert BM, Schwarz HP. Source: Thrombosis and Haemostasis. 2002 August; 88(2): 374-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195723&dopt=Abstract
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CHAPTER 2. NUTRITION AND HEMOPHILIA Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and hemophilia.
Finding Nutrition Studies on Hemophilia 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 “hemophilia” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7 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 information is typical of that found when using the “Full IBIDS Database” to search for “hemophilia” (or a synonym): •
A hemophilia model in zebrafish: analysis of hemostasis. Author(s): Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 78284-7964, USA.
[email protected] Source: Jagadeeswaran, P Liu, Y C Blood-Cells-Mol-Dis. 1997; 23(1): 52-7 1079-9796
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A method to estimate effects of amino acid substitutions in blood coagulation factor IX from hemophilia B patients. Author(s): Department of Information Science, Kyoto University of Education Fushimiku, Kyoto, 612 Japan. Source: Furutani, H Medinfo. 1995; 8 Pt 2909
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Acquired hemophilia and its treatment. Author(s): Laboratoire d'Hematologie, CHU La Miletrie, Poitiers, France. Source: Sultan, Y Blood-Coagul-Fibrinolysis. 1997 August; 8 Suppl 1S15-8 0957-5235
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Acquired hemophilia: a rare complication of Sjogren's syndrome. Author(s): Service de Medecine Interne, Hopital de la Pitie-Salpetriere, Paris, France. Source: Vignes, S Le Moing, V Meekel, P Papo, T Wechsler, B Godeau, P Clin-ExpRheumatol. 1996 Sep-October; 14(5): 559-60 0392-856X
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Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion. Author(s): DNA Viral Vectors Unit, Genetic Therapy, Inc., A Novartis Company, 9 West Watkins Mill Road, Gaithersburg, MD 20878, USA. Source: Bristol, J A Gallo Penn, A Andrews, J Idamakanti, N Kaleko, M Connelly, S Hum-Gene-Ther. 2001 September 1; 12(13): 1651-61 1043-0342
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Care of Thai hemophilia patients from 1969 to 1991. Author(s): Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Source: Chuansumrit, A Isarangkura, P Hathirat, P Chiewsilp, P Kittikol, J J-Med-AssocThai. 1993 October; 76 Suppl 292-102 0125-2208
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Clinical experience of a new monoclonal antibody purified factor IX: half-life, recovery, and safety in patients with hemophilia B. Author(s): Department of Medicine, UMDNJ, Robert Wood Johnson Medical School, New Brunswick 08903. Source: Kim, H C McMillan, C W White, G C Bergman, G E Saidi, P Semin-Hematol. 1990 April; 27(2 Suppl 2): 30-5 0037-1963
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ED visits by males with hemophilia. Author(s): Mountain States Regional Hemophilia and Thrombosis Center, University of Colorado Health Sciences Center and the Colorado Department of Public Health and Environment, Denver, CO, USA.
[email protected] Source: Nuss, Rachelle Hoffman, Richard Hammond, Lucinda Am-J-Emerg-Med. 2002 March; 20(2): 74-8 0735-6757
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Effects of glycyrrhizin (SNMC: stronger Neo-Minophagen C) in hemophilia patients with HIV infection. Author(s): Third Department of Internal Medicine, Tohoku University School of Medicine. Source: Mori, K Sakai, H Suzuki, S Sugai, K Akutsu, Y Ishikawa, M Seino, Y Ishida, N Uchida, T Kariyone, S et al. Tohoku-J-Exp-Med. 1989 May; 158(1): 25-35 0040-8727
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Evaluation of high concentration intranasal and intravenous desmopressin in pediatric patients with mild hemophilia A or mild-to-moderate type 1 von Willebrand disease. Author(s): Blood Center of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, 53201-2178, USA. Source: Gill, Joan Cox Ottum, Marilyn Schwartz, Bruce J-Pediatr. 2002 May; 140(5): 595-9 0022-3476
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Extravascular administration of factor IX: potential for replacement therapy of canine and human hemophilia B. Author(s): Department of Medicine, University of North Carolina at Chapel Hill, USA. Source: Liles, D Landen, C N Monroe, D M Lindley, C M Read, M S Roberts, H R Brinkhous, K M Thromb-Haemost. 1997 May; 77(5): 944-8 0340-6245
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Factor IX concentrate versus prothrombin complex concentrate for the treatment of hemophilia B during surgery. Author(s): Centre d'Accueil et de Traitement des Hemophiles, Hopital Cochin, Paris, France. Source: Bardin, J M Sultan, Y Transfusion. 1990 June; 30(5): 441-3 0041-1132
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Hematologic disorders including sickle-cell syndromes, hemophilia, and betathalassemia. Author(s): Division of Rheumatology, University of Alabama at Birmingham 352943296, USA. Source: Bastian, H M Curr-Opin-Rheumatol. 1995 January; 7(1): 70-2 1040-8711
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Hemorrhoidectomy in a hemophiliac with factor VIII inhibitors. Source: Murali, M S Jager, R M Indiana-Med. 1987 April; 80(4): 332-3 0746-8288
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Hemostasis in acquired hemophilia--role of intracavitary instillation of EACA. Author(s): Department of Dr J C Patel Hematology, KEM Hospital, Parel, Mumbai. Source: Sahu, S Raipancholia, R Pardiwalla, F K Pathare, A V J-Postgrad-Med. 1996 JulSeptember; 42(3): 88-90 0022-3859
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Humoral immune response in patients with hemophilia. Source: Matheson, D S Green, B J Fritzler, M J Poon, M C Bowen, T J Hoar, D I ClinImmunol-Immunopathol. 1987 July; 44(1): 41-50 0090-1229
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Inhibitors to factor VIII in a family with mild hemophilia: molecular characterization and response to factor VIII and desmopressin. Author(s): Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Italy. Source: Santagostino, E Gringeri, A Tagliavacca, L Mannucci, P M Thromb-Haemost. 1995 August; 74(2): 619-21 0340-6245
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Intranasal desmopressin (DDAVP) by spray in mild hemophilia A and von Willebrand's disease type I. Author(s): Department of Coagulation Disorders, University of Lund, Malmo General Hospital, Sweden. Source: Lethagen, S Harris, A S Nilsson, I M Blut. 1990 March; 60(3): 187-91 0006-5242
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Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses. Author(s): A. Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan, Italy. Source: Mannucci, P M Vicente, V Alberca, I Sacchi, E Longo, G Harris, A S Lindquist, A Thromb-Haemost. 1987 December 18; 58(4): 1037-9 0340-6245
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Management and surveillance of the hemophiliacs at the National Institute of Hematology and Blood Transfusion of Vietnam. Author(s): National Institute of Hematology and Blood Transfusion, Bach Mai Hospital, Hanoi, Vietnam. Source: Bach, Q T Colab Southeast-Asian-J-Trop-Med-Public-Health. 1993; 24 Suppl 1113-5 0038-3619
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Management of dental extractions in two hemophilia A patients with factor VIII inhibitor. Source: Shurafa, M MacIntosh, R B J-Oral-Maxillofac-Surg. 1987 August; 45(8): 698-701 0278-2391
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Prospective multicenter study on subcutaneous concentrated desmopressin for home treatment of patients with von Willebrand disease and mild or moderate hemophilia A. Author(s): Department of Hematology and Hemophilia, San Bortolo Hospital, Vicenza, Italy. Source: Rodeghiero, F Castaman, G Mannucci, P M Thromb-Haemost. 1996 November; 76(5): 692-6 0340-6245
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Some aspects on the management of hemophilia. Author(s): Mount Sinai School of Medicine, New York, NY 10029-6574, USA. Source: Aledort, L M Thromb-Haemost. 1995 July; 74(1): 440-3 0340-6245
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Successful treatment of high titer inhibitors in mild hemophilia A with avoidance of factor VIII and immunosuppressive therapy. Author(s): Michigan State University, Department of Pediatrics/Human Development, B220 Clinical Center, 138 Service Road, East Lansing, Michigan 48824-1313, USA. Source: Robbins, D Kulkarni, R Gera, R Scott Emuakpor, A B Bosma, K Penner, J A AmJ-Hematol. 2001 November; 68(3): 184-8 0361-8609
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Surgery-associated acquired hemophilia A. Author(s): First Regional Transfusion and Haemophilia Centre, Hippokration Hospital, Athens, Greece.
[email protected] Source: Theodossiades, G Tsevrenis, V Nomikou, E Dadiotis, L Kontopoulou Griva, I Ann-Hematol. 2001 November; 80(11): 691-3 0939-5555
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Surveillance and care of four Chinese hemophiliacs with human immunodeficiency virus (HIV) infection. Author(s): Institute of Hematology, Zhejiang Medical University, Hangzhou. Source: Tang, D Qu, G Pang, X Lang, Y Liang, Y Yu, Y Zeng, Y Shao, Y Chin-Med-Sci-J. 1993 March; 8(1): 41-3 1001-9294
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The lack of antiplatelet effect of crude extracts from ganoderma lucidum on HIVpositive hemophiliacs. Author(s): Section of Hematology, National Yang-Ming Medical College, Taipei, Taiwan. Source: Gau, J P Lin, C K Lee, S S Wang, S R Am-J-Chin-Med. 1990; 18(3-4): 175-9 0192415X
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Treatment of a patient with hemophilia A and hepatitis C virus-related cirrhosis by living-related liver transplantation from an obligate carrier donor. Author(s): Department of Surgery, Matsunami General Hospital, Gifu, Japan. Source: Horita, Kohjiro Matsunami, Hidetoshi Shimizu, Yasunobu Shimizu, Akira Kurimoto, Masaaki Suzuki, Kohji Tsukadaira, Toshihisa Arai, Morio Transplantation. 2002 June 27; 73(12): 1909-12 0041-1337
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Treatment protocol of haemophilia and other congenital bleeding disorders in Italy. Italian Association of Hemophilia Centers (AICE). Author(s): Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital, Italy. Source: Gringeri, A Haemophilia. 1998 July; 4(4): 423-4 1351-8216
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/
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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WebMD®Health: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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The following is a specific Web list relating to hemophilia; 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 Vitamin E Source: Prima Communications, Inc.www.personalhealthzone.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND HEMOPHILIA Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to hemophilia. 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 hemophilia 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 “hemophilia” (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 hemophilia: •
“Yakugai” AIDS and the Yokohama Xth international AIDS conference. Author(s): Haas GJ. Source: Common Factor. 1995 April; (No 10): 1, 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11362335&dopt=Abstract
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32P Radiosynoviorthesis in children with hemophilia. Author(s): Manco-Johnson MJ, Nuss R, Lear J, Wiedel J, Geraghty SJ, Hacker MR, Funk S, Kilcoyne RF, Murphy J. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 October; 24(7): 534-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368689&dopt=Abstract
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Activated recombinant human coagulation factor VII therapy for intracranial hemorrhage in patients with hemophilia A or B with inhibitors. Results of the novoseven emergency-use program.
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Author(s): Arkin S, Cooper HA, Hutter JJ, Miller S, Schmidt ML, Seibel NL, Shapiro A, Warrier I. Source: Haemostasis. 1998 March-April; 28(2): 93-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10087434&dopt=Abstract •
Ancient descriptions of hemophilia and preconception gender selection. Author(s): Rosner F. Source: Jama : the Journal of the American Medical Association. 1984 August 17; 252(7): 900. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6379212&dopt=Abstract
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Behavioral medicine in hemophilia arthritic pain management: two case studies. Author(s): Varni JW. Source: Archives of Physical Medicine and Rehabilitation. 1981 April; 62(4): 183-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7016064&dopt=Abstract
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Case report: the effect of a Chinese herbal medicine, BG-104 in two HIV positive hemophiliacs. Author(s): Arimori S, Nozaki H, Morita K, Arimori K. Source: Biotherapy (Dordrecht, Netherlands). 1993; 7(1): 55-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7915126&dopt=Abstract
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Dental extractions in the hemophiliac: control of the emotional factors by hypnosis. Author(s): LUCAS ON. Source: Am J Clin Hypn. 1965 April; 69: 301-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14280120&dopt=Abstract
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Factor IX and prothrombin in amniotic fluid and fetal plasma: constraints on prenatal diagnosis of hemophilia B and evidence of proteolysis. Author(s): Thompson AR. Source: Blood. 1984 October; 64(4): 867-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6478059&dopt=Abstract
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Failure in oral treatment of hemophilia by Huang-lien-chieh-tu-tang (plant extract), one of the kanpo medicines. Author(s): Brochier G, Bosser C, Noel L. Source: Haemostasis. 1984; 14(6): 508-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6534822&dopt=Abstract
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Hemophilia and AIDS: dealing with nurse burnout. Author(s): Bolivar E.
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Source: Caring. 1991 July; 10(7): 50-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10183513&dopt=Abstract •
Hemophilia in classic rabbinic texts. Author(s): Rosner F. Source: Journal of the History of Medicine and Allied Sciences. 1994 April; 49(2): 240-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8034967&dopt=Abstract
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Hemophilia in context: adjunctive hypnosis for families with a hemophiliac member. Author(s): Ritterman MK. Source: Family Process. 1982 December; 21(4): 469-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7160463&dopt=Abstract
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Hemophilia in the Talmud and rabbinic writings. Author(s): Rosner F. Source: Annals of Internal Medicine. 1969 April; 70(4): 833-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4890512&dopt=Abstract
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Hemophilia: a story of success--disaster and the perseverance of the human spirit, Part 2. Author(s): Dubin CS. Source: The Journal of the Association of Nurses in Aids Care : Janac. 1999 July-August; 10(4): 88-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10394564&dopt=Abstract
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High prevalence of GB virus C strains genetically related to strains with Asian origin in Nicaraguan hemophiliacs. Author(s): Gonzalez-Perez MA, Norder H, Bergstrom A, Lopez E, Visona KA, Magnius LO. Source: Journal of Medical Virology. 1997 June; 52(2): 149-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9179760&dopt=Abstract
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Holistic care for children with hemophilia. Author(s): Cogliano J. Source: Nurs Spectr (Wash D C). 1998 March 23; 8(6): 8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10542647&dopt=Abstract
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Hypnosis and stress in hemophilia. Author(s): Lucas ON. Source: Bibl Haematol. 1970; 34: 73-82. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5309421&dopt=Abstract
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Hypnosis for hemophiliacs: methodologic problems and risks. Author(s): LeBaron S, Zeltzer L. Source: Am J Pediatr Hematol Oncol. 1985 Fall; 7(3): 316-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2416232&dopt=Abstract
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Hypnosis for patients with hemophilia. Author(s): Newman M. Source: The Journal of the American Dental Association. 1978 July; 97(1): 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=277567&dopt=Abstract
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Hypnosis may reduce hemophiliacs' blood needs. Author(s): Martin J. Source: Jama : the Journal of the American Medical Association. 1983 October 14; 250(14): 1814-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6620471&dopt=Abstract
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Management and surveillance of the hemophiliacs at the National Institute of Hematology and Blood Transfusion of Vietnam. Author(s): Bach QT, Colab. Source: Southeast Asian J Trop Med Public Health. 1993; 24 Suppl 1: 113-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7886550&dopt=Abstract
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Management of tooth extractions in hemophiliacs by the combined use of hypnotic suggestion, protective splints and packing of sockets. Author(s): LUCAS ON, FINKELMAN A, TOCANTINS LM. Source: J Oral Surg Anesth Hosp Dent Serv. 1962 November; 20: 488-500. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13931407&dopt=Abstract
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Oral treatment of hemophilia A using traditional kanpo medicine, Huang-lien-chiehtu-tang (plant extract). Author(s): Adachihara A. Source: Haemostasis. 1983; 13(2): 78-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6409712&dopt=Abstract
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Orthopaedic and other surgical aspects of hemophilia. Introduction of topic. Author(s): Jordan HH. Source: Bibl Haematol. 1970; 34: 159-61. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5436342&dopt=Abstract
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Peripheral nerve complications in hemophilia. Author(s): Saraf SK, Singh OP, Singh VP.
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Source: J Assoc Physicians India. 2003 February; 51: 167-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725260&dopt=Abstract •
Progressive versus self-control relaxation to reduce spontaneous bleeding in hemophiliacs. Author(s): Lichstein KL, Eakin TL. Source: Journal of Behavioral Medicine. 1985 June; 8(2): 149-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3897550&dopt=Abstract
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Psychological factors in hemophilia--the concept of self care. Author(s): Agle D. Source: Annals of the New York Academy of Sciences. 1975 January 20; 240: 221-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1053867&dopt=Abstract
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Research on hypnosis in hemophilia--preliminary success and problems: a brief communication. Author(s): LeBaron S, Zeltzer LK. Source: Int J Clin Exp Hypn. 1984 July; 32(3): 290-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6490216&dopt=Abstract
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Successful surgical removal of a large arteriovenous malformation in a patient with hemophilia: case report. Author(s): Nakau H, Maruishi M, Takiguchi H, Shima K. Source: Neurosurgery. 1998 December; 43(6): 1459-61; Discussion 1461-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9848861&dopt=Abstract
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Surveillance and care of four Chinese hemophiliacs with human immunodeficiency virus (HIV) infection. Author(s): Tang D, Qu G, Pang X, Lang Y, Liang Y, Yu Y, Zeng Y, Shao Y. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 1993 March; 8(1): 41-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8274721&dopt=Abstract
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Telephone support group intervention for persons with hemophilia and HIV/AIDS and family caregivers. Author(s): Stewart MJ, Hart G, Mann K, Jackson S, Langille L, Reidy M. Source: International Journal of Nursing Studies. 2001 April; 38(2): 209-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11223062&dopt=Abstract
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The effects of a comprehensive self-hypnosis training program on the use of factor VIII in severe hemophilia. Author(s): Swirsky-Sacchetti T, Margolis CG.
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Source: Int J Clin Exp Hypn. 1986 April; 34(2): 71-83. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3084393&dopt=Abstract •
The lack of antiplatelet effect of crude extracts from ganoderma lucidum on HIVpositive hemophiliacs. Author(s): Gau JP, Lin CK, Lee SS, Wang SR. Source: The American Journal of Chinese Medicine. 1990; 18(3-4): 175-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2270852&dopt=Abstract
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The Missouri Hemophilia Program. Utilizing consumer involvement in the delivery of comprehensive public health services. Author(s): Wilson RB. Source: Mo Med. 1984 March; 81(3): 130-2, 135. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6708925&dopt=Abstract
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The use of hypnosis in hemophilia dental care. Author(s): Lucas ON. Source: Annals of the New York Academy of Sciences. 1975 January 20; 240: 263-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1078618&dopt=Abstract
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The use of hypnosis with hemophilia. Author(s): LaBaw W. Source: Psychiatr Med. 1992; 10(4): 89-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1289965&dopt=Abstract
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Update on the use of orthotics in hemophilia. Author(s): Heim M, Steinbach T. Source: Orthop Rev. 1988 October; 17(10): 975-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3054732&dopt=Abstract
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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WebMD®Health: 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 hemophilia; 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 Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Bruising Source: Healthnotes, Inc.; www.healthnotes.com Capillary Fragility Source: Healthnotes, Inc.; www.healthnotes.com Cyclic Mastalgia Alternative names: Cyclic Mastitis, Fibrocystic Breast Disease Source: Prima Communications, Inc.www.personalhealthzone.com Hemophilia Source: Integrative Medicine Communications; www.drkoop.com
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Herbs and Supplements Glycyrrhiza Glabra Source: Integrative Medicine Communications; www.drkoop.com Glycyrrhiza1 Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Licorice Alternative names: Glycyrrhiza glabra, Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com Origanum Alternative names: Oregano; Origanum vulgare Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com Willow Bark Alternative names: There are several species of willow includingSalix alba, Salix nigra, Salix fragilis, Salix purpurea, Salix babylonica, White Willow, European Willow, Black Willow, Pussy Willow, Crack Willow, Purple Willow, Weeping Willow, Liu-zhi Source: Integrative Medicine Communications; www.drkoop.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 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 HEMOPHILIA Overview In this chapter, we will give you a bibliography on recent dissertations relating to hemophilia. 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 “hemophilia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hemophilia, we have not necessarily excluded nonmedical dissertations in this bibliography.
Dissertations on Hemophilia 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 hemophilia. 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: •
Acute and Chronic Pain in Hemophilia Characteristic Pain Patterns and Coping Strategies by Choiniere, Manon; PhD from McGill University (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL31369
•
Impact of Hemophilia on the Father by Fung, Elizabeth Han, PhD from Institute for Clinical Social Work (Chicago), 1997, 140 pages http://wwwlib.umi.com/dissertations/fullcit/9724508
•
Normality Within Limits: Hemophilia, the Citizen-patient, and the Risks of Medical Management in the United States of America, from World War Ii to the Age of Aids (immune Deficiency) by Pemberton, Stephen Gregory; PhD from the University of North Carolina at Chapel Hill, 2001, 317 pages http://wwwlib.umi.com/dissertations/fullcit/3031893
•
Social Interactions in Growing Up with Hemophilia: Developmental Milestones and Associated Risks (chronic Illness, Illness As Identity, Childhood Illness, Self-care,
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Family Interaction) by Oremland, Evelyn K., PhD from University of California, San Francisco, 1985, 270 pages http://wwwlib.umi.com/dissertations/fullcit/8513662 •
The Development and Evaluation of a Handbook on Hemophilia and Von Willebrand Disease by O'Rourke, Serena Marie; MPH from California State University, Fresno, 2002, 133 pages http://wwwlib.umi.com/dissertations/fullcit/1412221
•
The Relationship between Sex, Hiv Status, Patient Status, and Knowledge, Attitudes, and Behavior Concerning Aids in a Hemophilia Population (immune Deficiency) by Chiampi, Sandra Ann, PhD from University of Missouri - Columbia, 1992, 112 pages http://wwwlib.umi.com/dissertations/fullcit/9400012
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 HEMOPHILIA Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning hemophilia.
Recent Trials on Hemophilia The following is a list of recent trials dedicated to hemophilia.8 Further information on a trial is available at the Web site indicated. •
Severe Hemophilia A Study Condition(s): Hemophilia A Study Status: This study is currently recruiting patients. Sponsor(s): Wyeth-Ayerst Research Purpose - Excerpt: To characterize the safety and efficacy of ReFacto AF in treating acute bleeding episodes during prophylaxis treatment, including neoantigenicity. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037544
•
Severe Hemophilia B Study Condition(s): Hemophilia B Study Status: This study is currently recruiting patients. Sponsor(s): Wyeth-Ayerst Research Purpose - Excerpt: To characterize the safety and efficacy of rFIX in children less than 6 years of age with severe hemophilia B in the setting of acute bleeding episodes, prophylaxis, and/or surgery.
8
These are listed at www.ClinicalTrials.gov.
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Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037557
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 “hemophilia” (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/
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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html
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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/
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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm
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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
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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
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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
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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm
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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/
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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
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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
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CHAPTER 6. PATENTS ON HEMOPHILIA 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 “hemophilia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hemophilia, we have not necessarily excluded nonmedical patents in this bibliography.
Patents on Hemophilia By performing a patent search focusing on hemophilia, 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 hemophilia: •
Activated factor VIII as a therapeutic agent and method of treating factor VIII deficiency Inventor(s): Curtis; Joseph E. (Glendora, CA), Helgerson; Sam L. (Pasadena, CA), Liu; Shu-Len (Cerritos, CA), Lundblad; Roger L. (Chapel Hill, NC) Assignee(s): Baxter International Inc. (Deerfield, IL) Patent Number: 5,576,291 Date filed: September 13, 1993 Abstract: Stabilized and activated Factor VIII is used as a therapeutic agent to treat patients with a Factor VIII deficiency. This includes hemophilia A patients as well as patients with Factor VIII inhibitors which block the hemostatic activity of Factor VIII. The stabilized and activated Factor VIII is also prepared in a therapeutic composition with a therapeutically acceptable adjuvant. Excerpt(s): This invention relates to a method of using activated Factor VIII as a therapeutic agent for patients having a deficiency of Factor VIII available for producing hemostasis. The invention also relates to a therapeutic composition containing activated Factor VIII. Hemophilia A is an X chromosome-linked congenital disorder caused by the lack of the biologically active coagulation protein Factor VIII. This congenital deficiency has been successfully treated by infusions of Factor VIII concentrate preparations isolated and purified from either blood plasma of donors having normal levels of Factor VIII, or cell cultures genetically engineered to express the Factor VIII coagulant protein. While this replacement therapy is effective in controlling bleeding episodes caused by the Factor VIII congenital disorder, approximately 15% of the hemophilia A patients treated in this manner develop inhibitors to Factor VIII after repeated infusions with Factor VIII concentrates. Patients who develop Factor VIII inhibitors, hereinafter inhibitor patients, become resistant to ordinary Factor VIII replacement therapy in varying degrees depending upon the quantity of inhibitors which are present in the patient's blood. Development of an inhibitor is suspected when the bleeding episode fails to respond to a previously adequate dose of Factor VIII concentrate. Inhibitors are currently believed to be antibodies which bind to the Factor VIII and diminish or destroy hemostatic function. Inhibitors to Factor VIII have also been observed in nonhemophiliacs who have normal levels of Factor VIII in their blood, although the incidence is far less common than in hemophiliacs. Patients with Factor VIII inhibitors are treated to correct hemostasis by a number of therapeutic approaches but these have generally been less than fully satisfactory. Prothrombin complex concentrates and their activated forms have been shown to be effective in treating some Factor VIII inhibitor patients, but allergic and thrombogenic responses have been reported. Activated coagulation factors not present in a complex of Factors II, VII, IX and X such as activated Factor VII; activated Factor X combined with phospholipids; and human recombinant tissue factor are currently being evaluated as other means for treatment of inhibitor patients. Web site: http://www.delphion.com/details?pn=US05576291__
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•
Agent for the therapy of factor VIII-resistant hemophilia A, and a process for the preparation thereof Inventor(s): Heimburger; Norbert (Marburg, DE), Wenz; Karlheinz (Weimar, DE), Wormsbacher; Wilfried (Kirchhain, DE) Assignee(s): Behringwerke Aktiengesellschaft (Marburg/Lahn, DE) Patent Number: 5,091,363 Date filed: August 10, 1988 Abstract: An agent for the therapy of hemophilia A which is resistant to treatment with factor VIII is described, and is obtainable by maintaining a mixture of factor VIII, antithrombin III, a phospholipid and calcium ions in an aqueous solution at a temperature of from 1.degree. to 45.degree. C. for at least one minute, adding factor IX, and maintaining the solution at a temperature offrom 1.degree. to 45.degree. C. until addition of a sample of this solution to an inhibitor plasma results in a partial thromboplastin time (PTT) of 15 to 30 seconds, where appropriate adding a polyol and, where appropriate, an amino acid, and, where appropriate, drying the solution. Excerpt(s): The invention relates to an agent for the treatment of patients who have hemophilia A and do not respond to the conventional treatment with factor VIII, and to a process for the preparation thereof. Up to about one quarter of patients who have hemophilia A and are treated with factor VIII concentrates develop what are called inhibitor hemophilias. It is characteristic of these that non-precipitating isoantibodies against the subunit of the factor VIII molecule which harbors the clotting activity (F VIII:C) circulate in the blood of the patient. These antibodies, which are found in titers which may reach very high levels, namely from 100 up to a few 1000 U/ml, in the plasma of hemophiliacs, neutralize corresponding activities of F VIII when they are infused for replacement in patients who do not synthesize factor VIII or synthesize it in inadequate amounts. The amount of inhibiting antibodies is often so high that even administration of large amounts of factor VIII do not result in successful therapy. A number of measures have been tried for the treatment of the serious hemorrhages which often occur in patients who have hemophilia A and have developed antibodies, but these measures have been only partially successful. These measures include infusion of prothrombin complex concentrates (PCC) which contain factors II, VII, IX and X. In emergency situations there has even been use of factor VIII from animal plasma, predominantly from bovine or porcine plasma, with acceptance of the risk of administration of foreign protein. In recent times, activated coagulation factors have also been used with a certain success. Web site: http://www.delphion.com/details?pn=US05091363__
•
Agents affecting thrombosis and hemostasis Inventor(s): Sinha; Uma (San Francisco, CA), Wolf; David L. (Palo Alto, CA) Assignee(s): COR Therapeutics Inc. (South San Francisco, CA) Patent Number: 5,990,079 Date filed: January 30, 1998 Abstract: Analogs of blood factors which are transiently inactive are useful in treatment of diseases characterized by thrombosis. In addition, modified forms of activated blood factors that generate the active blood factor in serum but have extended half-lives are
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useful in treating hemophilia conditions. These modified forms of the blood factor may be acylated forms which are slowly deacylated in vivo. Excerpt(s): The invention relates to peptide drugs for regulation of hemostatic and thrombotic processes. The invention also concerns coagulation factors whose protease or enzymatic activity has been transiently inactivated. Hemostasis, the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation. This invention is particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption. After initiation of clotting, blood coagulation proceeds through the sequential activation of certain plasma proenzymes to their enzyme forms. These plasma glycoproteins, including Factor XII, Factor XI, Factor IX, Factor X, Factor VII, and prothrombin, are zymogens of serine proteases. Most of these blood clotting enzymes are effective on a physiological scale only when assembled in complexes on membrane surfaces with protein cofactors such as Factor VIII and Factor V. Other blood factors modulate and localize clot formation, or dissolve blood clots. Activated protein C is a specific enzyme that inactivates procoagulant components. Calcium ions are involved in many of the component reactions. Blood coagulation follows either the intrinsic pathway, where all of the protein components are present in blood, or the extrinsic pathway, where the cellmembrane protein tissue factor plays a critical role. Clot formation occurs when fibrinogen is cleaved by thrombin to form fibrin. Blood clots are composed of activated platelets and fibrin. Thrombin is a multifunctional protease that regulates several key biological processes. For example thrombin is among the most potent of the known platelet activators. In addition, as described above, thrombin is essential for the cleavage of fibrinogen to fibrin to initiate clot formation. These two elements are involved in normal hemostasis but in atherosclerotic arteries can initiate the formation of a thrombus, which is a major factor in pathogenesis of vasoocclusive conditions such as myocardial infarction, unstable angina, nonhemorrhagic stroke and reocclusion of coronary arteries after angioplasty or thrombolytic therapy. Thrombin is also a potent inducer of smooth cell proliferation and may therefore be involved in a variety of proliferative responses such as restenosis after angioplasty and graft induced atherosclerosis. In addition, thrombin is chemotactic for leukocytes and may therefore play a role in inflammation. (Hoover, R. J., et al. Cell (1978) 14:423; Etingin, O. R., et al., Cell (1990) 61:657.) These observations indicate that inhibition of thrombin formation or inhibition of thrombin itself may be effective in preventing or treating thrombosis, limiting restenosis and controlling inflammation. Web site: http://www.delphion.com/details?pn=US05990079__ •
Biologically active fragments of human antihemophilic factor and method for preparation thereof Inventor(s): Andersson; Lars-Olof (Knivsta, SE), Forsman; Nanna (Jarfalla, SE), Larsen; Kerstin E. I. (Lidingo, SE), Lundin; Annelie B. (Stockholm, SE), Pavlu; Bohdan (Huddinge, SE), Sandberg; Inga H. (Sp.ang.nga, SE), Sewerin; Karin M. (Bromma, SE) Assignee(s): KabiVitrum AB (Stockholm, SE) Patent Number: 4,749,780 Date filed: March 4, 1986
Patents 143
Abstract: Novel, biologically active fragments of human antihemophilic factor, processes for their preparation, pharmaceutical preparations containing them and the use of such fragments in the treatment of patients suffering from hemophilia. Excerpt(s): The present invention relates to novel, biologically active fragments of human antihemophilic factor, processes for their preparation, pharmaceutical preparations containing them and the use of such fragments in the treatment of patients suffering from hemophilia. Hemophilia is an inherited disease which has been known for centuries but it is only within the last three decades that it has been possible to differentiate between the various forms; hemophilia A, hemophilia B and hemophilia C. Hemophilia A is the most frequent and affects only males in frequency of one or two individuals per 10,000 males. The disease is caused by strongly decreased level or absence of biologically active coagulation factor VIII or as it also has been called the antihemophilic factor. Factor VIII is a protein normally present in plasma. The clinical manifestation of hemophilia A is a strong bleeding tendency and before treatment with Factor VIII concentrates was introduced the mean age of death of hemophiliacs was less than 20 years. Concentrates of Factor VIII obtained from plasma has been available for treatment of hemophilia A for about two decades. This has improved the situation for hemophilia patients considerably and given most of them possibility to live a normal life. However, there are certain problems with the concentrates and their use. The concentrates presently available are rather impure having a specific activity of less than 2 units Factor VIII/mg protein and containing <1% of Factor VIII protein. Further they are fairly expensive because the starting material, plasma, is expensive and the yields in the purification processes used are low with the low purity products. There is also the risk for transmittance of hepatitis B virus and other infective agents. Finally, about one tenth of the patients with severe hemophilia A do develop antibodies against Factor VIII and then become very difficult to treat as the injected Factor VIII is neutralized and inhibited by the antibodies. J. Toole et al. Nature 312, 342-347, 1984), intact Factor VIII can be made in cell culture using recombinant DNA techniques. An additional advantage with active fragments of Factor VIII is that such fragments can probably be made more easily and efficiently by the recombinant DNA cell culture techniques than the whole Factor VIII molecule as they are smaller and can therefore be regarded as especially advantageous to produce by this technique. Web site: http://www.delphion.com/details?pn=US04749780__ •
Blood coagulation promoting product Inventor(s): Mitra; Gautam (Kensington, CA) Assignee(s): Cutter Laboratories, Inc. (Berkeley, CA) Patent Number: 4,404,132 Date filed: February 5, 1982 Abstract: This disclosure pertains to a concentrate for controlling bleeding in hemophilia, free of thrombin, heparin, thromboplastin activity, anticomplement activity, depressor activity, and activated Factor X, and containing coagulation Factors II, VII, IX, and X in non-activated form and containing no greater amounts of calciumactivated factors and Factor VIII Inhibitor Bypassing Activity substance than that found in concentrates of Factor II, VII, IX, and XI that have not been treated, respectively, with calcium or a material which would produce a Factor VIII Inhibitor Bypassing Activity substance in such concentrates and having a specific activity of at least about 1.5 Factor IX units per milligram of total protein and a Factor IX:Factor VII ratio of at least about
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6:1, a Factor IX:Factor II ratio of about 1:1 to 2:1, and a Factor IX:NAPTT ratio of at least about 5:1 on a Units per milliliter basis, a Factor II Specific Activity of about 1.0-4.0 Units per milligram of total protein, and a Factor IX:ceruloplasmin ratio of at least about 25:1. In the method of the invention a blood fraction containing coagulation Factors II, VII, IX, and X is applied to an anion exchanger to adsorb the coagulation Factors, which are selectively eluted therefrom using an aqueous sodium chloride-citrate solution of increasing ionic strength. The eluate is treated to reduce its concentration of non-volatile salt and concentrated to yield the above product. Excerpt(s): This invention relates to and has among its objects the provision of novel blood coagulation components and novel methods of making them. Further objects of the invention will be evident from the following description. There are estimated to be 100,000 cases of congenital hemophilia in the United States. Of these, approximately 20,000 are cases of hemophilia B, the blood of such patients being either totally devoid of plasma thromboplastin component or seriously deficient in plasma thrombopolastin component. The disease therefore exists in varying degrees of severity, requiring therapy anywhere from every week up to once or twice a year. The completely deficient cases require replacement therapy once every week; the partially deficient cases require therapy only when bleeding episodes occur, which may be as seldom as once a year. The bleeding episodes in congenital, partially-deficient cases are generally caused by a temporarily acquired susceptibility rather than by injury alone. Intravenous injection of a sufficiently large amount of fresh plasma, or an equivalent amount of fresh blood, temporarily corrects the defect of a deficient subject. The beneficial effect often lasts for two or three weeks, although the coagulation defect as measured by in-vitro tests on the patient's blood appears improved for only two or three days. Such therapy with fresh plasma or fresh blood is effective but it has several serious drawbacks: (1) it requires ready availability of a large amount of fresh plasma; (2) requires hospitalization for the administration of the plasma; (3) a great many of the patients become sensitized to repeated blood or plasma infusions and ultimately encounter fatal transfusion reactions; (4) at best plasma can only partially alleviate the deficiency; and (5) prolonged treatment or surgery is not possible because the large amounts of blood or plasma which are required will cause acute and fatal edema. Several investigators noted that the mixing of blood of certain hemophilic patients would result in the mutual correction of the clotting defect of each blood. Interpretation of these findings was eventually made by Aggeler and co-workers [Proc. Soc. Exptl. Biol. Med. 79:692-696 (1952)] and S. G. White et al. [Blood 8:101-124 (1953)]. These workers, studying a male patient with a severe hemorrahagic diathesis associated with a prolonged clotting time which was clinically indistinguishable from classic hemophilia, postulated the existence of a new clotting factor. Aggelar et al., recognizing that the new factor was a precursor of thromboplastin, named it Plasma Thromboplastin Component (PTC). The work was confirmed by Biggs et al. [Brit. Med. J. 2:1378-1382 (1952)] in England, who gave it the name Christmas Factor, and by Soulier and Larrieu [New Eng. J. Med. 249:547-553 (1953)] in France, who called it Antihemophilic Factor B. This factor is now officially designated Factor IX. Web site: http://www.delphion.com/details?pn=US04404132__
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•
Chimeric procoagulant proteins Inventor(s): Kaufman; Randal J. (Boston, MA), Pittman; Debra (Windham, NH), Rehemtulla; Alnawaz (Ann Arbor, MI), Wozney; John M. (Hudson, MA) Assignee(s): Genetics Institute, Inc. (Cambridge, MA) Patent Number: 5,563,045 Date filed: September 14, 1993 Abstract: Provided are porcine factor VIII nucleotide sequences and hybrid sequences encoding human/porcine chimeric factor VIII-type procoagulant proteins. DNAs encoding such chimeric factor VIII-type procoagulant proteins, pharmaceutical compositions containing such chimeric factor VIII-type procoagulant proteins, and methods of treating hemophilia using such chimeric factor VIII-type procoagulant proteins are also provided. Excerpt(s): The present invention relates generally to chimeric procoagulant proteins, to porcine factor VIII nucleotide sequences, and to hybrid sequences encoding human/porcine chimeric factor VIII-type activity. Factor VIII is a protein involved in clotting blood and plays a critical role in hemostasis. The lack of factor VIII leads to the bleeding disorder hemophilia A. Hemostasis is maintained by an intricate and complex regulation of both coagulation and anti-coagulation pathways in the blood. The clotting cascade begins when cell damage activates the enzyme factor XII and ends when soluble fibrinogen is converted into fibrin by thrombin. The pathway involves the interaction of many proteolytic enzymes, e.g., factors XII, XI, IX, X and prothrombin, as well as numerous co-factors such as factors VIII and V. Once coagulation is initiated, the response is amplified by a cascade of protease activation steps that occur on the surface of endothelial cells and platelets. At each step an inactive protein is converted into a protease which in turn activates the next protein in the pathway. The cascade includes both positive-feedback and negative-feedback loops. The clotting pathway eventually leads to the formation of insoluble fibrin which, together with platelets, obscures blood flow at the site of tissue damage. Certain steps of the pathway are accelerated by cofactors, such as factors VIII and V. Approximately 85 percent of hemophiliacs lack factor VIII; the remainder lack factor IX. Thrombin not only activates factors VIII and V, but it also can deactivate them, i.e., by activating protein C. The exact mechanisms by which the levels and activities of active factor VIII are controlled are still not completely understood. Web site: http://www.delphion.com/details?pn=US05563045__
•
Composition for controlling hemophilia in mammals Inventor(s): Giles; Alan R. (Kingston, CA), Mann; Kenneth G. (Rochester, MN) Assignee(s): Queen's University at Kingston (Kingston, CA) Patent Number: 4,610,880 Date filed: February 6, 1985 Abstract: A composition of matter for controlling Hemophilia A (Antihemophilic Factor (F. VIII:C) deficiency) in mammals is described. Factor VIII:C deficiency in the mammal is bypassed by infusion of a synergistic mixture of a phospholipid and Factor Xa so that the cascade process of blood clotting may continue. The proportions of phospholipid
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and Factor Xa in the mixture are critical as too little Xa has no effect while too much is toxic (thrombogenic). Excerpt(s): This invention relates to the control of hemophilic bleeding in mammals. More particularly this invention relates to the therapeutic treatment of Factor VIII:C deficient patients by means of a Factor VIII:C bypass technique using a synergistic mixture of phospholipids with Factor Xa. Classic Hemophilia A is a sex-linked recessive inherited disorder of the blood where the activity of a specific coagulation factor (protein), required for the cascade or chain process for blood coagulation, is either reduced or absent. Hemophilia afflicts about 1 in 10,000 of the male population. This produces a severe bleeding disorder and constitutes the most frequently clinically encountered congenital coagulation disorder. Since about 1965 the prognosis of affected individuals has considerably improved due to the availability of specific clotting factor replacement products derived from the blood of normal donors which can be transfused. These products contain the most usually absent factor, Factor VIII in a concentrated form. Unfortunately, however, approximately 10% of all treated hemophiliacs develop antibodies to the transfused Factor VIII:C and become untreatable by this means. It is an aim of the present invention to provide a method for the treatment and management of such antibody sensitized hemophiliacs. Heretofore hemophiliacs with antibodies to F. VIII:C have been managed by various therapies none of which are satisfactory. The use of immunosuppressive therapy is not entirely satisfactory and is associated with increased morbidity. The use of Factor VIII:C derived from other species, i.e. porcine or bovine, has been shown to be an effective replacement but may be associated with major side effects due to the development of heterologous antibodies. Recently considerable interest has been shown in using prothrombin complex concentrates (PCC). As explained in more detail hereinafter, blood coagulation proceeds by a series or cascade of activation steps where circulating inactive clotting factors (zymogens) are converted to proteolytic enzymes. The final product of the cascade is thrombin (IIa) which converts the sol protein, fibrinogen, to its gel form, fibrin. Recent work has demonstrated that Factor VIII:C is not a proteolytic enzyme but a potent co-factor of the activation step whereby Factor IXa activates Factor X to Xa. In classic Hemophilia A, this co-factor activity is reduced or missing so that insignificant activation of Factor X takes place despite all other clotting factors being present at normal levels. As noted above, transfusion of Factor VIII:C concentrates can correct this abnormality and similar concentrates have been developed for the congenital deficiency of Factor IX. These concentrates differ from those of Factor VIII:C in containing significant quantities of other clotting factors namely X, VII and II (prothrombin). Moreover, it is the rule that all concentrates contain trace contaminents of the activated products of these clotting factors, namely IXa, Xa, VIIa and IIa (thrombin). It will be noted that, with the exception of Factor IX, the remaining three clotting factors are placed in the cascade below the critically important Factor VIII:C-dependent step. It has been postulated, that these concentrates, by providing pre-formed activated products, may achieve Factor VIII:C bypassing activity (FEBA) in hemophiliacs where Factor VIII:C replacement is precluded by the development of antibodies to this clotting factor. Initial anecdotal clinical reports were promising but by no means unanimous. This lack of unanimity related to the uncertainty as to which, if any, of the component clotting factors were the most critical. The products used are of two types. The first are known as "unactivated" PCC and are products that have been developed specifically to replace deficiencies of the clotting factors that they contain. In such patients, it is considered undesirable to infuse preactivated clotting factors because of concern for thromboembolic side effects. Therefore, attempts are made, in the fractionation process, to minimize the activated clotting factor content although all products contain some. As
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it was the activated clotting factor content that was considered to be the putative agent(s) in the treatment of hemophiliacs with inhibitors, some manufacturers have deliberately activated the PCC preparations for this purpose. These are known as "activated" PCC. Recent clinical trials have confirmed the benefit of the use of nonactivated PCC as compared with placebo but the response was less than optimal in comparison to that which would be expected from conventional Factor VIII:C replacement in hemophiliacs without inhibitors. A similar study compared treatment with an unactivated PCC with an activated PCC prepared by the same manufacturer. There appeared to be a marginal benefit in favour of the activated preparation. Despite this, the response remained suboptimal and the absence of any clear indication as to the specific constituent of the preparation responsible for the effect seen, it is impossible to ensure inter-batch reproducibility of individual production lots of apparently the same product. As a result, there is still not universal agreement as to the validity of this approach. Web site: http://www.delphion.com/details?pn=US04610880__ •
Conjugates of a polypeptide and a biocompatible polymer Inventor(s): Dalborg; Johanna (Stockholm, SE), kerblom; Eva (Uppsala, SE), Sandberg; Helena (Bromma, SE), Smeds; Anna-Lisa (Sollentuna, SE) Assignee(s): Pharmacia & Upjohn AB (Stockholm, SE) Patent Number: 6,048,720 Date filed: May 21, 1998 Abstract: Processes for improving the in vivo function of factor VIII by shielding exposed targets of the factor VIII comprise a) immobilizing the factor VIII by interaction with a group-specific adsorbent carrying ligands manufactured by organic-chemical synthesis, for preventing polymer coupling to reactive amino acids of the immobilized factor VIII, within or adjacent to interaction domains; b) activating a biocompatible polymer; c) conjugating the activated biocompatible polymer to external sites of the immobilized factor VIII; and thereafter d) eluting the conjugate from the adsorbent. Processes for administering factor VIII comprise subcutaneously, intramuscularly, intradermally or intravenously administering a conjugate of factor VIII and a biocompatible polymer, and methods for treatment of hemophilia A comprise subcutaneous, intramuscular, intradermal or intravenous administration of a conjugate of factor VIII and a biocompatible polymer. Excerpt(s): The present invention relates to a process for improving the in-vivo function of a polypeptide by shielding exposed targets of said polypeptide, by immobilizing the polypeptide to a group-specific adsorbent carrying ligands manufactured by organicchemical synthesis, activating the biocompatible polymer, conjugating the thus activated biocompatible polymer to the immobilized polypeptide, and thereafter eluting the conjugate from the adsorbent. The present invention further relates to conjugates of a polypeptide and a biocompatible polymer obtainable by the present process, and use of said conjugates as medicaments. Specifically, the polypeptide is factor VIII, the von Willebrand factor or factor IX. The invention is particularly advantageous for conjugates where the polypeptide is factor VIII with a high specific activity using monomethoxy polyalkyleneoxide (mPEG) as the biocompatible polymer. It is well known, that the invitro stability and in-vivo half-life of polypeptides can be increased by covalent attachment of biocompatible polymers (in the following referred to as conjugation or modification). Modification of the polypeptide surface also has the advantage of
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decreasing the immunogenicity exhibited by the polypeptide. Pegylation, i.e. coupling of various polyethyleneglycols (PEG) to a polypeptide, is a technique widely used for increasing the in-vitro stability and in-vivo half-life of e.g. proteins. In pegylation, many techniques have been proposed over the years. Reference is here made to Zalipsky, S. et al in Poly(Ethylene Glycol) Chemistry, Biotechnical and Biomedical Applications, Plenum, N.Y. (1992), and Katre N. V., Adv. Drug Deliv. Rev., 10 91-114 (1993). Web site: http://www.delphion.com/details?pn=US06048720__ •
Expression of active human factor IX in mammary tissue and of milk non human transgenic mammals Inventor(s): Drohan; William N. (Springfield, VA), Johnson; John L. (late of Blacksburg, VA), Lubon; Henryk (Rockville, MD), Velander; William H. (Blacksburg, VA) Assignee(s): American Red Cross (Rockville, MD), Virginia Tech Intellectual Properties, Inc. (Blacksburg, VA) Patent Number: 6,344,596 Date filed: September 15, 1999 Abstract: Recombinant Factor IX characterized by a high percentage of active protein can be obtained in the milk of transgenic animals that incorporate chimeric DNA molecules according to the present invention. Transgenic animals of the present invention are produced by introducing into developing embryos DNA that encodes Factor IX, such that the foreign DNA is stably incorporated in the DNA of germ line cells of the mature animal. Particularly efficient expression was accomplished using a chimeric construct comprising a mammary gland specific promoter, Factor IX cDNA that lacked the complete or any portion of the 5'-untranslated and 3'-untranslated region, which is substituted with a 5'- and 3'-end of the mouse whey acidic protein gene. In vitro cell cultures of cells explanted from the transgenic mammal of the invention and methods of producing Factor IX from such said culture and methods of treating hemophilia B are also described. Excerpt(s): The present invention relates to the production of natural and modified forms of Factor IX. In particular, the invention relates to a transgenic animal containing, stably incorporated in its genomic DNA, an exogenous Factor IX gene that is expressed specifically in mammary tissue, such that Factor IX is secreted into milk produced by the animal. In particular, the invention relates to the production of human Factor IX in the milk of a transgenic non-human mammal using a DNA molecule that comprises a whey acidic protein promoter gene, 5' regulatory sequences containing the promoter, human Factor IX cDNA that lacks at least a portion of the complete or any portion of or the complete the 3'-untranslated region of the native human Factor IX gene, but contains the 5' and 3-untranslated region of the mouse whey acidic protein. gene. Human Factor IX, or "Christmas factor," is encoded by a single-copy gene residing on the X-chromosome at q27.1. For a review of Factor IX gene structure and expression, see High et al., "Factor IX," in MOLECULAR BASIS OF THROMBOSIS AND HEMOSTASIS, High (ed.), pages 215-237 (Dekker 1995); Kurachi et al., Thromb. Haemost. 73:333 (1995). The Factor IX gene is at least 34 kilobase (kb) pairs in size, and it is composed of eight exons. The major transcription start site of the Factor IX gene in human liver is located at about nucleotide-176. The human Factor IX mRNA is composed of 205 bases for the 5' untranslated region, 1383 bases for the prepro Factor IX, a stop codon and 1392 bases for the 3' untranslated region. Factor IX is synthesized as a prepropolypetide chain composed of three domains: a signal peptide of 29 amino acids, a propeptide of 17
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amino acids, which is required for.gamma.-carboxylation of glutamic acid residues, and a mature Factor IX protein of 415 amino acid residues. The Factor IX zymogen undergoes three types of post-translational modifications before it is secreted into the blood: a vitamin K-dependent conversion of glutamic acid residues to carboxyglutamic acids, addition of hydrocarbon chains, and.beta.-hydroxylation of an aspartic acid. Mature Factor IX protein contains 12.gamma.-carboxylated glutamic acid (Gla) residues. Due to the requirement of vitamin K by.gamma.-carboxylase, Factor IX is one of several vitamin K-dependent blood coagulation factors. Web site: http://www.delphion.com/details?pn=US06344596__ •
Hepatocellular chimeraplasty Inventor(s): Bandyopadhyay; Paramita (Minneapolis, MN), Kren; Betsy T. (Minneapolis, MN), Roy-Chowdhury; Jayanta (New Rochelle, NY), Steer; Clifford J. (St. Paul, MN) Assignee(s): Regents of the University of Minnesota (Minneapolis, MN), Yeshiva University (Bronx, NY) Patent Number: 6,524,613 Date filed: June 30, 1998 Abstract: The present invention concerns compositions and methods for the introduction of specific genetic changes in endogenous genes of the cells of an animal. The genetic changes are effected by oligonucleotides or oligonucleotide derivatives and analogs, which are generally less than about 100 nucleotides in length. The invention provides for macromolecular carriers, optionally incorporating ligands for clathrin coated pit receptors. In one embodiment the ligand is a lactose or galactose and the genetic changes are made in hepatocytes. By means of the invention up to 40% of the copies of a target gene have been changed in vitro. Repair of mutant genes having a Crigler-Najjar like phenotype and Hemophilia B phenotype were observed. Excerpt(s): The inclusion of a publication or patent application in this specification is not an admission that the publication or the invention, if any, of the application occurred prior to the present invention or resulted from the conception of a person other than the present inventors. The published examples of recombinagenic oligonucleobases are termed Chimeric Mutational Vectors (CMV) or chimeraplasts because they contain both 2'-O-modified ribonucleotides and deoxyribonucleotides. An oligonucleotide having complementary deoxyribonucleotides and ribonucleotides and containing a sequence homologous to a fragment of the bacteriophage M13mp19, was described in Kmiec, E. B., et al., November 1994, Mol. and Cell. Biol. 14, 7163-7172. The oligonucleotide had a single contiguous segment of ribonucleotides. Kmiec et al. showed that the oligonucleotide was a substrate for the REC2 homologous pairing enzyme from Ustilago maydis. Web site: http://www.delphion.com/details?pn=US06524613__
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Isolation and culture of adrenal medullary endothelial cells producing blood clotting factor VIII:C Inventor(s): Banerjee; Dipak (Rockville, MD), Heldman; Eli (Rockville, MD), Lelkes; Peter (Rockville, MD), Ornberg; Richard (Bethesda, MD), Pollard; Harvey B. (Potomac, MD), Youdim; Moussa (Rockville, MD) Assignee(s): The United States of America as represented by the Secretary of the (Washington, DC) Patent Number: 4,670,394 Date filed: November 16, 1984 Abstract: The present invention discloses a new line of endothelial cell of adrenal medullary origin capable of producing blood clotting Factor VIII:C. A method of isolating and culturing said cell line has also been disclosed. Factor VIII:C is useful in treating hemophilia. Excerpt(s): The present invention is directed to isolation and culture of adrenal medullary endothelial cells. More particularly, the present invention is related to a method of isolating and culturing endothelial cells of adrenal medullary origin which produce blood clotting Factor VIII:C. Factor VIII is a blood protein and a component of the normal human blood. It is generally recognized that Factor VIII has at least three different functional sub units: (a) Factor VIII antigen (VIII AGN); (b) Blood clotting factor (VIII:C) that corrects the blood coagulation abnormality in classic hemophilia (hemophilia A) sometimes also designated as (VIII:AHF); and (c) von Willebrand Factor (VIII: vWF or VIII:R). As used herein the term Factor VIII is defined as and specifically refers to only VIII:C, the anti-haemophilic blood clotting factor and none other, except when otherwise noted. The significance of this blood clotting Factor VIII, of course, can be easily understood from the fact that its deficiency results in a bleeding disease commonly known as hemophilia. Blood clotting Factor VIII is, therefore, required for the treatment of hemophilia. Factor VIII: C is quite distinct from other blood protein components. As mentioned supra, Factor VIII deficiency is associated with classic hemophilia A and von Willebrand's disease. Without being bound to any theory, it is hypothesized that two separate proteins may be involved. One is FVIII/vWF protein which is a glycoprotein that is multimeric, with molecular weights ranging from 850,000 to 30 million. The second protein is a 200,000 MW glycoprotein noncovalently complexed to the FVIII/vWF protein. It has procoagulant activity, termed VIII:C. The function of FVIII/vWF is to promote adhesion of platelets with the collagen coat associated with endothelial cells. It is controlled by a gene on the X-chromosome. The drug ristocetin causes platelets to aggregate by interacting with FVIII/vWF protein attached to platelets. In this guise it is also called FVIII:R or FVIII:RCoF. "RCoF" stands for ristocetin cofactor. An additional function of FVIII:R (or FVIII/vWF) may be to stabilize circulating FVIII:C for elaboration of its activity. The antibody usually raised against crude Factor VIII preparations is against FVIII:R, also termed Factor VIII-related antigen in the immunologically oriented literature. The site of synthesis of these factors is still not precisely known. The protein that resembles FVIII:R (factor VIII-related antigen, FVIII/vWF) has been shown to be synthesized by endothelial cells. The procoagulant component of factor VIII comes from an yet unidentified source (Fundamentals of Clinical Hematology, ed. by J. L. Spivak, Harper and Row Publ., Philadelphia, 1984, pages 367-372). Web site: http://www.delphion.com/details?pn=US04670394__
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Method for controlling bleeding and microbial infections by administering thrombin, casein kinase II, and sphingosine Inventor(s): Han; Moon Hi (Taejon, KR), Kim; Seung-Ho (Taejon, KR), Lee; Jin Young (Kyungki-do, KR) Assignee(s): Korea Institute of Science Technology (Seoul, KR) Patent Number: 5,897,860 Date filed: September 30, 1996 Abstract: The present invention relates to a hemostatic composition comprising at least 0.1 NIH U/ml of thrombin, about 0.01 mU/ml of casein kinase II, and from 10 ng/ml to 100 ng/ml of sphingosine or a sphingosine derivative. The composition is effective in treating patients suffering from hemophilia, ulcers, or microbial infections. In addition, the composition is effective in reducing clotting time during the surgical procedure of suturing blood vessels. Excerpt(s): The present invention is related to a novel hemostatic composition. More specifically, the present invention is related to a hemostatic composition comprising thrombin, casein kinase II, and sphingosine or a sphingosine derivative and providing rapid clotting and hemostasis. Hemostasis involves three complex mechanisms: clot formation, rapid constriction of the injured blood vessel and the aggregation of platelets to form a plug on the injured surface of the blood vessel. A clot is formed by a series of transformations involving more than ten different proteins, calcium ion (Ca2+) and thromboplastin. When bleeding occurs, fibrinogen, which is highly soluble, is converted into insoluble fibrin monomer by the proteolytic action of thrombin. The fibrin monomers spontaneously associate to form a clot, on which factor XIIIa acts to aggregate platelets to form a plug on the injured surface of the blood vessel. It has been reported that phosphate groups attached to fibrinogen affect the gelation of thrombin (Forsberg, P. O., Thromb. Res., 53, 1-9, 1989). And, various protein kineses such as protein kinase A (Engstrim, L., Edlund B., Rangnarsson, U., Dahlqvist-Edberg, U., and Humble, E., Biochem. Biophys. Res. Commun., 96, 1507, 1980), protein kinase C, casein kinase I (Itarte, E., Plana, M., Guasch, M. D., and Martos, C., Biochem. Biophys, Res. Commun., 117, 631-636, 1983), and casein kinase II (Humble, E., Heldin, P., Forsberg, P. O. and Engstrom, L., Arch, Biochem. Biophys., 241, 225-231, 1985) have been reported to be involved in the phosphorylation of fibrinogen. The effect of the phosphorylation of fibrinogen on the thrombin-induced gelation of fibrinogen varies depending on thekinase used to phosphorylate fibrinogen. The phosphorylated fibrinogen is ineffeciently cleaved by plasmin regardless of the kind of the kinase involved in the phosphorylation thereof (Martin, S. C., et al., Thromb. Res. 61, 243252, 1991). Web site: http://www.delphion.com/details?pn=US05897860__
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Method for treatment of hemophilia by extravascular administration of factor VIII deletion derivatives Inventor(s): Osterberg; Thomas (Stockholm, SE), Spira; Jack (Stockholm, SE), Widlund; Lars (Sp.ang.nga, SE) Assignee(s): Pharmacia & Upjohn Aktiebolag (Stockholm, SE) Patent Number: 5,972,885 Date filed: December 21, 1995
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Abstract: A pharmaceutical formulation for subcutaneous, intramuscular or intradermal administration comprising recombinant coagulation factor VIII and use thereof for manufacture of a medicament for treating haemophilia is provided. The formulation comprises a highly purified recombinant coagulation factor VIII in a concentration of at least 1000 IU/ml, which gives surprisingly high levels of active factor VIII in the blood stream after subcutaneous, intramuscular or intradermal administration. The formulation is intended for treatment of haemophilia by subcutaneous, intramuscular or intradermal administration. The recombinant factor VIII is preferably a deletion derivative thereof, which can be used for the manufacture of a medicament for subcutaneous administration. Excerpt(s): This application claims the benefit of Swedish Application No. 9302308-3, filed on Jul. 5, 1993, and PCT/SE94/00297, filed Mar. 31, 1994. The present invention relates to a pharmaceutical formulation for subcutaneous, intramuscular or intradermal administration comprising recombinant coagulation factor VIII and use thereof for manufacture of a medicament for treating haemophilia. The formulation comprises a highly purified recombinant coagulation factor VIII in a concentration of at least 1000 IU/ml, which gives surprisingly high levels of active factor VIII in the blood stream after subcutaneous, intramuscular or intradermal administration. The formulation is intended for treatment of haemophilia by subcutaneous, intramuscular or intradermal administration. The recombinant factor VIII is preferably a deletion derivative thereof, which can be used for the manufacture of a medicament for subcutaneous administration. Haemophilia is an inherited disease which has been known for centuries but it is only within the last three decades that it has been possible to differentiate between the various forms; haemophilia A, haemophilia B and haemophilia C. Haemophilia A is the most frequent form. It affects only males with an incidence of one or two individuals per 10 000 live-born males. The disease is caused by strongly decreased level or absence of biologically active coagulation factor VIII (antihaemophilic factor), which is a protein normally present in plasma. The clinical manifestation of haemophilia A is a strong bleeding tendency and before treatment with factor VIII concentrates was introduced, the mean age of those patients was less than 20 years. Concentrates of factor VIII obtained from plasma have been available for about three decades. This has improved the situation for treatment of haemophilia patients considerably and given them possibility to live a normal life. Web site: http://www.delphion.com/details?pn=US05972885__ •
Methods and compositions for use in gene therapy for treatment of hemophilia Inventor(s): Herzog; Roland W. (Glenolden, PA), High; Katherine A. (Merion, PA) Assignee(s): Childrens Hospital of Phildelphia (Philadelphia, PA) Patent Number: 6,093,392 Date filed: March 12, 1998 Abstract: The invention includes a composition comprising a recombinant adenoassociated viral vector comprising at least two adeno-associated virus inverted terminal repeats, a promoter/regulatory sequence, isolated DNA encoding Factor IX and accompanying 5' and 3' untranslated regions and a transcription termination signal, and methods of use thereof. Excerpt(s): The field of the invention is gene therapy for treatment of diseases involving a deficiency of proteins in the blood stream. The process of blood coagulation involves a
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series of proteins known as blood coagulation proteins which act in a cascade fashion to effect the formation of a blood clot. Hemophilia is a disease of humans and other mammals wherein a gene encoding a blood coagulation factor contains a mutation such that the encoded protein does not function normally in the cascade process. Specifically, the hereditary disease, hemophilia B, is characterized by a mutation in the gene encoding the blood coagulation protein, Factor IX (F.IX). F.IX is reviewed in High et al. (1995, "Factor IX" In: Molecular Basis of Thrombosis and Hemostasis, High and Roberts, eds., Marcel Dekker, Inc.). Adenoviral vectors are well known in gene therapy and have been used to effect expression of high levels of canine factor IX in immunodeficient mice or in immunocompetent mice when the virus is administered in conjunction with immunosuppressive agents. When adenoviral vectors are administered to immunocompetent mice in the absence of immunosuppressive agents, these vectors induce a strong inflammatory and cytotoxic T lymphocyte (CTL) response (Dai et al., 1995, Proc. Natl. Acad. Sci. USA 92:1401-1405) which negates the beneficial effects of the therapy. In addition, there are reports which suggest that intramuscular injection of replication defective adenovirus provides long-term expression of a transgene, provided that the transgene encodes a self-protein (i.e., a host protein), such that a strong host immune response is avoided (Tripathy et al., 1996, Nature Med. 2:545-550; Yang et al., 1996, Hum. Mol. Genet. 5:1703-1712). Thus, while there has been significant progress in the area of gene therapy in in vivo expression of a selected transgene following direct injection of an adenoviral vector into skeletal muscle, the use of adenoviral vectors may not be the optimal method for gene therapy in light of these immunological considerations. Web site: http://www.delphion.com/details?pn=US06093392__ •
Methods for treating bleeding disorders Inventor(s): Kaye; James A. (Brookline, MA) Assignee(s): Genetics Institute, Inc. (Cambridge, MA) Patent Number: 5,582,821 Date filed: July 22, 1994 Abstract: Provided by the present invention is a method for treating von Willebrand Disease (vWD) by administering IL-11. The present invention relates generally to novel methods for treating bleeding disorders and more specifically relates to methods for treating von Willebrand Disease (vWD) hemophilia A, and various hemostatic disorders such as uremia, cirrhosis, congenital platelet defects, congenital and acquired storage pool deficiency, patients with unexplained prolongations of bleeding time, as well as prophylactic treatment before surgeries. Excerpt(s): The present invention relates generally to novel methods for treating bleeding disorders and more specifically relates to methods for treating von Willebrand Disease (vWD), hemophilia A, and various hemostatic disorders such as uremia, cirrhosis, congenital platelet defects, congenital and acquired storage pool deficiency, patients with unexplained prolongations of bleeding time, as well as prophylactic treatment before surgeries. Patients having von Willebrand's disease (vWD), blood coagulation disorders, such as hemophilia A, and including various hemostatic disorders such as uremia, cirrhosis, congenital platelet defects, congenital and acquired storage pool deficiency, and patients with unexplained prolongations of bleeding time, are exposed to risks of viral infection when treated with plasma derivatives. Even patients with mild forms of these disorders who normally require no supplementation
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with blood products are exposed to these risks when surgical procedures are undertaken. Von Willebrand factor (vWF) is a heterogeneous, multimeric plasma glycoprotein (Zimmerman T S, Roberts J, Edgington T S: Factor VIII-related antigen: multiple molecular forms in human plasma. Proc Natl Acad Sci USA 72:5121, 1975; Hoyer L W, Shainoff J R: Factor VIII-related protein circulates in normal human plasma as high molecular weight multimers. Blood 55:1056, 1980) that plays an important role in platelet adhesion (Sakariassen K S, Bolhuis P A, Sixma J J: Human blood platelet adhesion to artery subendothelium is mediated by factor VIII/von Willebrand factor bound to the subendothelium. Nature 279:636, 1979; Stel H V, Sakariassen K S, de Groot P G, et al: von Willebrand factor in the vessel wall mediates platelet adherence. Blood 65:85, 1985; Turitto V T, Weiss H J, Zimmerman T S, et al: Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion. Blood 65:623, 1985) and also functions as the plasma binding (carrier) protein for factor VIII. Web site: http://www.delphion.com/details?pn=US05582821__ •
Methods for treating hemophilia A and B and AIDS and devices used therein Inventor(s): Pollard; Harvey B. (11008 Lamplighter La., Potomac, MD 20854) Assignee(s): none reported Patent Number: 5,908,399 Date filed: September 26, 1996 Abstract: The present invention provides a method for treating Hemophilia A or B which comprises implanting in fluid communication with the bloodstream of a mammal in need of such treatment a permeable membrane having one or more walls, a hollow chamber therewithin, a plurality of holes extending through the walls of the membrane and permitting fluid to enter and exit the chamber of the membrane, each of the holes being sized so that it is large enough to permit inactive Factor VII to enter the chamber of the membrane and activated Factor VIIa to exit the chamber of the membrane but small enough to prevent fibrinogen from entering the chamber of the membrane, a plurality of supports being disposed within the chamber, and an effective amount of a Factor VII activator or a source of the activator being bound to the supports, wherein inactive Factor VII in blood passing through the membrane becomes activated into Factor VIIa upon contact with the activator within the chamber.The present invention also provides a method for treating Hemophilia A or B extracorporeally. The present invention further provides methods for treating AIDS as well as permeable membranes for use in the methods above. Excerpt(s): The treatment of choice for these disorders is presently replacement therapy, and is the basis of a one billion dollar per year business worldwide. The extrinsic pathway in hemophilia patients is normal, but since all of Factor VII is in the inactivated state, little or no activation of the extrinsic pathway occurs when needed. Apparently, the intrinsic pathway is needed for tonic activation of Xa and generation of VIIa. The relative rate of conversion of X to Xa by VIIa alone is 15 million-fold less than the rate observed when VIIa is complexed with Tissue Factor (Bom, VJJ and Bertina, RM (1990) Biochem. J. 265:327-336). Nonetheless, the small amount of Xa generated by the administration of r-Factor VIIa is sufficient to reduce bleeding in afflicted patients. A critical problem yet to be solved is the fact that r-Factor VIIa itself has a short half-life (about 2 hours). This means that sustained, exogenous replacement of this material would be necessary for treating patients. The present invention avoids the need for exogenous replacement (e.g. hourly or daily therapy in the case of accident, or
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preventive therapy in the event of dental or surgical procedures (Hadner, U. et al. (1988) Lancet II, 1193)) by employing the patient's own Factor VII to generate activated Factor VII (Factor VIIa). Web site: http://www.delphion.com/details?pn=US05908399__ •
Pharmaceutical composition for oral administration containing coagulation factor VIII or IX Inventor(s): Horikoshi; Isamu (Toyama, JP), Sakuragawa; Nobuo (Toyama, JP), Takahashi; Kaoru (Toyama, JP), Ueno; Masaharu (Toyama, JP) Assignee(s): Dainippon Pharmaceutical Co., Ltd. (Osaka, JP) Patent Number: 4,348,384 Date filed: October 7, 1981 Abstract: A pharmaceutical composition suitable for the treatment and prophylaxis of hemophilia A or B, which comprises coagulation factor VIII or IX and a protease inhibitor (particularly aprotinin) which are incorporated in liposomes and optionally lyophilized and/or encapsulated in intestine capsules. The composition can give high absorption of the required coagulation factor from intestinal tract without being decomposed in gastrointestinal tract even by administration in oral route. Excerpt(s): The present invention relates to a pharmaceutical composition for oral administration containing coagulation factor VIII or IX. More particularly, it relates to a novel pharmaceutical composition suitable for the treatment or prophylaxis of hemophilia A or B by oral administration, which comprises coagulation factor VIII or IX and a protease inhibitor which are incorporated in liposomes and optionally lyophilized and/or encapsulated in intestine capsules. It is well known that hemophilia is one of the hereditary coagulation disorders due to bleeding factors, and the existent hemophiliac appears one per 22 thousand persons in men and such a disorder may appear in a ratio of one per about 8,000 birth population in men. Among these coagulation disorders, hemophilia A is due to hereditary deficiency of coagulation factor VIII and hemophilia B is due to hereditary deficiency of coagulation factor IX. Such disorders may be substantially remedied by supplement of the coagulation factors to patients who are deficient in such factors. The supplement of the required coagulation factors had been done by infusion of fresh blood, but recently, with development of preparation containing the factors in high concentration, there have widely been used concentrated preparations containing much amounts of the coagulation factors and less amount of other factors such as fibrinogen. Web site: http://www.delphion.com/details?pn=US04348384__
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Preparation for the treatment of hemophilia A inhibitor patients and a process for producing such a preparation Inventor(s): Nordfang; Ole (Selskovvej 6, DK-3400 Hillerod, DK), Rasmussen; Mirella E. (Abildgaardsgade 24, DK-2100 Copenhagen 0, DK) Assignee(s): none reported Patent Number: 4,831,119 Date filed: June 20, 1986
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Abstract: A preparation for the treatment of hemophilia A inhibitor patients contains a protein or peptide having a specific Factor VIII:CAg activity of at least 0.5, preferably at least 1 VIII:CAg unit per mg protein, the ratio between the VIII:CAg activity and the VIII:C procoagulant activity being greater than 5:1, preferably greater than 10:1. A fragment of Factor VI-II:C, which displays a doublet of a molecular weight of 80/77 kD in electrophoresis, is reactive hemophilia A inhibitor antibodies and has VIII:CAg activity. This fragment and more low-molecular fragments of Factor VIII:C are capable of neutralizing the coagulation inhibiting effect of all tested antibodies. Such fragments can therefore be used as active component in preparations for providing immunotolerance towards Factor VIII:C in high-dose treatment of inhibitor patients. The peptides are moreover useful as an immunosorbent in specific extracorporeal adsorption treatment of inhibitor patients. The inhibitor reactive peptides can e.g. be recovered from plasma fractions by affinity chromatography, hydrophobic interaction chromatography or cation exchange or they may be biosynthetically and recovered in a similar manner. Excerpt(s): The present invention relates to a preparation for the treatment of hemophilia A inhibitor patients and processes for producing such a preparation. Hemophilia A is a congenital disease which is due to lack of coagulation Factor VIII:C. This factor is present in blood plasma and can be partially purified from blood. Preparations containing this factor (AHF) can be administered to hemophilia A patients so that the patients' blood will be able to coagulate. Production of this type of preparation is described e.g. in the U.S. Pat. No. 3,652,530 and International Application WO No. 84/03628. In these preparations the Factor VIII:C protein typically amounts to 0.1% of the total protein amount. Factor VIII:C of greater purity can be obtained by affinity chromatography (Zimmerman et al., U.S. Pat. No. 4,361,509, Fass et al. Blood 59, 394, 1982). The Factor VIII:C protein has still not been fully characterized, but part of the structure is known (L. W. Hoyer, Blood 58, 1, 1981; M. Weinstein et al., Proc. Natl. Acad. Sci., USA 78, 5137, 1981; G. Kuo et al., Thromb. Haemostas. 50, 262, 1983). The molecular weight is about 300 kD. Web site: http://www.delphion.com/details?pn=US04831119__ •
Process for producing a protein Inventor(s): Adamson; Lars (Lidingo, SE), Dixelius; Johan (Uppsala, SE), Lie; Kristina Lima (Stockholm, SE), Walum; Erik (Akersberga, SE) Assignee(s): Pharmacia & Upjohn AB (Stockholm, SE) Patent Number: 5,851,800 Date filed: May 7, 1997 Abstract: A process is presented for reducing the detrimental influence of certain proteases on recombinant human protein and polypeptide production in a cell culture, which comprises adding an inhibitor of metal-dependent proteases or chymotrypsins to the cell culture medium. The cell culture medium for cultivating cells expressing and secreting a biologically active recombinant human polypeptide contains an inhibitor of metal-dependent proteases or chymotrypsins, or a combination thereof. Recombinant factor VIII which has been produced in a cell culture medium according to the present process is useful for the manufacture of a medicament for administration to a patient having the symptoms of hemophilia A and for treatment of hemophilia A by administration of a therapeutically effective amount of recombinant factor VIII.
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Excerpt(s): This application is based upon provisional application Ser. No. 60/018,874, filed May 29,1996. The present invention relates to a process for producing recombinant human proteins and polypeptides, and a cell culture medium for use in said production. More particularly, the invention relates to cultivating cells in a cell culture medium containing an inhibitor of metal-dependent proteases or chymotrypsins, or a combination thereof. Proteolytic enzymes are involved in all bodily functions, and most of them have natural regulatory counterparts, i.e. protease inhibitors. The International Commission on Enzymes has established a systematic classification and nomenclature for proteolytic enzymes: 1) serine proteinases, 2) cystein proteinases, 3) aspartic proteinases, 4) metalloproteinases, all classified according to an essential group in their active center, and finally 5) a subclass of proteinases with catalytic mechanism yet unknown (Borivoj Keil, Specificity of Proteolysis, Springer-Verlag NY, 1992, 336 pages). The intention of this classification is not functional, neither is it related to the biological source of the enzyme at issue. The problem of classification of proteolytic enzymes, often abbreviated proteases, is described in the introduction chapter: "The Classification of enzymes in Enzyme Nomenclature (1200) is made according to the reactions they catalyze. Thus rule can hardly be applied for endopeptidases. The overall reaction catalyzed by this large group of enzymes is essentially always the same: cleavage of a peptide bond. A protein, however, cannot be considered as a substrate in the classical term: it contains hundreds of potential substrates, a set of qualitatively different peptide bond types with varying quantitative representation. Moreover, the availability of these bonds vary according to the overall conformation of the polypeptide chain. Therefore, the Enzyme Nomenclature makes an exception of endopeptidases from its rule: instead of classification according to the catalyzed reaction, endopeptidases are classified by the type of their active site. In this way, enzymes with completely different specificity (like trypsin, chymotrypsin and prolyl peptidase) are found in the same group." As further illustrated in the same reference, the substrate and inhibitor specificity is far more complicated than a simple relation to five classes of enzymes. Nevertheless, this classification is widely used in the literature, for example when various effects of proteolysis are to be described. Web site: http://www.delphion.com/details?pn=US05851800__ •
Process for purifying coagulation factor VIII using DEAE-crosslinked dextran Inventor(s): Iga; Yoshiro (Nishinomiya, JA), Shiga; Masashi (Nagaokakyo, JA) Assignee(s): The Green Cross Corporation (Osaka, JA) Patent Number: 4,093,608 Date filed: April 1, 1977 Abstract: A process for purifying coagulation factor VIII which comprises contacting a plasma or a plasma fraction containing prothrombin complex and coagulation factor VIII (antihemophilic factor A) with diethylaminoethyl-crosslinked dextran to adsorb and remove the prothrombin complex from said plasma or plasma fraction. Coagulation factor VIII thus obtained can be administered to control the bleeding in hemophilia A patients. Excerpt(s): This invention relates to a process for separating coagulation factor VIII (hereinafter referred to as "factor VIII") from human fresh pooled plasma and purifying it. More particularly, this invention relates to a process for separating and purifying factor VIII characterized by absorbing and removing prothrombin complex, the instabilization factor for factor VIII, from human pooled plasma containing factor VIII or
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factor VIII fractions thereof by the use of diethylaminoethyl-crosslinked dextran. Factor VIII has another name of anti-hemophilic factor A. It is one of the most important coagulation factors participating into the intrinsic thromboplastin generation. When attempting to treat hemorrhage of a hemophiliac patient, the most rational and effective method is to directly introduce the deficient factor, namely factor VIII, into the bloodstream. However, factor VIII is quite difficult to separate and purify because of its low content in the plasma and the instableness of its activity. At the present time, a few kinds of factor VIII preparations are commercially available and extensively used for the treatment of hemophiliac A patients. They are prepared from the fraction I separated from plasma by means of Cohn's ethanol fractionation method or from the cryoprecipitate obtained by freezing a plasma and then thawing it at a low temperature. However, they are all crude products of low purity and contain a large quantity of fibrinogen. If given at a large or frequently repeated dose, they may make the state of patient quite danger clinically, bringing an excessively overloading fibrinogen in the circulating system. Moreover, it is difficult to determine their accurate dose because of the deviation in the activity in each preparation. For the above-mentioned reasons, the current trend in the world is towards the development of a highly purified, highly concentrated factor VIII preparation from a large quantity of pooled plasma. The high potency factor VIII concentrates hitherto disclosed are generally produced by once preparing crude fractions of factor VIII, such as Cohn's fraction I or cryoprecipitate, followed by purifying them by the method of polyethylene glycol fractionation or glycine-precipitated fractionation. Partial improvements of these processes are disclosed in U.S. Pat. Nos. 3,631,018 and 3,652,530. As Kisker [Thromb. Diath. Haemorrhagica, 17, 381 (1967)], as well as Penick and Brinkhouse [Amer. J. Med. Sciences, 232, 434 (1956)], have pointed out in their papers, in the preparative process of such high potency factor VIII concentrates, particularly in the course of separating and purifying factor VIII, the coexisting prothrombin complex and active forms of its constitutive factors, such as IIa, Xa and the like, are markedly detrimental to the stability of factor VIII and sometimes irreversibly injure the latter to inactivate it. In order to improve stability, yield and solubility of factor VIII, therefore, it is quite important and essentially necessary to inactivate or eliminate said instabilization factors at the earliest stage of the separationpurification step. Method for inactivating said instabilization factors has been disclosed in, for example, U.S. Pat. No. 3,803,115. It has also been disclosed that said instabilization factors can be removed by the use of an adsorbent such as aluminum hydroxide, magnesium hydroxide, barium carbonate, barium sulfate, rivanol (6,9diamino-2-ethoxyacridine lactate), ion-exchange resin (Amberlite IRC-50), glycine ethyl ester or the like [Bidwell, E. et al.: Brit. J. Haemat., 13, 568 (1967); Soulier, J. P. et al.: Presse med., 72, 1223 (1964); Surgenor, P. M. et al.: J. Phys. Colloid Chem., 55, 94 (1951); Hoag, M. S. et al.: J. Clin. Invest., 39, 554 (1960)]. Among them, aluminum hydroxide is known to be relatively good adsorbent of said instabilization factors and therefore has been used most frequently. However, aluminum hydroxide is still disadvantageous in the following respects: (1) it cannot be said to be satisfactory in the removal rate of said instabilization factors, particularly of prothrombin complex, and it can exercise an undesirable effect upon the stability or some other properties of factor VIII; (2) it reacts with citric acid (or its salts) to form a gel, so that its use precludes the possibility of employing citric acid salt as an effective solubilizing and stabilizing composition for factor VIII throughout the fractionation process of the latter; and (3) after the treatment with aluminum hydroxide, there remains a small quantity of aluminum ion (Al.sup.+++) capable of reacting with the subsequently added citric acid salt to form a small quantity of gel, which causes clogging of the membrane filter, makes the procedure of steril-filtration quite difficult, and thereby causes a great loss in factor VIII. As above, the treatment with aluminum hydroxide can profoundly affect the stability,
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yield and solubility of factor VIII as well as the procedure for separating and purifying it. Solution of these problems, therefore, has a deep significance in the production of high potency factor VIII concentrates. Web site: http://www.delphion.com/details?pn=US04093608__ •
Proteins with factor VIII activity: process for their preparation using geneticallyengineered cells and pharmaceutical compositions containing them Inventor(s): Pannekoek; Hans (Aalsmeer, NL), van Leen; Robert W. (Nijmegen, NL), van Ooyen; Albert J. J. (Voorburg, NL), Verbeet; Martinus P. (Amsterdam, NL) Assignee(s): Gist-Brocades N.W. (Delft, NL) Patent Number: 5,171,844 Date filed: June 10, 1988 Abstract: Novel polypeptides having Factor VIII activity are provided as well as compositions and methods for their preparation. The polypeptides comprise derivatives and fragments of Factor VIII and have sequences substantially similar to portions of naturally occuring Factor VIII. The polypeptides find use in treatment of Hemophilia A. Excerpt(s): The invention relates to novel proteins having Factor VIII activity and methods for their preparation using genetically engineered cell-lines and microorganisms. Hemophilia A is a sex-linked bleeding disorder characterized by a deficiency in Factor VIII, an essential element in the blood coagulation cascade. The disease occurs in about 0.01% of the male population. Hemophilia A can be treated by administering Factor VIII-containing blood plasma obtained from healthy donors. This treatment has several disadvantages however. The supply of Factor VIII is limited and very expensive; the concentration of Factor VIII in blood is only about 100 ng/ml and the yields using current plasma fractionation methods are low. Since the source of Factor VIII is pooled donor blood, the recipient runs a high risk of acquiring various infectious diseases, including those caused by hepatitis non-A, non-B, hepatitis B or AIDS viruses which may be present in the donor blood. In addition, recipients may develop antibodies against the exogenous Factor VIII, which can greatly reduce its effectiveness. Factor VIII comprises three regions, an N-terminal region, the so-called "A1A2-domain"; a central region, the so-called "B domain"; and a C-terminal region comprising the A3, C1 and C2 domains. The A1A2-domain and the C-terminal region are believed essential for clotting activity. Factor VIII circulates in the blood combined with a protein, the von Willebrand factor (vWf), which is believed to protect the sensitive Factor VIII against early degradation. Web site: http://www.delphion.com/details?pn=US05171844__
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Retroviral delivery of full length factor VIII Inventor(s): Bodner; Mordechai (San Diego, CA), Chang; Stephen (Poway, CA), De Polo; Nicholas J. (Solana Beach, CA), Hsu; David Chi-Tang (San Diego, CA), Respess; James G. (San Diego, CA) Assignee(s): Chiron Viagene, Inc. () Patent Number: 5,681,746 Date filed: December 30, 1994
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Abstract: Retroviral vectors for directing expression of full length factor VIII in transduced host cells, plasmids encoding the same, and host cells transformed, transfected, or transduced therewith are disclosed. Also disclosed are retroviral particles comprising such retrovital vectors, as are methods for making such particles in suitable packaging cells. Retroviral particles so produced may be amphotropic, ecotropic, polytropic, or xenotropic; alternatively, they may comprise chimeric or hybrid envelope proteins to alter host range. Also described are retrovital particles comprising retroviral vectors for directing full length factor VIII expression which are complement resistant. Pharmaceutical compositions comprising retrovital particles of the invention are also disclosed, as are methods of treating mammals, particularly humans, afflicted with hemophilia. Excerpt(s): The present invention relates to retroviral-mediated gene therapy. Specifically, the invention relates to recombinant retroviral vectors capable of delivering nucleic acid constructs encoding full length factor VIII to a patient, pharmaceutical compositions comprising such retroviral vectors, and methods of making and using the same. Numerous methods exist for genetically engineering vertebrate cells. Of particular interest are those methods that may be used to engineer mammalian cells, so as to enable the production of large quantities of various polypeptides (such as erythropoietin and factor VIII), as well as to treat various diseases, for instance serious vital infections, cancers, and genetic diseases. One method for successfully introducing nucleic acid molecules into cells involves the use of viral vectors, with vectors derived from retroviruses being prototypic examples. Retroviruses are RNA viruses, meaning their genomes comprise RNA. Upon infection of a replicating cell, the retroviral genome is reverse transcribed into DNA, which is then made double stranded. The doublestranded DNA copy then stably integrates into a chromosome of the infected cell, forming a "provirus" which is inherited by daughter cells as is any other gene. Web site: http://www.delphion.com/details?pn=US05681746__ •
Treatment of bleeding with modified tissue factor in combination with FVIIa Inventor(s): Comp; Philip C. (Oklahoma City, OK), Morrissey; James H. (Oklahoma City, OK) Assignee(s): Oklahoma Medical Research Foundation (Oklahoma City, OK) Patent Number: 5,374,617 Date filed: May 13, 1992 Abstract: It has been discovered that it is possible to administer truncated tissue factor (not having the transmembrane region) (tTF) in combination with factor VIIa (F VIIa) to treat bleeding disorders such as those resulting from hemophilia or cirrhosis of the liver. The tTF is administered to produce up to 10.mu.g tTF/ml of plasma. The F VIIa is administered to produce levels of between 40 ng VIIa/ml and 4.mu.g F VIIa/ml of plasma. The effective dosages of both tTF and VIIa are significantly and surprisingly less than the administration of either alone to stop bleeding. Examples demonstrate safety and efficacy in normal and hemophilic dogs. Excerpt(s): Blood coagulation results from the production of thrombin, a proteolytic enzyme inducing platelet aggregation and cleaving fibrinogen to fibrin, which stabilizes the platelet plug. A number of proenzymes and procofactors circulating in the blood interact in this process through several stages during which they are sequentially or simultaneously converted to the activated form, ultimately resulting in the activation of
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prothrombin to thrombin by activated factor X (fXa) in the presence of factor Va, ionic calcium, and platelets. Factor X can be activated by either of two pathways, termed the extrinsic and intrinsic pathways. The intrinsic pathway, or surface-mediated activation pathway, consists of a series of reactions where a protein precursor is cleaved to form an active protease, beginning with activation of factor XII to factor XIIa, which converts factor XI to factor XIa, which, in the presence of calcium, converts factor IX to factor IXa. Factors IX and X can also be activated via the extrinsic pathway by tissue factor (TF) in combination with activated factor VII (factor VIIa; fVIIa). Activated factor IX, in the presence of calcium, phospholipid (platelets), and factor VIIIa, activates factor X to factor Xa. Physiologically, the major pathway involved in coagulation is believed to be the extrinsic pathway, an essential step of which is tissue factor-mediated activation of factor VII to factor VIIa. Tissue factor is an integral membrane glycoprotein having a protein and a phospholipid component. It has been isolated from a variety of tissues and species and reported to have a molecular mass of between 42,000 and 53,000. DNA encoding tissue factor and methods for expression of the protein have now been reported, for example, in European Patent Application 0 278 776 by Genentech, Inc. and by J. H. Morrissey, et al. Cell 50, 129-135 (1987). Web site: http://www.delphion.com/details?pn=US05374617__ •
Virus-inactivated factor Xa preparation Inventor(s): Johann; Eibl (Vienna, AT), Schwarz; Hans-Peter (Vienna, AT), Turecek; Peter (Vienna, AT) Assignee(s): Immuno Aktiengesellschaft (Vienna, AT) Patent Number: 5,593,968 Date filed: August 2, 1994 Abstract: A virus-inactivated Factor-Xa preparation with at least 100 units coagulation factor activity per mg protein is described, wherein this preparation is produced by activation of a corresponding starting material and subsequent treatment for the inactivation of infectious agents, particularly viruses. By incubation, the preparation obtained in this manner is transformed into a stable beta-Factor Xa preparation. In addition, the use of the present preparation for the treatment of hemophilia A inhibitor patients is disclosed. Excerpt(s): The invention relates to a virus-inactivated Factor Xa preparation, especially to a Factor Xa preparation of high purity. A method for the production of this virusinactivated, highly pure Factor Xa preparation is described, wherein this method also allows especially a virus-inactivated, highly pure beta-Factor Xa preparation to be obtained which is distinguished by particular stability. The blood coagulation Factor X represents a plasma glycoprotein which is involved in the intrinsic as well as the extrinsic blood coagulation cascade. During blood coagulation, Factor X is activated to Factor Xa. The latter represents a serine protease which catalyses the transformation of prothrombin to thrombin. Factor X comprises two subunits, namely a heavy chain with a relative molar mass of 49 kD and a light chain with a relative molar mass of 17 kD which are connected by a disulfide bridge. Through the enzyme-catalysed activation of the zymogen to Factor Xa, an amino-terminal peptide with a relative molar mass of 11 kD is cleaved from the heavy chain. Through this, alpha-Factor Xa with a relative molar mass of approximately 55 kD results which represents the proteolytically active Factor Xa (J. C. Giddings, Molecular Genetics and Immunoanalysis in Blood Coagulation, Weinheim, Cambridge, N.Y., Basel, Verlag Chemie 1988, p. 47ff).
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Web site: http://www.delphion.com/details?pn=US05593968__
Patent Applications on Hemophilia 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 hemophilia: •
Adeno-associated virus vectors encoding factor VIII and methods of using the same Inventor(s): Burstein, Haim; (Redmond, WA), Chao, Hengjun; (Carrboro, NC), Lynch, Carmel; (Kenmore, WA), Munson, Keith; (Seattle, WA), Stepan, Tony; (Seattle, WA), Walsh, Christopher E.; (Chapel Hill, NC) Correspondence: Alston & Bird Llp; Bank OF America Plaza; 101 South Tryon Street, Suite 4000; Charlotte; NC; 28280-4000; US Patent Application Number: 20020131956 Date filed: March 12, 2002 Abstract: The present invention provides recombinant adeno-associated virus (rAAV) vectors comprising a heterologous nucleotide sequence encoding factor VIII (factor VIII). In preferred embodiments, the factor VIII is a B-domain deleted factor VIII. Also provided are methods of producing a high titer stock of the inventive rAAV/factor VIII vectors. Another aspect of the invention is a method of delivering a nucleotide sequence encoding factor VIII to a cell, preferably for subsequent administration to a subject. The present invention further provides methods of administering rAAV/factor VIII to a subject, e.g., for the treatment of hemophilia. The rAAV vector may be administered by any route, but is preferably administered to the liver. Excerpt(s): The present application claims the benefit of U.S. Provisional Application Serial No. 60/158,780 filed Oct. 12, 1999, entitled "Adeno-Associated Virus Vectors Encoding Factor VIII and Methods of Using the Same," the contents of which are herein incorporated by reference in their entirety. This invention relates to reagents and methods for providing Factor VIII, and more particularly relates to viral reagents and methods for providing Factor VIII. Hemophilia A is an inherited sex-linked bleeding disease resulting from deficiency of coagulation factor VIII (factor VIII). Hemophilia A comprises the majority of hemophilia patients (80%) with an incidence of 1 in 5-10,000 live males births (Antonarakis et al. (1998) Haemophilia 4:1). Hemophilia patients suffer from spontaneous bleeding into the large joints, soft tissue, and are at risk for intracranial hemorrhage. Recurrent episodes of joint bleeding are the most frequent manifestation of the disease leading to crippling arthropathy, particularly in severely affected patients. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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This has been a common practice outside the United States prior to December 2000.
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ADENOVIRAL VECTORS FOR TREATMENT OF HEMOPHILIA Inventor(s): CONNELLY, SHEILA; (GAITHERSBURG, MD), KALEKO, MICHAEL; (ROCKVILLE, MD), SMITH, THEODORE; (GERMANTOWN, MD) Correspondence: Raymond J Lillie; C/o Carella Byrne Bain Gilfillan; Cecchi Stewart & Olstein; 6 Becker Farm Road; Roseland; NJ; 07068 Patent Application Number: 20020064812 Date filed: September 10, 1998 Abstract: An adenoviral vector including at least one DNA sequence encoding a clotting factor, such as, for example, Factor VIII, or Factor IX. Such vectors may be administered to a host in an amount effective to treat hemophilia in the host. The vectors infect hepatocytes very efficiently, whereby the hepatocytes express the DNA sequence encoding the clotting factor. Excerpt(s): This application is a continuation-in-part of application Ser. No. 08/218,335, filed Mar. 25, 1994, which is a continuation-in-part of application Ser. No. 074,920, filed Jun. 10, 1993. This invention relates to adenoviral vectors. More particularly, this invention relates to adenoviral vectors which may be employed in the treatment of hemophilia. Hemophilias A and B are X-linked, recessive bleeding disorders caused by deficiencies of clotting Factors VIII and IX, respectively. In the United States there are approximately 17,000 patients with hemophilia A and 2,800 with hemophilia B. The clinical presentations for both hemophilias are characterized by episodes of spontaneous and prolonged bleeding. Patients frequently suffer joint bleeds which lead to a disabling arthropathy. Current treatment is directed at stopping the bleeding episodes with intravenous infusions of plasma-derived clotting factors or, for hemophilia A, recombinant Factor VIII. However, therapy is limited by the availability of clotting factors, their short half-lives in vivo, and the high cost of treatment, which can approach 100,000 dollars per year. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compositions and methods for the expression of factor VIII polypeptides and uses therefor Inventor(s): Do, Hung V.; (Atlanta, GA), Healey, John F.; (Snellville, GA), Lollar, John S.; (Decatur, GA), Waller, Edmund K.; (Atlanta, GA) Correspondence: Alston & Bird Llp; Bank OF America Plaza; 101 South Tryon Street, Suite 4000; Charlotte; NC; 28280-4000; US Patent Application Number: 20030129174 Date filed: December 3, 2002 Abstract: Compositions and methods are provided for the in vivo gene delivery of nucleic acid sequences encoding the factor VIII protein to the liver endothelial sinusoidal cells (LSECs). Compositions and methods are also provided for the ex vivo gene transfer of nucleic acid sequences encoding the factor VIII protein to cultured LSECs and the implantation of the transformed LSECs in vivo. These methods and compositions increase the level of factor VIII in the blood stream and find use in the gene therapy treatment of hemophilia A. Excerpt(s): This application is a continuation of U.S. application Ser. No. 09/633,020, filed Aug. 4, 2000, which claims the benefit of U.S. Provisional Application Serial No.
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60/147,407, filed Aug. 8, 1999, the contents of which are herein incorporated by reference. The invention relates to methods for the expression and secretion of factor VIII polypeptides. Hemophilia A affects one in every 10,000 males and is caused by a deficiency of the factor VIII protein in the plasma. Based on the level of factor VIII activity in the blood, hemophilia A is categorized into mild, moderate, and severe forms. Fifty percent of hemophilia A patients have the severe form of the disease that is characterized by spontaneous and prolonged bleeding episodes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Expression of active human factor IX in mammary tissue of transgenic animals Inventor(s): Drohan, William N.; (Springfield, VA), Johnson, John L.; (Blacksburg, VA), Johnson, Mary Ann H.; (Blacksburg, VA), Lubon, Henryk; (Rockville, MD), Velander, William H.; (Blacksburg, VA) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20020166130 Date filed: February 5, 2002 Abstract: Recombinant Factor IX characterized by a high percentage of active protein can be obtained in the milk of transgenic animals that incorporate chimeric DNA molecules according to the present invention. Transgenic animals of the present invention are produced by introducing into developing embryos DNA that encodes Factor IX, such that the foreign DNA is stably incorporated in the DNA of germ line cells of the mature animal. Particularly efficient expression was accomplished using a chimeric construct comprising a mammary gland specific promoter, Factor IX cDNA that lacked the complete or any portion of the 5'-untranslated and 3'-untranslated region, which is substituted with a 5-' and 3'- end of the mouse whey acidic protein gene. In vitro cell cultures of cells explanted from the transgenic mammal of the invention and methods of producing Factor IX from such said culture and methods of treating hemophilia B are also described. Excerpt(s): This application is a division of application No. 09/367,087, filed Sep. 15, 1999, now pending, which is a 371 of PCT/US98/02638, filed Feb. 13, 1998, which claims benefit of 60/037,145 filed Feb. 14, 1997. This application claims only subject matter disclosed in the parent application and therefore presents no new matter. The present invention relates to the production of natural and modified forms of Factor IX. In particular, the invention relates to a transgenic animal containing, stably incorporated in its genomic DNA, an exogenous Factor IX gene that is expressed specifically in mammary tissue, such that Factor IX is secreted into milk produced by the animal. In particular, the invention relates to the production of human Factor IX in the milk of a transgenic non-human mammal using a DNA molecule that comprises a whey acidic protein promoter gene, 5' regulatory sequences containing the promoter, human Factor IX cDNA that lacks at least a portion of the complete or any portion of or the complete the 3'-untranslated region of the native human Factor IX gene, but contains the 5' and 3'untranslated region of the mouse whey acidic protein. gene. Human Factor IX, or "Christmas factor," is encoded by a single-copy gene residing on the X-chromosome at q27.1. For a review of Factor IX gene structure and expression, see High et al., "Factor IX," in MOLECULAR BASIS OF THROMBOSIS AND HEMOSTASIS, High (ed.), pages 215-237 (Dekker 1995); Kurachi et al., Thromb. Haemost. 73:333 (1995). The Factor IX gene is at least 34 kilobase (kb) pairs in size, and it is composed of eight exons. The
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major transcription start site of the Factor IX gene in human liver is located at about nucleotide-176. The human Factor IX mRNA is composed of 205 bases for the 5' untranslated region, 1383 bases for the prepro Factor IX, a stop codon and 1392 bases for the 3' untranslated region. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Ex-vivo and in vivo factor XII gene therapy for hemophilia A and B Inventor(s): Pollard, Bette; (Potomac, MD), Pollard, Harvey; (Potomac, MD) Correspondence: Arent Fox Kintner Plotkin & Kahn; 1050 Connecticut Avenue, N.W.; Suite 400; Washington; DC; 20036; US Patent Application Number: 20030073652 Date filed: May 17, 2001 Abstract: Bypass activity for hemophilia A and B can be generated by natural or recombinant Factor VIIa. Factor XIIa when implanted into a guinea pig or monkey also facilitates the conversion of endogenous factor VII to VIIa, thereby providing bypass activity. Additionally, certain modified versions of Factor XII are known to be intrinsically active, with properties like Factor XIIa. Administration of unencapsulated Factor XIIa to a guinea pig causes a transient increase in plasma bypass activity. A continuous source of Factor XIIa, as provided by a gene therapy, is therapeutic for both Hemophilia A and B. There are three ways to provide for gene therapy. In each case, the gene for Factor XII (or Factor XIIa) can be introduced into the cell by the usual means, including, but not limited to, as naked DNA, as a DNA/lipid mixture, or as part of a viral vector system. In one manifestation, cells can be transfected with full length or modified versions of Factor XII, ex-vivo, and allowed to continuously express versions of recombinant Factor XII from unencapsulated recombinant cells implanted in the body of the patient. A second mechanism would require encapsulating the cells within the body. As a third mechanism of introducing Factor XIIa into the patient, full length or modified versions of the gene for human Factor XII can be directly administered in vivo. The advantage is provision of a universal gene therapy for hemophilia A and B, rather than separate gene therapies involving either Factor VIII (Hemophilia A) or Factor IX (Hemophilia B). Excerpt(s): This application claims priority under 35 U.S.C.sctn.1.119(e) to provisional application serial No. 60/205,014, filed May 17, 2000. The invention relates to the use of recombinant Factor XII and truncated or mutated forms thereof, in gene therapy for conversion of inactive Factor VII to its active form in the treatment of Hemophelia A and B. Hemophilia A is a coagulation disorder caused by a deficiency in Factor VIII:C (Factor 8) (Bloom, 1991; Rosendaal et al, 1991; Thompson, 1991; Handin et al, 1994). Hemophilia B is a coagulation disorder caused by a deficiency of Factor IX. Most U.S. and European hemophiliacs are undertreated due to the extraordinary cost of recombinant Factor VIII:C, and the high incidence of "inhibitors" or auto-antibodies to Factor VIII:C in patients (Aledort, 1998). Not only do these antibodies inhibit Factor VIII activity, but they also have a catalytic destructive effect (Lacroix-Desmazes, et al, 1999). Between 10% (Yee, et al, 1999) and 25% (Prescott et al, 1997) of hemophiliacs have such inhibitors, and they cost 10-fold more than the average to treat due to more frequent hospitalizations (Goudemand, 1998). Attempts to induce immune tolerance to Factor VIII:C are not often successful. Initially, such antibody development was not as frequently reported for recombinant Factor VIII:C as for plasma-derived Factor VIII:C (see Seremetis et al, 1999). However, Prescott et al (1997) from the American Red Cross report that there is no
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significant difference between the two classes of patients. Given financial limitations, priorities have been established for access to therapy, in which HIV-positive and/or hepatitis C-positive hemophiliacs are less likely to be treated optimally (Giangrande, 1997). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
FACTOR IX ANTIHEMOPHILIC FACTOR WITH INCREASED CLOTTING ACTIVITY Inventor(s): CHANG, JIN LI; (CHAPEL HILL, NC), STAFFORD, DARREL W.; (CARRBORO, NC) Correspondence: Myers Bigel Sibley & Sajovec; PO Box 37428; Raleigh; NC; 27627; US Patent Application Number: 20020031799 Date filed: July 17, 1998 Abstract: A non-naturally occuring Factor IX protein having an amino acid substitution at amino acid position 338 is provided. Preferred substitutions include the substitution of analanine, leucine, or valine for the arginine at amino acid position 338. Factor IX of the present invention is non-naturally occuring (e.g., does not contain only an arginine to proline substitution at amino acid position 338). Factor IX proteins of the invention are useful for facilitating blood clotting in subjects in need thereof, such as subjects afflicted with hemophilia B. Pharmaceutical formulations comprising Factor IX of the invention are provided, along with nucleic acids encoding the same and vectors containing such nucleic acids. Excerpt(s): This application claims priority from provisional application Serial Number 60/053,571, filed Jul. 21, 1997, the disclosure of which is incorporated by reference herein in its entirety. This invention concerns Factor IX in general, and particularly concerns Factor IX containing a mutation that enhances the clotting activity thereof. This invention also concerns DNA constructs encoding such Factor IX, along with vectors containing such constructs. Factor IX (FIX; also known as "Christmas Factor") plays a key role in both the intrinsic and extrinsic coagulation pathways (E. Davie et al., Biochemistry 30, 10363 (1991); B. Furie and B. Furie, Cell 53, 505 (1988)). Human Factor IX and DNA encoding the same is disclosed in U.S. Pat. No. 4,994,371 to Davie et al., and in European Patent 0107278 to Brownlee. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Inactivation resistant factor VIII related applications Inventor(s): Amano, Kagehiro; (Tokyo, JP), Kaufman, Randal J.; (Ann Arbor, MI), Pipe, Steven W.; (Ypsilanti, MI) Correspondence: Lahive & Cockfield; 28 State Street; Boston; MA; 02109; US Patent Application Number: 20020132306 Date filed: April 11, 2001 Abstract: The present invention provides novel purified and isolated nucleic acid sequences encoding procoagulant-active FVIII proteins. The nucleic acid sequences of the present invention encode amino acid sequences corresponding to known human FVIII sequences, wherein residue Phe3O9 is mutated. The nucleic acid sequences of the
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present invention also encode amino acid sequences corresponding to known human FVIII sequences, wherein the APC cleavage sites, Arg336 and Ile562, are mutated. The nucleic acid sequences of the present invention further encode amino acid sequences corresponding to known human FVIII sequences, wherein the B-domain is deleted, the von Willebrand factor binding site is deleted, a thrombin cleavage site is mutated and an amino acid sequence spacer is inserted between the A2- and A3-domains. Methods of producing the FVIII proteins of the invention, nucleotide sequences encoding such proteins, pharmaceutical compositions containing the nucleotide sequences or proteins, as well as methods of treating patients suffering from hemophilia, are also provided. Excerpt(s): The present application claims priority under 35 U.S.C.sctn.120 from PCT International Application No. PCT/US97/06563, filed Apr. 24, 1997, which is a continuation-in-part of U.S. Ser. No. 60/016,117, filed Apr. 24, 1996 and U.S. Ser. No. 60/017,785, filed May 15, 1996, all hereby expressly incorporated by reference. The present invention relates generally to procoagulant-active proteins and more particularly, nucleotide sequences encoding factor VIII protein capable of secretion at levels higher than typically obtained with wild-type factor VIII, APC resistant factor VIII protein and inactivation resistant factor VIII protein. Human factor VIII:C (FVIII) is the coagulation factor deficient in the X-chromosome-linked bleeding disorder hemophilia A, a major source of hemorrhagic morbidity and mortality in affected males. Traditionally, hemophiliacs were treated with transfusions of whole blood. More recently, treatment has been with preparations of FVIII concentrates derived from human plasma. However, the use of plasma-derived product exposes hemophiliac patients to the possible risk of virus- transmissible diseases such as hepatitis and AIDS. Costly purification schemes to reduce this risk increases treatment costs. With increases in costs and limited availability of plasma-derived FVIII, patients are treated episodically on a demand basis rather than prophylactically. Recombinantly produced FVIII has substantial advantages over plasma-derived FVIII in terms of purity and safety, as well as increased availability and accordingly, much research effort has been directed towards the development of recombinantly produced FVIII. Due to the labile nature of FVIII, especially following its activation, large and repeated doses of protein whether plasma or recombinantly-derived, must be administered to achieve a therapeutic benefit. However, the amount of FVIII protein the patient is exposed to has been correlated with the development of antibodies which inhibit its activity. In light of this known immunogenicity, one of the goals in developing new recombinant forms of FVIII for use as a therapeutic agent is the development of products that reduce or eliminate such an immune response. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Lentiviral vectors encoding clotting factors for gene therapy Inventor(s): Dull, Thomas; (San Francisco, CA), Kelly, Michael; (Carlsbad, CA), McArthur, James G.; (San Carlos, CA), McGuinness, Ryan; (Oakland, CA), Simmons, Andrew D.; (San Mateo, CA), Talbot, Dale John; (San Francisco, CA), Tsui, Lisa V.; (Mountain View, CA) Correspondence: Gates & Cooper Llp; Howard Hughes Center; 6701 Center Drive West, Suite 1050; Los Angeles; CA; 90045; US Patent Application Number: 20030077812 Date filed: May 14, 2002
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Abstract: Recombinant lentiviruses and transfer vectors for transgene delivery as well as methods for gene therapy using such vectors are disclosed. The invention provides a third generation lentiviral packaging system and a set of vectors for producing recombinant lentiviruses, as well as novel tissue specific enhancer and promoter elements useful for optimizing liver specific transgene delivery. The transgene is preferably a blood clotting factor such as human factor IX (hFIX) or human factor VIII (hFVIII) and can be used for treatment of hemophilia. Excerpt(s): This application claims benefit of U.S. provisional application serial No. 60/291,083, filed May 14, 2001, the entire contents of which are incorporated herein by reference. The present invention relates to gene therapy. In particular it relates to vectors for use in the preparation of recombinant lentiviruses and the use of replicationdeficient lentiviral vectors to deliver a therapeutic gene to a target tissue of a subject. Suitable therapeutic genes include genes that encode clotting factors, such as factor VIII or factor IX, to treat a blood clotting disease such as hemophilia. The invention further relates to enhancers and promoters useful for tissue-specific gene therapy. Gene therapy generally relates to the delivery of one or more heterologous genes to a subject in order to treat a disease. Hemophilia is a genetic disease caused by a deficiency of a blood clotting factor. There are two types of X-linked bleeding disorders, hemophilia A and hemophilia B. In some cases of von Willebrand disease, the most common bleeding disorder, deficient levels of vWF result in low levels of factor VIII, mimicking hemophilia A. Hemophilia A affects about 17,000 people in the US and is caused by a deficiency in factor VIII. The incidence of hemophilia B is 1 out of 34,500 men, and it is caused by a deficiency in factor IX. Each of these diseases is an excellent theoretical candidate for gene therapy, as each has a reasonably simple molecular pathology and should be remediable by the delivery of a single gene. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method to treat hemophilia by hepatic gene transfer of factor VIII/IX with vesicle vector Inventor(s): Chien, Kenneth; (La Jolla, CA), Hoshijima, Masahiko; (La Jolla, CA) Correspondence: Brown, Martin, Haller & Mcclain Llp; 1660 Union Street; San Diego; CA; 92101-2926; US Patent Application Number: 20030044982 Date filed: April 25, 2002 Abstract: Hemophilia is one of the most common genetic disorders. Standard therapies include transfusions with plasma products to provide clotting factors. The invention is a non-viral vesicle vector and method for the treatment of hemophilia. The vesicle vector contains the hepatitis B envelope protein to target the vesicle to the liver for delivery of an expression construct containing the coding sequence for factor VIII or IX driven by an appropriate promoter or factor VIII or IX protein. Excerpt(s): This application claims the benefit of priority of U.S. provisional application Serial No. 60/286,314 filed Apr. 25,2001 which is incorporated herein by reference in its entirety. A sequence listing is submitted herewith under 35 C.F.R.sctn.1.821 and is incorporated herein by reference. Hemophilia is one of the most common genetic disorders. Hemophilia A caused by deficiency of Factor VIII occurs in about 1 in 5000 male births, while hemophilia B caused by a defect in Factor IX is around 1 in 30,000 male births. The prevalence is very general in all populations studied. Hemophilia has
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long been treated with clotting factor concentrates, but the aim of this therapy is to control bleeding and requires lifelong repetitive intravenous infusions. Because of the increasing awareness of the risk of plasma derived products, the importance of the development of new and effective treatments is increased. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods and compositions for the diagnosis and treatment of hematological disorders using 2777 Inventor(s): Carroll, Joseph M.; (Cambridge, MA) Correspondence: Millennium Pharmaceuticals, INC.; 75 Sidney Street; Cambridge; MA; 02139; US Patent Application Number: 20030091571 Date filed: October 28, 2002 Abstract: The present invention relates to methods and compositions for the diagnosis and treatment of hematological disorders, including, but not limited to, apalstic anemia, hemophilia, sickle cell anemia, thalassisemia, blood loss and other blood disorders, e.g., blood diorders related to bone marrow irradiation or chemotherapy treatment or renal failure. The invention further provides methods for identifying a compound capable of treating a hematological disorder. The invention also provides methods for identifying a compound capable of modulating a hematopoietic cell activity. Yet further, the invention provides a method for modulating a hematopoietic cell activity. In addition, the invention provides a method for treating a subject having a hematological disorder characterized by aberrant 2777 polypeptide activity or aberrant 2777 nucleic acid expression. In another aspect, the invention provides methods for increasing hematopoietic cell proliferation in a subject and methods for modulating hematopoietic cell apoptosis in a subject. Excerpt(s): This application claims priority to U.S. provisional application No. 60/335,251, filed Oct. 31, 2001, the entire contents of which are incorporated herein by reference. Hematological disorders are blood associated disorders. Blood is a highly specialized tissue which carries oxygen and nutrients to all parts of the body and waste products back to the lungs, kidneys and liver for disposal. Thus, blood maintains communication between different parts of the body. Blood is also an essential part of the immune system, crucial to fluid and temperature balance, a hydraulic fluid for certain functions and a highway for hormonal messages. All blood cells in adults are produced in the bone marrow. Red cells, white cells and platelets are produced in the marrow of bones, especially the vertebrae, ribs, hips, skull and sternum. These essential blood cells fight infection, carry oxygen and help control bleeding. Specifically, red blood cells are disc-shaped cells containing hemoglobin, which enables these cells to pick up and deliver oxygen to all parts of the body. White blood cells are the body's primary defense against infection. They can move out of the blood stream and reach tissues being invaded. Platelets are small blood cells that control bleeding by forming clusters to plug small holes in blood vessels and assist in the clotting process. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Minimal adenoviral vector Inventor(s): Alemany, Ramon; (Grayslake, IL), Ayares, David; (Blacksburgh, VA), Balague, Cristina; (Grayslake, IL), Dai, Yifan; (Grayslake, IL), Josephs, Steven; (Grayslake, IL), Schneiderman, Richard; (Highland Park, IL), Zhang, Wei-Wei; (Libertyville, IL) Correspondence: Mcdonnell Boehnen Hulbert & Berghoff; 300 South Wacker Drive; Suite 3200; Chicago; IL; 60606; US Patent Application Number: 20030192066 Date filed: May 28, 2002 Abstract: This invention is related to adenoviral (Ad) vectors and their applications in the field of genetic medicine, including gene transfer, gene therapy, and gene vaccination. More specifically, this invention is related to the Ad vectors that carry the minimal cis-element of the Ad genome (mini-Ad vector) and are capable of delivering transgenes and/or heterologous DNA up to 36 kb. The generation and propagation of the mini-Ad vectors require trans-complementation of a packaging-attenuated and replication-defective helper Ad (helper) in an Ad helper cell line.This invention further comprises a methodology for generating a mini-adenoviral (mini-Ad) vector for use in gene therapy of hemophilia and animal test systems for in vivo evaluation of the Ad vectors. More specifically, this invention describes factor VIII (FVIII) Ad vectors that only contain minimal cis-elements of the Ad genome (so called mini-Ad) and comprise a human FVIII cDNA with other supporting DNA elements up to 36 kb. The FVIII miniAd can be generated and preferentially amplified through the assistance of a packagingattenuated helper Ad and a helper cell line. This invention also reports designs and methods for producing transgenic mouse models that can be used for in vivo testing the mini-Ad. Excerpt(s): This application claims priority to U.S. application Ser. No. 08/658,961 filed on May 31, 1996 and U.S. application Ser. No. 08/791,218 filed on Jan. 31, 1997. This invention further comprises a methodology for generating a mini-adenoviral (mini-Ad) vector for use in gene therapy of hemophilia and animal test systems for in vivo evaluation of the Ad vectors. More specifically, this invention describes factor Vif (FVII) Ad vectors that only contain minimal cis-elements of the Ad genome (so called mini-Ad) and comprise a human FVIII CDNA with other supporting DNA elements up to 36 kb. The FVIH mini-Ad can be generated and preferentially amplified through the assistance of a packaging-attenuated helper Ad and a helper cell line. This invention also reports designs and methods for producing transgenic mouse models that can be used for in vivo testing the mini-Ad. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Modified cDNA for high expression levels of factor VIII and its derivatives Inventor(s): Hauser, Hans-Peter; (Marburg, DE), Negrier, Claude; (Irigny, FR), Plantier, Jean-Luc; (Gringy, FR), Rodriguez, Marie-Helene; (L'isle d'Abeau, FR) Correspondence: Finnegan, Henderson, Farabow, Garrett &; Dunner Llp; 1300 I Street, NW; Washington; DC; 20006; US Patent Application Number: 20030083257 Date filed: August 2, 2002
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Abstract: A modified factor VIII CDNA is disclosed, wherein one or more spliceable nucleotide sequences have been inserted into introns 1 and/or 13 of the wild-type factor VIII cDNA. Further, a process for the production of a biologically active recombinant human factor VIII or its derivative is disclosed, which is performed by cultivating an animal cell line comprising a recombinant expression vector containing said modified factor VIII cDNA. Moreover, a transfer vector for use in the human gene therapy is described which comprises said modified factor VIII cDNA. Finally, the use of recombinant human factor VII and its derivatives for the treatment of hemophilia is disclosed. Excerpt(s): The present application claims benefit of priority of European Patent Application No. 01118775.4, filed Aug. 8, 2001, the disclosure of which is incorporated herein by reference in its entirety. The present invention relates to modified DNA sequences coding for biologically active recombinant human factor VIII and its derivatives, recombinant expression vectors containing such DNA sequences, host cells transformed with such recombinant expression vectors, processes for the manufacture of the recombinant human factor VIII and its derivatives, and use of the recombinant human factor VII and its derivatives for the treatment of hemophilia. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA sequences. Classic hemophilia, or hemophilia A, is the most common of the inherited bleeding disorders. It results from a chromosome X-linked deficiency of blood coagulation factor VIII and affects almost exclusively males with an incidence of between one and two individuals per 10,000. The X-chromosome defect is transmitted by female carriers who are not themselves hemophiliacs. The clinical manifestation of hemophilia A is an abnormal bleeding tendency. Before treatment with factor VIII concentrates was introduced, the mean life span for a person with severe hemophilia was less than 20 years. The use of concentrates of factor VIII from plasma has considerably improved the situation for the hemophilia patients. The mean life span has increased significantly, giving many hemophilia patients the possibility to live a more or less normal life. However, there have been certain problems with the plasma-derived concentrates and their use, the most serious of which has been the transmission of viruses. So far, viruses causing AIDS, hepatitis B, non A hepatitis and non B hepatitis have hit the hemophilia population seriously. Although different viral inactivation methods and new highly purified factor VIII concentrates have recently been developed, viral contamination is still a possibility. Also, the factor VIII concentrates are fairly expensive because of the limited supply of human plasma raw material. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Modified factor VIII Inventor(s): Lollar, John S.; (Decatur, GA) Correspondence: Greenlee Winner And Sullivan, P.C.; Suite 201; 5370 Manhattan Circle; Boulder; CO; 80303; US Patent Application Number: 20020182670 Date filed: September 19, 2001 Abstract: Specific amino acid loci of human factor VIII interact with inhibitory antibodies of hemophilia patients after being treated with factor VIII. Modified factor VIII is disclosed in which the amino acid sequence is changed by a substitution at one or more of the specific loci. The modified factor VIII is useful for hemophiliacs, either to avoid or prevent the action of inhibitory antibodies.
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Excerpt(s): This application claims priority under 35 U.S.C.sctn. 119(e) to U.S. Provisional Applications 60/236,460 filed Sep. 29, 2000, and 60/234,047 filed Sep. 19, 2000, both of which are hereby incorporated by reference to the extent not inconsistent with the disclosure herein. This invention relates generally to a modified mammalian factor VIII having amino acid substitutions which reduce its immunogenicity and/or antigenicity as compared to the proteins from which they were derived or other factor VIII preparations such as human factor VIII. Blood clotting begins when platelets adhere to the cut wall of an injured blood vessel at a lesion site. Subsequently, in a cascade of enzymatically regulated reactions, soluble fibrinogen molecules are converted by the enzyme thrombin to insoluble strands of fibrin that hold the platelets together in a thrombus. At each step in the cascade, a protein precursor is converted to a protease that cleaves the next protein precursor in the series. Co-factors are required at most of the steps. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel nucleic acid molecules and polypeptides encoding baboon TAFI Inventor(s): Hsu, Mei-Yin; (Hillsboro, NJ), Matsueda, Gary R.; (Princeton, NJ), Nayeem, Akbar; (Newtown, PA), Tamura, James K.; (Yardley, PA) Correspondence: Stephen B. Davis; Bristol-myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20030215850 Date filed: March 4, 2003 Abstract: The present invention relates to the isolation and identification of novel baboon nucleic acid molecules and proteins and polypeptides encoded by such nucleic acid molecules, or degenerate variants thereof, which proteins and polypeptides comprise novel baboon thrombin-activatable fibrinolysis inhibitors or "TAFI" enzyme molecules. Because the novel baboon TAFI proteins and polypeptides of the invention inhibit the breakdown of blood clots, they may be therapeutically useful for the treatment of blood disorders wherein clotting needs to be regulated or promoted, such as hemophilia or von Willebrand's disease or in other situations, such as trauma, wherein blood clotting or coagulation needs to be regulated or promoted. The sequences of the invention are also useful in screening methods for the identification of compounds that modulate the expression of the baboon TAFI nucleic acids and/or the activity of the baboon TAFI proteins and polypeptides of the invention. Such agonist or antagonist compounds may be useful in the treatment of various blood clotting disorders and conditions requiring hemostatic control such as hemophilia or various thrombotic diseases such as deep venous thrombosis, coronary artery disease, stroke associated with atrial fibrillation and recurrent thrombosis following stroke or myocardial infarction. Excerpt(s): This application is a continuation-in-part Application of and claims benefit to provisional application U.S. Serial No. 60/361,523 filed Mar. 4, 2002, under 35 U.S.C. 119(e). The entire teachings of the referenced application are incorporated herein by reference. The sequences of the invention are also useful in screening methods for the identification of compounds that modulate the expression of the baboon TAFI nucleic acids and/or the activity of the baboon TAFI proteins and polypeptides of the invention. Such agonist or antagonist compounds may be useful in the treatment of various blood clotting disorders and conditions requiring hemostatic control such as hemophilia or various thrombotic diseases such as deep venous thrombosis, coronary artery disease,
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stroke associated with atrial fibrillation and recurrent thrombosis following stroke or myocardial infarction. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
RECOMBINANT AAV VECTORS FOR GENE THERAPY OF HEMOPHILIA A Inventor(s): DULL, THOMAS J.; (SAN FRANCISCO, CA), FINER, MITCHELL H.; (WOODSIDE, CA), MCGUINNESS, RYAN; (HALF MOON BAY, CA), SNYDER, RICHARD; (OAKLAND, CA) Correspondence: Roylance, Abrams, Berdo & Goodman, Llp; 1300 19th Street, NW; Suite 600; Washington; DC; 20036-2680; US Patent Application Number: 20020155580 Date filed: May 27, 1998 Abstract: The instant invention provides methods and materials for expressing a polypeptide with factor VIII activity comprising administering an rAAV vector encoding a truncated version of human factor VIII, containing, for example, a 90 kD heavy chain of factor VIII fused to a light chain of factor VIII. Excerpt(s): Adeno-associated virus (AAV) is a defective parvovirus whose genome is encapsidated as a single-stranded DNA molecule. Strands of plus and minus polarity are packaged with equal efficiency, but in separate virus particles. Efficient replication of AAV generally requires coinfection with a helper virus of the herpesvirus or adenovirus family, although under special circumstances, AAV can replicate in the absence of helper virus. In the absence of helper virus, AAV establishes a latent infection in which the viral genome exists as an integrated provirus in the host cell. Integration of the virus occurs on human chromosome 19. If a latently infected cell line later is superinfected with a suitable helper virus, generally the AAV provirus is excised and the AAV virus enters the "productive" phase. AAV isolates have been obtained from human and simians. The host range for lytic growth of AAV is broad. Cell lines from virtually every mammalian species tested, including a variety of human, simian, canine, bovine and rodent cell lines, can be infected productively with AAV, provided an appropriate helper virus is used (e.g., canine adenovirus in canine cells). However, no disease has been associated with AAV in either human or other animal populations. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Recombinant adeno-associated vector-mediated delivery of B-domain-deleted factor VIII constructs for the treatment of hemophilia Inventor(s): Colosi, Peter C.; (Alameda, CA), Couto, Linda B.; (Pleasanton, CA), Qian, Xiaobing; (Alameda, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030099618 Date filed: November 12, 2002 Abstract: One form of a composition has two types of recombinant adeno-associated virus. The first type encodes a portion of Factor VIII operably linked to an expression control element; and the second type encodes a different portion of Factor VIII operably linked to an expression control element. The first and second nucleotide sequences
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collectively encode a functional Factor VIII protein. Another form of the composition is a recombinant adeno-associated virus containing a nucleotide sequence encoding functional Factor VIII light or heavy chain operably linked to a tissue-specific promoter. Excerpt(s): This Application is a Continuation of U.S. application Ser. No. 10/007,968, filed Nov. 16, 2001, now abandoned, which is a divisional of U.S. application Ser. No. 09/740,211, filed Dec. 18, 2000, which is a continuation of U.S. application Ser. No. 09/470,618, filed Dec. 22, 1999, which is a continuation-in-part of U.S. application Ser. No. 09/364,862, filed Jul. 30, 1999, which claims benefit under 35 U.S.C.sctn.119(e) of U.S. Provisional Application Nos. 60/125,974 and 60/104,994, filed Mar. 24, 1999 and Oct. 20, 1998, respectively. All of these prior applications are hereby incorporated by reference in their entireties. The present invention relates to AAV vectors suitable for hemophilia gene therapy. More particularly, these AAV vectors are suitable for delivering nucleic acids encoding Factor VIII into a recipient subject suffering from hemophilia A, such that the subject's blood is able to clot. Hemophilia is a genetic disease characterized by a blood clotting deficiency. In hemophilia A (classic hemophilia, Factor VIII deficiency), an X-chromosome-linked genetic defect disrupts the gene encoding Factor VIII, a plasma glycoprotein, which is a key component in the blood clotting cascade. Human Factor VIII is synthesized as a single chain polypeptide, with a predicted molecular weight of 265 kDa. The Factor VIII gene codes for 2351 amino acids, and the protein has six domains, designated from the amino to the carboxy terminus as A1-A2-B-A3-C1-C2 (Wood et al., Nature 312:330 [1984]; Vehar et al., Nature 312:337 [1984]; and Toole et al., Nature 312:342 [1984]). Human Factor VIII is processed within the cell to yield a heterodimer primarily comprised of a heavy chain of 200 kDa containing the A1, A2, and B domains and an 80 kDa light chain containing the A3, C1, and C2 domains (Kaufman et al., J. Biol. Chem., 263:6352-6362 [1988]). Both the single chain polypeptide and the heterodimer circulate in the plasma as inactive precursors (Ganz et al., Eur. J. Biochem., 170:521-528 [1988]). Activation of Factor VIII in plasma is initiated by thrombin cleavage between the A2 and B domains, which releases the B domain and results in a heavy chain consisting of the A1 and A2 domains. The 980 amino acid B domain is deleted in the activated procoagulant form of the protein. Additionally, in the native protein, two polypeptide chains ("a" and "b"), flanking the B domain, are bound to a divalent calcium cation. Hemophilia may result from point mutations, deletions, or mutations resulting in a stop codon (See, Antonarakis et al., Mol. Biol. Med., 4:81 [1987]). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Recombinant adeno-associated virus-mediated gene transfer via retroductal infusion of virions Inventor(s): McClelland, Alan; (Danville, CA), Scollay, Roland; (Melbourne, AU) Correspondence: Cooley Godward Llp (R & P); Five Palo Alto Square; 3000 EL Camino Real; Palo Alto; CA; 94306-2155; US Patent Application Number: 20030147853 Date filed: March 14, 2002 Abstract: Methods for introducing recombinant adeno-associated virus (rAAV) virions into a cell or cells of a secretory gland are described. Recombinant AAV virions containing a heterologous gene are introduced into a duct of a secretory gland resulting in transduction of one or more secretory gland cells. Once a secretory gland cell is transduced by the rAAV virion, the heterologous gene is expressed and the expression
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product is then secreted. Exemplary examples of secretory glands are the liver, the submandibular gland, the parotid gland, and the sublingual gland. Using the methods of the invention, therapeutic levels of a protein are achieved. Methods for treating hemophilia are also disclosed. Excerpt(s): This application claims the benefit under 35 U.S.C.sctn. 119(e)(1) of Provisional Application Ser. No. 60/275,908, filed on Mar. 14, 2001. The present invention relates to methods of delivering recombinant adeno-associated virus (rAAV) virions to a mammalian subject. More specifically, the invention relates to methods in which rAAV virions are administered to the duct of a secretory gland of a mammalian subject, including a human, to deliver therapeutic proteins. Scientists are continually discovering genes that are associated with human diseases such as diabetes, hemophilia, and cancer. Research efforts have also uncovered genes, such as erythropoietin, that are not associated with genetic disorders but instead code for proteins that can be used to treat numerous diseases. Despite significant progress in the effort to identify and isolate genes, however, a major obstacle facing the biopharmaceutical industry is how to safely and persistently deliver therapeutically effective quantities of gene products to patients. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Single tube PCR assay for detection of chromosomal mutations: application to the inversion hotspot in the factor VIII gene including optional use of subcycling PCR Inventor(s): Liu, Qiang; (Arcadia, CA), Sommer, Steve S.; (Duarte, CA) Correspondence: Rothwell, Figg, Ernst & Manbeck, P.C.; 1425 K Street, N.W.; Suite 800; Washington; DC; 20005; US Patent Application Number: 20020146729 Date filed: December 13, 2001 Abstract: Methods are presented for determining the presence of an inversion in the factor VIII gene which cause hemophilia A. The methods encompass long distance, multiplex PCR (including overlapping PCR). The use of deaza-dGTP, high levels of DNA polymerases and high levels of DMSO aid in successfully performing the PCR. The use of a novel technique called subcycling PCR can also be applied as part of the methods. The technique allows for the determination of whether a person is homozygous or hemizygous for the inversion and has hemophilia A or whether a person is heterozygous for the inversion and is a carrier. The technique of long distance, multiplex PCR including use of deaza-dGTP, high levels of DNA polymerases and high levels of DMSO are applicable to the determination of the presence of other gross chromosomal aberrations such as deletions/inversions, translocations and inversions. The use of subcycling PCR can achieve efficient and more even amplification than normal two or three temperature PCR and is applicable to long distance, multiplex PCR. Excerpt(s): The present invention is a continuation-in-part of application Ser. No. 09/103,505 filed Jun. 24, 1998. Hemophilia A is one of the most common coagulation disorders with an incidence of about one in 5,000 males. The disease is caused by mutations in the factor VIII gene located on the X chromosome. About half the families with severe disease have a large genomic inversion of the factor VIII gene which separates the first 22 exons from the final four exons. This inversion results from a hotspot of recombination between a 9.5 kb region in intron 22 (Int22h1) and either of two extragenic, distal homologs, Int22h2 and Int22h3 near the Xq telomere which are
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repeats of Int22h1. These repeated sequences are more than 99% identical with one another (Naylor et al., 1995). Int22h2 and Int22h3 are in the opposite orientation of Int22h1 and therefore recombination produces an inversion. Intrachromosomal homologous recombination occurs between Int22h1 and the distal extragenic homolog (Int22h3), or between Int22h1 and the proximal Int22h2 homolog (types 1 and 2 inversions, respectively) (Antonarakis et al., 1995; Naylor et al., 1993; Lakich et al., 1993). Some patients have more than two copies of the extragenic homologs causing inversion types 3A and 3B. Multiplex PCR is a rapid and convenient method, but uneven amplification is common (Chamberlain et al., 1998). Efforts have been made to achieve uniform amplification. Since primer concentration is often difficult to optimize, Shuber et al. (1995) developed a simplified optimization procedure based on the use of chimeric primers. Each primer contains a 3' region complementary to sequence-specific recognition sites and a 5' region made up of a universal 20-nucleotide sequence. Each individual PCR was first optimized by adjusting primer concentrations, cycling times, and annealing temperatures (Shuber et al., 1995). In another approach, two detergents, DMSO and betaine, were combined to achieve uniform amplification for three templates differing in GC contents (Baskaran et al., 1996). Additional approaches include adjusting the annealing temperature, KCl (salt) concentration, and primer concentration for each locus encountered in developing multiplex PCR of small sizes (Henegariu et al., 1997). The instant disclosure sets out a detailed, novel method, termed S-PCR, to more evenly and efficiently amplify the multiplex segments. Although S-PCR results in more even amplification, it is not a necessary step in any of the assays described herein. 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 hemophilia, 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 “hemophilia” (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 hemophilia. You can also use this procedure to view pending patent applications concerning hemophilia. 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 HEMOPHILIA Overview This chapter provides bibliographic book references relating to hemophilia. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on hemophilia 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 “hemophilia” (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 hemophilia: •
A New Decade; Hopes and Challenges: Abstract Book, XIX International Congress of The World Federation of Hemophilia, Washington, D.C., August 14-19, 1990 Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: These abstracts of proceedings from the XIX International Congress of the World Federation of Hemophilia, held August 14-19, 1990, in Washington, D.C., summarize research conducted on issues related to persons with hemophilia, including Acquired immunodeficiency syndrome (AIDS). Those on scientific topics describe musculoskeletal diseases and disorders, oral surgery, genetic diseases and disorders, FVIII assays, inhibitors, Von Willebrand's disease, Hepatitis, new methods for clotting factor concentrates, and Human immunodeficiency virus (HIV) and AIDS. The sociomedical abstracts deal with various aspects of treating persons with hemophilia, psychosocial and stress factors, and sexual behavior. Many of the scientific and
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sociomedical sessions discuss similar topics, as well as research related to children with AIDS, family relations, and treatment programs. •
The National Hemophilia Foundation Chapter Roster Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This directory lists the names, addresses, and telephone numbers of the chapter offices and chapter officers of the National Hemophilia Foundation. A map showing chapter locations and lists of Federal government regions for hemophilia treatment and the regions of the National Hemophilia Foundation are also included.
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Directory of Hemophilia Treatment Centers and Facilities Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This directory provides access to hemophilia treatment centers in the United States. It also includes the National Hemophilia Foundation (NHF) Mission statement, a message from the president of the NHF, a message from the chair of the Treatment Center Standards and Criteria Committee, Ten Tips for the Traveler with Hemophilia, and 1990 NHF Standards and Criteria for Hemophilia Treatment Facilities. Broken down by states, the entries for the treatment centers include name of the organization, address, telephone number, and contact persons. The mission statement includes Human immunodeficiency virus (HIV) infection as one of the complications of hemophilia.
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HIV, AIDS and Hemophilia: Perspectives on Chronic Illness Contact: Canadian Hemophilia Society, Calgary Region, AIDS and Hemophilia Support and Education Program, Alberta Children' Hospital, 1820 Richmond Rd SW, Calgary, (250) 229-7211. Summary: This monograph examines the psychosocial issues of Acquired immunodeficiency syndrome (AIDS) and Human immunodeficiency virus (HIV) infection in the hemophiliac community in Canada. It provides basic information about AIDS and its transmission, antibody testing, and, particularly, the meaning of seropositive test results. In discussing the implications of seropositivity regarding sexual practice, pregnancy, and personal health status, it focuses on personal choice issues and a wellness approach. The monograph also lists financial and community resources.
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Financial Considerations for Reimbursement of New Technology Hemophilia Products Contact: Great Lakes Hemophilia Foundation, PO Box 704, Milwaukee, WI, 53201-0704, (414) 257-0200, http://www.glhf.org. Summary: This monograph is addressed to hemophilia professionals and others who are interested in the management of hemophilia medical service costs and related insurance concerns. It helps professionals develop a financial plan to manage associated costs for hemophiliacs receiving new technology products. Factors that are considered in such a plan include product costs, insurance coverage and reimbursement, provider
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charges and billing, and insurance options. New technology products are used to counteract the threat of viruses, including hepatitis and HIV. •
Your Child and Hemophilia Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This monograph provides information to new parents of babies with hemophilia about comprehensive care issues, symptoms and treatment of bleeding episodes, and well baby care. A potential complication of hemophilia is AIDS.
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HIV Disease in People With Hemophilia: Your Questions Answered Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This monograph uses a question-and-answer format to discuss the connection between hemophilia and AIDS. Divided into five sections, it starts with general information on AIDS. This section discusses the HIV-antibody test, why and how often people with hemophilia should be tested, and the meaning of positive and negative results. The safety of clotting factor today is compared to its safety prior to 1985. Section B, on the management of HIV disease, looks at symptoms, diagnosis, treatment programs, and when to seek medical attention. The benefits of early intervention with azidothymidine (AZT) are explained. Risks to sexual partners are discussed in the third section, which explains safer sexual conduct and the risks involved in pregnancy. Myths of casual contact transmission are dispelled. The fourth section analyzes the effects of HIV on children with hemophilia. This chapter includes a listing of universal precautions to prevent HIV transmission while giving personal care. The final two sections look at what individuals should do when confronted with HIV, and what the National Hemophilia Foundation is doing.
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The Hemophilia Patient/Family Module. AIDS & Hemophilia Module Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This teaching guide on Acquired immunodeficiency syndrome (AIDS) is designed to educate and guide hemophilia patients and their families in preventing, alleviating, and coping with common stresses and concerns related to the risk of AIDS and Human immunodeficiency virus (HIV) diagnosis.
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From Theory to Action: Effective Behavior Change in the Hemophilia Community; Trainer's Guide Contact: Hemophilia of Georgia Incorporated, 8800 Roswell Rd Ste 170, Atlanta, GA, 30350, (770) 518-8272, http://www.hog.org. Summary: This trainer's guide is meant to accompany a behavior change course. The participant's manual contains information about the development of the curriculum. Each section of the trainer's guide is organized to ease course preparation and delivery. The course is designed for health care professionals in the hemophilia community who are actively involved with clients who need assistance in implementing and sustaining
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behavior change. The focus of this curriculum is helping clients develop realistic and achievable behavioral plans that are specific to their needs and situations. Emphasis is placed on working with the client where he or she is at a specific point in time so that the behavioral changes are sustainable. Techniques for working effectively with various age, cultural, and ethnic groups are presented. •
Hemophilia and AIDS: AIDS in the Hemophilia Community Source: Working With AIDS: A Resource Guide for Mental Health Professionals. Contact: University of California San Francisco, AIDS Health Project, PO Box 0884, San Francisco, CA, 94143-0884, (415) 476-6430. Summary: Written for mental health professionals, this paper focuses on the impact of AIDS on the hemophiliac community, the psychosocial issues involved, and treatment issues. The incidence of AIDS is higher in persons with hemophilia A, although a few individuals with hemophilia B have also developed AIDS. Clients may continue to fear using the clowning factors needed for hemophilia treatment. Some have discontinued their self treatments, risking the pain and disability that may result from uncontrolled bleeding episodes. Hemophiliacs diagnosed with AIDS experience the same complex set of emotions that confront others with AIDS. In addition, they may fear further misunderstanding and isolation by the public and are angry about their exposure to AIDS. A discussion of general treatment issues, two case examples, counseling plans for each case, a counseling plan checklist, and cross-references to related information in other book chapters are included.
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 “hemophilia” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “hemophilia” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “hemophilia” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
30th Hemophilia Symposium: Hamburg 1999 by I. Scharrer (Editor), W. Schramm (Editor); ISBN: 3540676775; http://www.amazon.com/exec/obidos/ASIN/3540676775/icongroupinterna
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31st Hemophilia Symposium Hamburg 2000 by Germany)/ Scharrer, I./ Schramm, W. Hamophilie-Symposion 2000 Hamburg, et al (2002); ISBN: 3540421319; http://www.amazon.com/exec/obidos/ASIN/3540421319/icongroupinterna
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32nd Hemophilia Symposium: Hamburg 2001 by W. Schramm (Editor), Inge Scharrer (2003); ISBN: 354043884X; http://www.amazon.com/exec/obidos/ASIN/354043884X/icongroupinterna
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33rd Hemophilia Symposium: Hamburg, 2002 by Germany)/ Scharrer, I./ Schramm, W. Hamophilie-Symposion 2002 Hamburg, I. Scharrer (2004); ISBN: 3540009027; http://www.amazon.com/exec/obidos/ASIN/3540009027/icongroupinterna
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Acquired Hemophilia by Craig M. Kessler (Editor), David 1934 Acquired Hemophilia Green (Editor); ISBN: 0444019081; http://www.amazon.com/exec/obidos/ASIN/0444019081/icongroupinterna
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Activated Prothrombin Complex Concentrates: Managing Hemophilia with Factor VIII Inhibitor by G. Mariani (Author), et al; ISBN: 0275913732; http://www.amazon.com/exec/obidos/ASIN/0275913732/icongroupinterna
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Blood Brothers: Ryan, Chris, and Hemophilia by Nancy Shaw; ISBN: 0915541602; http://www.amazon.com/exec/obidos/ASIN/0915541602/icongroupinterna
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Blood Saga: Hemophilia, AIDS, and the Survival of a Community by Susan Resnik (1999); ISBN: 0520211952; http://www.amazon.com/exec/obidos/ASIN/0520211952/icongroupinterna
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Comprehensive Management of Hemophilia by Donna C. Boone; ISBN: 0803610009; http://www.amazon.com/exec/obidos/ASIN/0803610009/icongroupinterna
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Comprehensive management of musculoskeletal disorders in hemophilia; a symposium held in Miami Beach, Florida, October 12-14, 1972; ISBN: 0309021391; http://www.amazon.com/exec/obidos/ASIN/0309021391/icongroupinterna
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Diagnostic imaging in hemophilia : musculoskeletal and other hemorrhagic complications by Holger Pettersson; ISBN: 0387139915; http://www.amazon.com/exec/obidos/ASIN/0387139915/icongroupinterna
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Genetic Disorders Sourcebook: Basic Consumer Health Information About Hereditary Diseases and Disorders, Including Cystic Fibrosis, Down Syndrome, Hemophilia, Huntington's Disease by Kathy Massimini (Editor); ISBN: 0780802411; http://www.amazon.com/exec/obidos/ASIN/0780802411/icongroupinterna
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Genetic Disorders Sourcebook: Basic Information About Heritable Diseases and Disorders Such As Down Synd Rome, Pku, Hemophilia, Von Willebrand Disease, Gaucher Disease, Tay-Sachs d (Health Reference Series, Vol 13) by Karen Bellenir (Editor) (1996); ISBN: 0780800346; http://www.amazon.com/exec/obidos/ASIN/0780800346/icongroupinterna
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Handbook of hemophilia; ISBN: 0444167072; http://www.amazon.com/exec/obidos/ASIN/0444167072/icongroupinterna
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Hemophilia by Barbara Sheen, Beverly Britton (2003); ISBN: 1560069066; http://www.amazon.com/exec/obidos/ASIN/1560069066/icongroupinterna
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Hemophilia by C. D. Forbes (Editor), et al (1997); ISBN: 0412638207; http://www.amazon.com/exec/obidos/ASIN/0412638207/icongroupinterna
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Hemophilia (Diseases and People) by Edward Willett (2001); ISBN: 0766016846; http://www.amazon.com/exec/obidos/ASIN/0766016846/icongroupinterna
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Hemophilia and new hemorrhagic states; international symposium, New York; ISBN: 0807811335; http://www.amazon.com/exec/obidos/ASIN/0807811335/icongroupinterna
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Hemophilia and Related Disorders of Hemostasis by Bruce Ewenstein; ISBN: 0070198640; http://www.amazon.com/exec/obidos/ASIN/0070198640/icongroupinterna
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Hemophilia and Von Willebrand's Disease in the 1990's: A New Decade of Hopes and Challenges: Proceedings of the XIX Congress of the World Federatio by Jeanne M.
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Lusher, Craig M. Kessler (Editor); ISBN: 0444814329; http://www.amazon.com/exec/obidos/ASIN/0444814329/icongroupinterna •
Hemophilia Care in the New Millennium (Advances in Experimental Medicine and Biology, 489) by Dougald McDougald Monroe (Editor), et al (2001); ISBN: 0306465213; http://www.amazon.com/exec/obidos/ASIN/0306465213/icongroupinterna
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Hemophilia Home Therapy by Peter Jones; ISBN: 0839116608; http://www.amazon.com/exec/obidos/ASIN/0839116608/icongroupinterna
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Hemophilia in children; ISBN: 0884161382; http://www.amazon.com/exec/obidos/ASIN/0884161382/icongroupinterna
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Hemophilia in the Child and Adult by Margaret W. Hilgartner, Carl Pochedly (Editor); ISBN: 0881674923; http://www.amazon.com/exec/obidos/ASIN/0881674923/icongroupinterna
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Hemophilia in the Child and Adult; ISBN: 0893521310; http://www.amazon.com/exec/obidos/ASIN/0893521310/icongroupinterna
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Hemophilia: A Manual of Outpatient Management. by Ill., Thomas [1973 Springfield; ISBN: 0398028532; http://www.amazon.com/exec/obidos/ASIN/0398028532/icongroupinterna
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Hemophilia: A Study in Hope and Reality by Alfred Hyman Katz; ISBN: 0398009783; http://www.amazon.com/exec/obidos/ASIN/0398009783/icongroupinterna
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Inside Hemophilia: Milestones in Hemophilia and Von Willebrand's Disease in the Last 25 Years, Dedicated to Dr. J. Martin Villar in His Retirement by M. Magallon Martinez (Editor); ISBN: 3805557175; http://www.amazon.com/exec/obidos/ASIN/3805557175/icongroupinterna
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Living With Hemophilia by Peter Jones; ISBN: 0803650604; http://www.amazon.com/exec/obidos/ASIN/0803650604/icongroupinterna
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Management of the hemophilias : a system for home treatment : first European Workshop held on February 25th and 26th, 1976 in Findel (Luxembourg); ISBN: 8716026357; http://www.amazon.com/exec/obidos/ASIN/8716026357/icongroupinterna
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Recent Advances in Hemophilia Care: Proceedings of the Symposium on Recent Advances in Hemophilia Care Held in Los Angeles, April 13-15, 1989 (progre by Carol K. Kasper (Editor); ISBN: 0471566780; http://www.amazon.com/exec/obidos/ASIN/0471566780/icongroupinterna
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Ricky Ray Hemophilia Relief Fund Act of 1995 : hearing before the Subcommittee on Immigration and Claims of the Committee on the Judiciary, House of Representatives, One Hundred Fourth Congress, second session, on H.R. 1023. September 19, 1996 (SuDoc Y 4.J 89/1:104/122); ISBN: 0160552338; http://www.amazon.com/exec/obidos/ASIN/0160552338/icongroupinterna
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Ricky Ray Hemophilia Relief Fund Act of 1998 : report (to accompany H.R. 1023) (SuDoc Y 1.1/8:105-465/PT.1-) by U.S. Congressional Budget Office; ISBN: B00010W0J8; http://www.amazon.com/exec/obidos/ASIN/B00010W0J8/icongroupinterna
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Social Work and Chronic Health Conditions: An Orientation Manual With Special Reference to Hemophilia by John R. McDonald (1984); ISBN: 0889530610; http://www.amazon.com/exec/obidos/ASIN/0889530610/icongroupinterna
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The 2002 Official Patient's Sourcebook on Hemophilia by James N., Md. Parker (Editor), Philip M., Ph.d Parker (Editor) (2002); ISBN: 0597831815; http://www.amazon.com/exec/obidos/ASIN/0597831815/icongroupinterna
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The Child With a Chronic Medical Problem-Cardiac Disorders, Diabetes, Hemophilia (National Children's Bureau Bibliographies, 3) by Rosemary Dinnage; ISBN: 0700510133; http://www.amazon.com/exec/obidos/ASIN/0700510133/icongroupinterna
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The Hemophilias; ISBN: 0443024391; http://www.amazon.com/exec/obidos/ASIN/0443024391/icongroupinterna
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The Management of Musculoskeletal Problems in the Hemophilias (Oxford Medical Publications) by Robert B. Duthie, et al (1994); ISBN: 0192623176; http://www.amazon.com/exec/obidos/ASIN/0192623176/icongroupinterna
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Treatment of Hemophilia and Von Willebrand's Disease: New Developments by Robert G. Westphal, Dennis M. Smith (Editor); ISBN: 0915355728; http://www.amazon.com/exec/obidos/ASIN/0915355728/icongroupinterna
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Understanding Hemophilia by Marie Berger; ISBN: 1853980102; http://www.amazon.com/exec/obidos/ASIN/1853980102/icongroupinterna
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Vox Sanguinis (Viral Safety of Plasma-Derived Replacement Factors for Hemophilia , Vol 67, Suppl 4) by P. M. Mannucci, S.M. Lemon (Editor) (1994); ISBN: 3805560664; http://www.amazon.com/exec/obidos/ASIN/3805560664/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 “hemophilia” (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 •
A study of the social, vocational and educational capability of the adult hemophiliac in Ontario, by Ron Rosenthal, Mira Friedlander, and Richard Nelson. Author: Rosenthal, Ron.; Year: 1970; Toronto, 1973
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Comprehensive management of hemophilia Author: Boone, Donna C.; Year: 1973; Philadelphia: Davis, c1976; ISBN: 0303610009
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Diagnosis and treatment of hemophilia, a practical guide. Author: Strauss, Herbert S.,; Year: 1968; Boston, Children's Hospital Medical Center [c1967]
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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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Hemophilia and hemophilioid diseases; international symposium [held in New York City, August 24-25, 1956]. Author: Brinkhous, K. M. (Kenneth Merle),; Year: 1967; Chapel Hill, Univ. of North Carolina Press [c1957]
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Hemophilia and other hemorrhagic states; international symposium, Rome. Author: Brinkhous, K. M. (Kenneth Merle),; Year: 1944; Chapel Hill, Univ. of North Carolina Press [c1959]
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Hemophilia today; a handbook of information. Author: Junior League of Montreal.; Year: 1971; [Montreal] 1962
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Hemophilia: a total approach to treatment and rehabilitation. Author: Dietrich, Shelby L.,; Year: 1953; Los Angeles, Orthopaedic Hospital, c1968
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Hemophilia; a Canadian handbook. Author: Canadian Hemophilia Society.; Year: 1973; [Toronto, 1972]
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Plasma fractions for the treatment of hemophilia. Anticoagulant therapy, standardization of tests, transactions of the conference held under the auspices of the International Committee on Haemostasis and Thrombosis, Washington, D. C., U. S. A., December 1967. P. A. Owren, chairman; K. M. Brinkhous, secretary general and editor. Author: Brinkhous, K. M. (Kenneth Merle),; Year: 1971; Stuttgart, Schattauer, 1969
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Prothrombin in enzymology, thrombosis and hemophilia. Author: Seegers, Walter H. (Walter Henry),; Year: 1960; Springfield, Ill., Thomas [c1967]
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Surgery in the hemophiliac. Author: Tarnay, Thomas J.,; Year: 1969; Springfield, Ill., Thomas c1968]
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The hemophiliac and his world. L'univers de l'hémophile. Proceedings of the 5th congress of the World Federation of Hemophilia, Montreal, August 26-28, 1968. Edited by R. Gourdeau. Author: World Federation of Hemophilia.; Year: 1970; Basel, New York, Karger, 1969
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The hemophilias; international symposium, Washington. Author: Brinkhous, K. M. (Kenneth Merle),; Year: 1958; Chapel Hill, Univ. of North Carolina Press [c1964]
Chapters on Hemophilia In order to find chapters that specifically relate to hemophilia, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and hemophilia 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 “hemophilia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on hemophilia: •
Bleeding Disorders Source: in Little, J.W., et al. Dental Management of the Medically Compromised Patient. 5th ed. St. Louis, MO: Mosby, Inc. 1997. p. 466-494. Contact: Available from Harcourt Health Sciences. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Fax (800) 874-6418. Website: www.harcourthealth.com. PRICE: $48.00 plus shipping and handling. ISBN: 0815156340.
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Summary: A working knowledge of the multitude of compromised health states is essential for dental professionals, as the majority of medically compromised patients need or want oral health care. This chapter on bleeding disorders is from a text that provides the dental practitioner with an up to date reference work describing the dental management of patients with selected medical problems. In this chapter, the authors provide dentists with an understanding of the mechanisms involved in the normal control of bleeding, describe the common causes of bleeding problems, present an approach for indentifying patients with possible bleeding disorders, and describe in general terms the management of these patients once they have been identified. The authors discuss incidence and prevalence, etiology, pathophysiology and complications, classification, signs and symptoms (clinical presentation and laboratory findings), the medical management of patients with various bleeding diseases, and the dental management of this population. Topics covered in the last section include aspirin therapy, Coumarin therapy, possible liver disease, chronic leukemia, malabsorption syndrome, long term antibiotic therapy, end stage renal disease (ESRD), hemodialysis, vascular wall alteration, and management of the patient with a serious bleeding disorder (e.g., hemophilia or thrombocytopenia). 9 figures. 23 tables. 50 references. •
Disability, the Young and the Elderly Source: in Scully, C. and Cawson, R.A. Medical Problems in Dentistry. 4th ed. Woburn, MA: Butterworth-Heinemann. 1998. p. 470-487. Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801-2041. (800) 366-2665 or (781) 904-2500. Fax (800) 446-6520 or (781) 933-6333. E-mail:
[email protected]. Website: www.bh.com. PRICE: $110.00. ISBN: 0723610568. Summary: Disability is caused by handicapping conditions that impair normal social, educational, or recreational activities. Such patients need dental attention and treatment to at least the same standard as non-handicapped patients; frequently this population has a greater predisposition to dental disease. This chapter on disability, the young and the elderly is from a text that covers the general medical and surgical conditions relevant to the oral health care sciences. This chapter covers only patients with mental and related handicaps, some specific conditions, children, and the elderly; patients with other important specific diseases, such as hemophilia, neurological disorders and muscular dystrophies, are covered in other chapters. Topics include learning disability, chromosomal anomalies (including Down syndrome and fragile X syndrome), thalidomide defect, hydrocephalus, cleft lip and palate, autism, the overactive child (hyperkinetic child), child abuse, self-inflicted oral lesions, juvenile delinquency, and problems in the elderly, including multiple disease, intellectual failure, social problems, drug compliance and reactions. For each condition, the authors discuss general aspects, diagnosis and management issues, dental aspects, and patient care strategies. The chapter includes a summary of the points covered. 1 appendix. 5 figures. 8 tables. 46 references.
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Why Me? What About Them? How You Got Infected and How to Avoid Infecting Others Source: in Everson, G.T. and Weinberg, H. Living with Hepatitis C: A Survivor's Guide. New York, NY: Hatherleigh Press. 1999. p. 31-47. Contact: Available from Hatherleigh Company, Ltd. 1114 First Avenue, Suite 500, New York, NY 10021. (800) 367-2550 or (212) 832-1039. Website: hatherleigh.com. PRICE: $14.95 plus shipping and handling. ISBN: 1578260345.
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Summary: Hepatitis C is a viral infection that causes inflammation, injury, and ultimately scarring of the liver (cirrhosis). This chapter on the transmission of hepatitis C is from a book that offers information and guidance for people living with hepatitis C. The authors explain in nontechnical language some basic facts about contracting hepatitis C virus (HCV) and how to avoid infecting others. Topics include intravenous drug abuse, intranasal use of cocaine, transfusion of blood or blood products (including that related to surgery or medical treatment, or hemophilia), needle stick accidents, tattooing and body piercing, sharing sharp instruments, birth and delivery (a rare incidence of transmission), and organ transplantation (also a rare incidence of transmission). One of the most common risk factors for hepatitis C is a history of using intravenous illicit drugs: many people share needles and subsequently spread hepatitis among themselves and maintain a pool of infected people. The chapter concludes with a section of commonly asked questions about the transmission of hepatitis C. The chapter includes lengthy quotes from patients with hepatitis, which offer the patients' perspectives, insights, and experiences to the reader. 1 figure. 3 tables. 1 reference. •
Oral Signs of Systemic Disease Source: in Fenton, S.J.; Perlman, S.; Turner, H., eds. Oral Healthcare for People with Special Needs: Guidelines for Comprehensive Care. River Edge, NJ: Exceptional Parent, Psy-Ed Corp. 2003. p. 29-33. Contact: Available as part of a monograph from Exceptional Parent, Psy-Ed Corp. 65 East Route 4, River Edge, NJ 07661. (800) EPARENT or (800) 372-7368. E-mail:
[email protected]. Website: www.eparent.com. PRICE: Contact publisher. Summary: The mouth has often been called the barometer of a person's health. Serious illnesses, conditions or genetic disorders may first present with mouth conditions such as unusual bleeding or multiple lumps and bumps in the mouth, extra or missing teeth, or their premature loss. These mouth changes are frequently helpful in determining the underlying disease or its cause. This article on the oral signs of systemic disease is from a monograph that offers guidelines for the comprehensive oral health care for people with special needs. The monograph is designed to help oral health care providers embrace more fully all the members of their communities, while being respectful of a variety of special needs. In this article, the authors consider unusual bleeding in the mouth, infectious mononucleosis, measles, hemophilia, leukemia, vitamin C and K deficiencies, multiple lumps or bumps in the mouth, enlarged tongue, hypothyroidism, Beckwith-Widemann syndrome, the mucopolysaccharidoses, multiple neoplasia syndrome type 2B, neurofibromatosis, granulomatous diseases, and extra or missing teeth, or premature loss of teeth.
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Radiology in Children Source: in Maddison, P.J.; et al., Eds. Oxford Textbook of Rheumatology. Volume 1. New York, NY: Oxford University Press, Inc. 1993. p. 440-455. Contact: Available from Oxford University Press, Inc., New York, NY. Summary: This chapter for health professionals focuses on the imaging techniques available for assessment of rheumatic diseases in children. These techniques include plain radiography and tomography, computerized tomography, arthrography, isotope bone scanning, ultrasonography, and magnetic resonance imaging. Radiographic changes of bone and joints observed in polyarthritis, osteochondritis, septic arthritis, hemophilia, epiphyseal dysplasias, and tumors are described. Changes in polyarthritis
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include soft tissue swelling, demineralization, growth abnormalities, erosions, bone fusion, and alignment deformities. 11 references, 22 figures, and 3 tables. •
Communication-Other Disabilities: Scholarships, Fellowships-Grants, Loans, Grantsin-Aid, Awards Source: in Schlachter, G.A.; Weber, R.D. Financial Aid for the Disabled and Their Families. 1996-1998. El Dorado Hills, CA: Reference Service Press. 1996. p. 199-207. Contact: Available from Reference Service Press. 5000 Windplay Drive, Suite 4, El Dorado Hills, CA 95762. (916) 939-9620; Fax (916) 939-9626. PRICE: $39.50 plus shipping and handling. ISBN: 0918276365. Summary: This chapter on communication and other disabilities is from a Directory that provides comprehensive information about more than 800 resources set aside for persons with disabilities or for members of their family. This chapter describes 30 programs open to individuals who have a communication disorder (such as stuttering or voice impairment), have a learning disability (including such conditions as brain injury and dyslexia), are emotionally disturbed, or have other chronic or acute health problems, such as heart condition, tuberculosis, epilepsy, or hemophilia. Included are scholarships, fellowships or grants, loans, grants-in-aid, and awards. Entries list program title, sponsoring organization, purpose of the program, eligibility, financial data, duration and renewal, special features, limitations, number awarded, and deadline.
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Diseases and Oral Manifestations of Systemic Disease Source: in Pinkham, J.R., et al., eds. Pediatric Dentistry: Infancy Through Adolescence. 3rd ed. Philadelphia, PA: W.B. Saunders Company. 1999. p. 54-67. Contact: Available from W.B. Saunders Company. Book Orders Fulfillment Department, Harcourt Health Sciences, 11830 Westline Industrial Drive, Saint Louis, MO 63146-9988. (800) 545-2522. Website: www.wbsaunders.com. PRICE: $69.00 plus shipping and handling. ISBN: 0721682383. Summary: This chapter on diseases and oral manifestations of systemic disease is from a textbook on pediatric dentistry. Topics include herpetic gingivostomatitis, recurrent herpes simplex (herpes labialis), herpes zoster (chicken pox), herpangina, hand, foot and mouth disease, impetigo, scarlet fever, candidiasis, diabetes mellitus, acute lymphoblastic leukemia, sickle cell anemia, histiocytoses (hystiocytosis X), hemophilia (hemophilia A; Factor VIII deficiency), and pediatric human immunodeficiency virus (HIV) infection. For each disease, the author reviews the causative agent, evaluation of the patient, diagnosis, and therapy. The chapter includes illustrative case studies for some of the diseases. The chapter is illustrated with numerous black and white photographs of the conditions under consideration. 9 figures. 3 tables. 41 references.
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Disorders of the Haemostasis Source: in Scully, C. and Cawson, R.A. Medical Problems in Dentistry. 4th ed. Woburn, MA: Butterworth-Heinemann. 1998. p. 82-105. Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801-2041. (800) 366-2665 or (781) 904-2500. Fax (800) 446-6520 or (781) 933-6333. E-mail:
[email protected]. Website: www.bh.com. PRICE: $110.00. ISBN: 0723610568.
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Summary: This chapter on disorders of hemostasis is from a text that covers the general medical and surgical conditions relevant to the oral health care sciences. Disorders of hemostasis cause management problems mainly because of prolonged postoperative bleeding, but hypercoagulability and thromboses can be as, or more, life-threatening. The authors discuss bleeding tendencies, the investigation of the patient with hemorrhagic disease, platelet disorders, vascular purpura, congenital coagulation defects (including hemophilia), acquired coagulation defects, and tendency to thrombosis. For each condition, the authors discuss general aspects, diagnosis and management issues, dental aspects, and patient care strategies. The chapter includes a lengthy summary of the points covered. 1 appendix. 13 tables. 69 references. •
Oral Bleeding Source: in Montgomery, M.T.; Redding, S.W., eds. Oral-Facial Emergencies: Diagnosis and Management. Portland, OR: JBK Publishing, Inc. 1994. p. 103-125. Contact: Available from Special Care Dentistry. 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2660. Fax (312) 440-2824. PRICE: $27.00 (member) or $30.00 (nonmember), plus shipping and handling; institutional prices and bulk orders available. ISBN: 0945892055. Summary: This chapter on oral bleeding is from an emergency room handbook that addresses a variety of orofacial injuries that are likely to be encountered in an acute care setting. Acute oral bleeding is a diverse condition, ranging from minor oozing secondary to a tooth extraction, to life-threatening bleeding in patients with severe hemostatic defects. The oral cavity is a common site for hemorrhagic problems because of its rich blood supply and susceptibility to trauma from such normal activities as speaking and eating. Commonly performed dental manipulations such as extractions, periodontal surgery, biopsies and scaling expose the oral soft tissues to significant iatrogenic insults. The author covers the normal physiology of hemostasis; disorders of hemostasis, including idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and thrombasthenia; the patient evaluation, including history taking, physical findings, and laboratory evaluation; and treatment recommendations, including therapies to reduce bleeding in hemophilia A. The author notes that patients with occult bleeding defects are often initially diagnosed following a dental procedure. 10 figures. 6 tables. 12 references. (AA-M).
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Management of the Medically Compromised Patient: Hematology, Oncology, Hepatitis, and AIDS Source: in McDonald, R.E. and Avery, D.A., eds. Dentistry for the Child and Adolescent. 7th ed. St. Louis, MO: Mosby, Inc. 2000. p. 600-625. Contact: Available from Harcourt Health Sciences. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Fax (800) 874-6418. Website: www.harcourthealth.com. PRICE: $72.00 plus shipping and handling. ISBN: 0815190174. Summary: This chapter on the management of the medically compromised patient is from a textbook on dentistry for the child and adolescent that is designed to help undergraduate dental students and postdoctoral pediatric dentistry students provide comprehensive oral health care for infants, children, teenagers, and individuals with various disabilities. The authors of this chapter focus on patients dealing with disorders of blood disease, cancer, hepatitis, and AIDS. The authors stress that in order to achieve optimal oral health for these medically compromised patients, the dentist and physician must establish a close working relationship. To minimize the risk of possible
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complications that may affect their general physical health, these patients need an aggressive prevention oriented program. The authors discuss hemophilia, viral hepatitis, AIDS (including the oral manifestations of HIV infection), leukemia, bone marrow or stem cell transplantation, and solid tumors. For each condition, the authors cover symptoms, etiology, treatment options, complications, risks to the dental staff, and dental treatment planning, including pain control. 4 figures. 6 tables. 40 references. •
Chapter 8-A: Musculoskeletal Signs and Symptoms: Monoarticular Joint Disease Source: in Klippel, J.H., et al., eds. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis Foundation. 2001. p. 157-160. Contact: Available from Arthritis Foundation. P.O. Box 1616, Alpharetta, GA 300091616. (800) 207-8633. Fax (credit card orders only) (770) 442-9742. Website: www.arthritis.org. PRICE: $69.95 plus shipping and handling. ISBN: 0912423293. Summary: This chapter provides health professionals with information on the diagnosis and treatment of monarticular joint disease. The causes of monarthritis are divided into inflammatory diseases and mechanical or infiltrative disorders. Diagnosis is based on the medical history; the physical examination; and the results of diagnostic tests such as synovial fluid analysis, laboratory tests, radiographs, and synovial biopsy. Treatment decisions must often be made before all test results are available, so antibiotics or nonsteroidal antiinflammatory drugs may be prescribed as an initial step in treating monarthritis. The chapter describes specific types of monarthritis, including infection, crystal induced arthritis, osteoarthritis (OA), osteonecrosis, trauma, foreign body reactions, hemarthrosis, systemic rheumatic diseases, and monarthritis of undetermined cause. The majority of nongonoccocal bacterial infections are monarticular. The most common agents are gram positive aerobes. Neisseria gonorrhoeae is probably still the most common cause of infectious arthritis. Gout, a crystal induced arthritis, is the most common type of inflammatory monarthritis. OA is a chronic and slowly progressive disease. Trauma to a joint can lead to monarticular disease. Hemarthrosis is caused by clotting abnormalities due to anticoagulant therapy or congenital disorders such as hemophilia. Many systemic diseases may begin as acute monarticular arthritis. In many patients, the cause of monarthritis cannot be determined. 2 tables and 15 references.
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Disorders of the Blood Source: in Grundy, M.C.; Shaw, L.; and Hamilton, D.V. Illustrated Guide to Dental Care for the Medically Compromised Patient. St. Louis, MO: Mosby-Year Book, Inc. 1993. p. 27-36. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-9934. (800) 426-4545 or (314) 872-8370; Fax (800) 535-9935 or (314) 4321380; E-mail:
[email protected]; http://www.mosby.com. PRICE: $24.95 plus shipping and handling. ISBN: 0815140223. Summary: This chapter, from an illustrated guide to dental care for medically compromised patients, discusses disorders of the blood. Topics covered include hemophilia; Christmas disease (hemophilia B); Von Willebrand's disease (vascular hemophilia); thrombocytopenia; anemia, including sickle cell anemia and thalassemia; and leukemia. For each condition, the authors provide a brief description, the components of medical management, and suggestions for dental care. Illustrations, including photographs, are included. 7 figures.
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Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to hemophilia have been published that consolidate information across various sources. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:12 •
Pediatric/family AIDS health care demonstration program: Directory Source: Newark, NJ: National Pediatric HIV Resource Center. 1993-. annual?. Contact: Available from National Pediatric and Family HIV Resource Center, 30 Bergen Street, ADMC no. 4, Newark, NJ 07107. Telephone: 973-972- 0410 (800) 362-0071 / fax: (973-972-0399 / e-mail: / Web site: http://www.pedhivaids.org. Summary: This directory lists the organizations involved in the Pediatric/Family AIDS Demonstration Project in the United States. It describes the goals of the program and lists lead organizations and affiliates that provide comprehensive direct services. Entries are organized by state, with the mailing address, telephone and fax numbers, and contact names provided for each organization. (Contact names are also indexed for easy reference.) In addition, the directory lists organizations involved in the Hemophilia Special Initiatives, as well as participants who provide training or technical assistance. [Funded by the Maternal and Child Health Bureau].
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You will need to limit your search to “Directory” and “hemophilia” using the "Detailed Search" option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Select your preferred language and the format option “Directory.” Type “hemophilia” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.
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CHAPTER 8. MULTIMEDIA ON HEMOPHILIA Overview In this chapter, we show you how to keep current on multimedia sources of information on hemophilia. 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 hemophilia is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “hemophilia” 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 “hemophilia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on hemophilia: •
AIDS: All Involved Deserve Support; Hemophilia Segment Contact: California Health and Welfare Agency, Department of Mental Health, Publications Section, 1600 Ninth St Rm 150, Sacramento, CA, 95814, (916) 654-2542. Summary: This videorecording discusses the impact of Acquired immunodeficiency syndrome (AIDS), caused by Human immunodeficiency virus (HIV), on the hemophiliac community. The videorecording notes that, while hemophiliacs have adjusted to the realities of their genetic disease, they now must cope with the psychological and stress factors associated with AIDS. Scenarios depicting two families whose members have been diagnosed with AIDS stress the importance of family relations, the necessity for support groups oriented towards hemophiliacs, and the difficulty of coping with grief.
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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. 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 “hemophilia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on hemophilia: •
Panel: Special Community Programs; Alternative Schools, Minneapolis Urban League, University of Minnesota Comprehensive Hemophilia Clinic, University of Minnesota Youth and AIDS Project Contact: University of Minnesota, Continuing Medical Education, 420 Delaware St SE, Box 202 UMHC, Minneapolis, MN, 55455, (612) 626-5525. Summary: This sound recording of proceedings from the 12th Annual Adolescent Health Care Conference, held October 12-13, 1990, in Minneapolis, MN, features four speakers who discuss peer education programs. Sandy Naughton, the first speaker, talks about recruiting students to act as peer educators in special community programs through alternative schools. She says it has improved students' sexual and drug-using behaviors in a dramatic fashion. Next, Grace Moore talks about peer education for African American adolescents through the Minneapolis Urban League. She says the program is called PREP, Planned Responsibility Equals Prevention, and that they train youth to become peer educators and to present information on AIDS, sexuality, sexually transmitted diseases (STDs), and drug abuse. Next, Roxanna Boelson, a nurse, tells about her work at the University of Minnesota Comprehensive Hemophilia Center. She explains that the center began in the mid-1970s to teach persons with hemophilia to become more independent in living with a chronic illness, but that HIV has added a whole new dimension to their work. She began working with the center in 1988, counseling adolescent hemophiliacs and their sex partners. Boelson started a program of handing out condoms and evaluating adolescents for inclusion in clinical trials. All information is kept confidential from their parents. The final speaker, Dr. Gary Remafedi, details his work with homosexual youth at the University of Minnesota Youth and AIDS Project. The goal of the program, he says, is to prevent transmission of HIV to and from homosexual youth. Remafedi says that aside from transfusion-related AIDS, 70 percent of all adolescent AIDS cases are among homosexuals. He says some adolescents come to the project through self-referral, some through peer referral, and some through professional referral. At the project, they are counseled on sexuality and HIV prevention. He says that according to their behaviors, 75 percent are at extreme risk. A question-and-answer period follows the panel discussion.
Bibliography: Multimedia on Hemophilia 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 hemophilia (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 hemophilia:
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Biopharmaceutical research [videorecording]; Treating cardiac r[h]ythm; Immunodiagnostic testing; Earth-friendly food packing; Hemophilia medication; Alternative trading systems. Year: 2001; Format: Videorecording; [Boca Raton, Fla.]: Multi-Media Productions, c2001
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Hemophilia [slide] Source: American Society of Hematology; Year: 1974; Format: Slide; [Seattle: The Society: for sale by American Society of Hematology National Slide Bank, 1974]
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Hemophilia [slide]: orthopaedic manifestations and treatment Source: American Academy of Orthop[a]edic Surgeons; Year: 1985; Format: Slide; [Park Ridge, Ill.]: AAOS, [1985]
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Hemophilia [slide]. Year: 1987; Format: Slide; [Columbus, Ohio]: Center for Continuing Medical Education, the Ohio State University College of Medicine, [1987]
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Hemophilia [videorecording] Source: [Stanley P.] Balcerzak; produced by Ohio State University, Medical Audiovisual and Television Center; Year: 1971; Format: Videorecording; [Columbus, Ohio]: The Center, c1971
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Hemophilia [videorecording] Source: Children's Hospital, Boston; Year: 1994; Format: Videorecording; Boynton Beach, FL: Universal Health Communications, [1994]
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Hemophilia and von Willebrand's disease [videorecording] Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1982; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1982
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Hemophilia in infants and children [videorecording] Source: [presented by] the Medical University of South Carolina, Departments of Pathology and Laboratory Medicine and Pediatrics; produced by the Health Communications Network, Division of Television Services; Year: 1993; Format: Videorecording; Charleston, S.C.: The University, c1993
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Hemophilia in the 1990's [videorecording] Source: produced by UT-TV Houston; Year: 1991; Format: Videorecording; [Houston, Tex.]: UT-TV Houston, c1991
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Hemophilia update [videorecording] Source: College of Medicine, Division of Hemophilia, the Pennsylvania State University; produced by Penn-State Television; Year: 1975; Format: Videorecording; University Park, Pa.: The University: [for loan or sale by its Audio-Visual Services], c1975
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Information system for healthcare [videorecording]; Manipulating macromolecules; Genomic research & disease; Hemophilia medication: home delivery; Biopharmaceuticals research development; Treating cardiac rhythm disorders. Year: 2001; Format: Videorecording; Boca Raton, FL: Multi-Media Productions, 2001
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Orthopaedic surgery [sound recording]: AIDS--trauma and hemophilia Source: American College of Surgeons; Year: 1989; Format: Sound recording; Chicago, IL: The College, [1989]
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X-ray findings related to hemophilia [videorecording] Source: M.I. Goldstein; produced by Ohio State University Medical Audiovisual and Television Center; Year: 1972; Format: Videorecording; [Columbus, Ohio]: The Center, c1972
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CHAPTER 9. PERIODICALS AND NEWS ON HEMOPHILIA Overview In this chapter, we suggest a number of news sources and present various periodicals that cover hemophilia.
News Services and Press Releases One of the simplest ways of tracking press releases on hemophilia 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 “hemophilia” (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 hemophilia. 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 “hemophilia” (or synonyms). The following was recently listed in this archive for hemophilia: •
Baxter hemophilia drug appears slow to catch on Source: Reuters Industry Breifing Date: November 11, 2003
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Baxter hemophilia drug gets recommendation in Europe Source: Reuters Industry Breifing Date: October 23, 2003
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Avigen to resume gene therapy trial for hemophilia B Source: Reuters Medical News Date: September 09, 2003
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Hemophilia carriers are protected against fatal ischemic heart disease Source: Reuters Medical News Date: July 31, 2003
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FDA approves recombinant Factor VIII hemophilia therapy Source: Reuters Medical News Date: July 28, 2003
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Baxter wins FDA approval for new hemophilia therapy Source: Reuters Industry Breifing Date: July 28, 2003
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Avigen receives $2.5 million milestone from Bayer for hemophilia treatment Source: Reuters Industry Breifing Date: March 03, 2003
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CCR5 genotype does not influence HIV infection in children with hemophilia Source: Reuters Medical News Date: January 21, 2003
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Curative Health to expand hemophilia offerings through OptCare Plus acquisition Source: Reuters Industry Breifing Date: November 14, 2002
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Bayer receives US approval to increase production of hemophilia drug Source: Reuters Industry Breifing Date: October 01, 2002
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Baxter files US marketing application for hemophilia A treatment Source: Reuters Industry Breifing Date: June 27, 2002
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Sales of hemophilia agents help Baxter meet 1Q estimates Source: Reuters Industry Breifing Date: April 18, 2002
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Baxter to triple hemophilia treatment output by 2006, reaffirms financial forecasts Source: Reuters Industry Breifing Date: March 14, 2002
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Hemophiliacs may be first to benefit from gene therapy Source: Reuters Medical News Date: January 28, 2002
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Avigen cleared to continue phase I trial of hemophilia B gene therapy Source: Reuters Industry Breifing Date: December 20, 2001
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Trial of Avigen hemophilia B therapy on hold Source: Reuters Medical News Date: October 08, 2001
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Avigen phase I hemophilia B therapy on hold Source: Reuters Industry Breifing Date: October 08, 2001
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GenStar cleared to re-start trial of hemophilia A gene therapy Source: Reuters Industry Breifing Date: September 25, 2001
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Catheter use in hemophiliacs linked with blood clot risk Source: Reuters Medical News Date: September 17, 2001
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Avigen starts clinical study of hemophilia gene therapy Source: Reuters Industry Breifing Date: August 16, 2001
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Gene treatment for hemophilia A shows promise in early phase l report Source: Reuters Medical News Date: July 12, 2001
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Avigen says hemophilia B therapy eligible for orphan drug program Source: Reuters Industry Breifing Date: July 09, 2001
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Cell Genesys drops intramuscular hemophilia gene therapy on preclinical data Source: Reuters Industry Breifing Date: June 19, 2001
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Hemophilia drug shortage will persist into 2002 Source: Reuters Medical News Date: June 11, 2001
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Hemophilia drug shortage to persist into 2002 Source: Reuters Industry Breifing Date: June 11, 2001
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TKT gene therapy for hemophilia appears successful in phase I Source: Reuters Industry Breifing Date: June 07, 2001
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Implantation of fibroblasts expressing factor VIII feasible in hemophilia A patients Source: Reuters Medical News Date: June 07, 2001
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FDA approves second Avigen trial on a gene therapy for hemophilia B Source: Reuters Industry Breifing Date: June 04, 2001
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American Home Products unit licenses Dyax's hemophilia ligand Source: Reuters Industry Breifing Date: May 22, 2001
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Baxter, AHP settle hemophilia drug supply dispute Source: Reuters Industry Breifing Date: April 17, 2001
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Expiration of waiting period triggers Avigen, Bayer deal for hemophilia B product Source: Reuters Industry Breifing Date: February 12, 2001
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Bayer acquires rights to market Avigen hemophilia B treatment Source: Reuters Industry Breifing Date: November 17, 2000
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Baxter to launch trial of novel hemophilia candidate Source: Reuters Industry Breifing Date: November 16, 2000
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Wyeth-Ayerst unit, Targeted Genetics to develop hemophilia drugs Source: Reuters Industry Breifing Date: November 09, 2000
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Europe approves Baxter's California site to make anti-hemophilia protein Source: Reuters Industry Breifing Date: November 09, 2000
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Continuous-injection factor VIII benefits hemophiliacs undergoing surgery Source: Reuters Medical News Date: October 11, 2000
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FDA approves Baxter facility for expanded production of hemophilia drug Source: Reuters Industry Breifing Date: October 05, 2000
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National Hemophilia Foundation protests Bayer drug distribution program Source: Reuters Industry Breifing Date: September 27, 2000
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First HIV-infected hemophiliac patients to get Ricky Ray Fund monies Source: Reuters Medical News Date: August 30, 2000
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FDA approves Bayer's Kogenate to treat hemophilia A Source: Reuters Industry Breifing Date: June 29, 2000
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Cell Genesys reports positive preclinical results for hemophilia B therapy Source: Reuters Industry Breifing Date: June 06, 2000
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Transposon-based gene therapy successfully treats hemophilia in mice Source: Reuters Medical News Date: May 10, 2000
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Skin graft gene therapy effective in murine hemophilia Source: Reuters Medical News Date: May 04, 2000
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Coagulation device may treat hemophilia Source: Reuters Health eLine Date: March 09, 2000
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Hemophilia drug wins FDA approval Source: Reuters Health eLine Date: March 08, 2000
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FDA approves AHP hemophilia drug Source: Reuters Medical News Date: March 08, 2000
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Factor IX gene therapy promising in hemophilia B patients Source: Reuters Medical News Date: March 03, 2000
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Promising results from gene therapy trial for hemophilia B Source: Reuters Health eLine Date: March 02, 2000 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. 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 “hemophilia” (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 “hemophilia” (or synonyms). If you know the name of a company that is relevant to hemophilia, 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 “hemophilia” (or synonyms).
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Newsletters on Hemophilia Find newsletters on hemophilia using the Combined Health Information Database (CHID). You will need to use the “Detailed Search” option. To access CHID, go to the following hyperlink: http://chid.nih.gov/detail/detail.html. Limit your search to “Newsletter” and “hemophilia.” 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.” Type “hemophilia” (or synonyms) into the “For these words:” box. The following list was generated using the options described above: •
HANDI quarterly Source: New York, NY: National Hemophilia Foundation. 1992-. quarterly. Contact: Available from Hemophilia and AIDS/HIV Network for the Dissemination of Information, 116 West 32nd Street, 11th Floor, New York, NY 10001. Telephone: (212) 328-3700 or (800) 42-HANDI / fax: (212) 328-3799 / e-mail:
[email protected] / Web site: http://WWW.INFONHF.ORG. Available at no charge. Summary: This newsletter is the official publication of the Hemophilia and AIDS-HIV Network for the Dissemination of Information (HANDI). It provides information for people with hemophilia and those with hemophilia and HIV. Each issue focuses on a single topic, such as nutrition, financing care, or information needs, and includes a listing of resources most of which are available through HANDI.
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 “hemophilia” (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 hemophilia: •
Warning Signs in the Mouth Source: Closing the Gap. p. 13. July 1999. Contact: Available from Office of Minority Health Resource Center. P.O. Box 37337, Washington, DC 20013-7337. (800) 444-6472. Summary: This brief newsletter article describes the warning signs and symptoms that may show up in the mouth with systemic diseases such as kidney disease, anemia, hemophilia and other bleeding disorders, adrenal gland disorders, and inflammatory bowel diseases. Chronic renal (kidney) disease has several early oral signs, including a metallic taste in the mouth, dry mouth, swelling glands, and frequent infection of the soft tissues. In the early stages of anemia, patients often complain about their tongue becoming smooth and glistening and feeling like it is burning. Unprovoked bleeding of the gums is a warning sign of bleeding disorders such as hemophilia, von Willebrand's disease, leukemia, and lymphomas. Brown or black splotches on the inner lining of the cheeks and lips are seen in the early stages of Addison's disease and other adrenal gland
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disorders. A cobblestone appearance of the soft tissue of the mouth and a generalized swelling of the linings of the cheeks and lips are early signs of inflamed bowels and Crohn's disease. Patients with ulcers often have a history of oral cold sores because mouth and intestinal tissues are closely related.
Academic Periodicals covering Hemophilia Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to hemophilia. In addition to these sources, you can search for articles covering hemophilia 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 hemophilia. 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 hemophilia. 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 hemophilia: Antihemophilic Factor •
Systemic - U.S. Brands: Alphanate; Bioclate; Helixate; Humate-P; Hyate:C; Koate-HP; Kogenate; Monarc-M; Monoclate-P; Recombinate http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202671.html
Desmopressin •
Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202671.html
Factor Ix •
Systemic - U.S. Brands: BeneFix; Mononine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202674.html
Factor Viia •
Systemic - U.S. Brands: NovoSeven http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500113.html
Hepatitis A Vaccine Inactivated •
Systemic - U.S. Brands: Havrix; Vaqta http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202902.html
Vitamin K •
Systemic - U.S. Brands: Note: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202599.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
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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 hemophilia 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 “hemophilia” (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 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 hemophilia: •
Adenovirus-based vector Factor VIII complementary (trade name: MiniAdFVIII) http://www.rarediseases.org/nord/search/nodd_full?code=1008
•
Adeno-associated viral vector containing the gene (trade name: Coagulin-B) http://www.rarediseases.org/nord/search/nodd_full?code=1110
•
Adeno-associated viral vector containing the gene (trade name: Coagulin-B) http://www.rarediseases.org/nord/search/nodd_full?code=1111
•
Adeno-associated viral vector containing the gene (trade name: Coagulin-B) http://www.rarediseases.org/nord/search/nodd_full?code=1140
•
Adeno-associated viral vector containing the gene (trade name: Coagulin-B) http://www.rarediseases.org/nord/search/nodd_full?code=1141
•
R-VIII SQ (trade name: REFACTO) http://www.rarediseases.org/nord/search/nodd_full?code=450
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•
Desmopressin acetate http://www.rarediseases.org/nord/search/nodd_full?code=470
•
Factor VIIa (recombinant, DNA origin) http://www.rarediseases.org/nord/search/nodd_full?code=497
•
Antihemophilic factor (recombinant) (trade name: Kogenate) http://www.rarediseases.org/nord/search/nodd_full?code=563
•
Coagulation Factor IX (human) (trade name: AlphaNine) http://www.rarediseases.org/nord/search/nodd_full?code=656
•
Coagulation Factor IX (recombinant) (trade name: BeneFix) http://www.rarediseases.org/nord/search/nodd_full?code=657
•
Coagulation factor IX (trade name: Mononine) http://www.rarediseases.org/nord/search/nodd_full?code=659
•
Recombinant humanized MAb 5c8 http://www.rarediseases.org/nord/search/nodd_full?code=946
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 Institute13: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
•
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
•
National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
•
National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
•
National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
•
National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
•
National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
13
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/
•
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
•
National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
•
National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
•
National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
•
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
•
National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
•
National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
•
National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
•
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
•
National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
•
National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
•
Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
•
National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
•
National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
•
Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
•
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.14 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:15 •
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/
•
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
•
Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
•
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/
•
Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
•
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
•
Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
•
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
14
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). 15 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 “hemophilia” 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 “hemophilia” (or synonyms) into the “For these words:” box. The following is a sample result: •
HIV Risk Reduction Planning for the Hemophilia Community; World Hemophilia Federation Meeting, Washington, D.C., August 13-19, 1990 Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This conference paper from the World Hemophila Federation Meeting held in Washington, D.C., on August 13-19, 1990, describes the collaborative efforts of the Office of Maternal and Child Health, Centers for Disease Control and Prevention (CDC), and the National Hemophilia Foundation in designing, implementing, and evaluating programs to reduce the risk of exposure to Human immunodeficiency virus (HIV), the etiologic agent of Acquired immunodeficiency syndrome (AIDS), among persons with hemophilia, their sex partners, and their children.
•
Adolescents, Hemophilia, & HIV: Speaker B's Adviser Contact: CSG Enterprises, 301 N Harrison St Ste 156, Princeton, NJ, 08540. Summary: This manual gives instruction on a program of structured role play simulations, designed to teach adolescents with hemophilia, or those associated with someone who has hemophilia, about the connection between that illness and Human immunodeficiency virus (HIV) infection. Each encounter consists of before, during, and after instructions, and a role-play scenario. Subjects addressed include parental role, safer sex, family situations, physician patient relations, and condom use. This manual is for those taking the role of Speaker B's adviser.
•
Women, Hemophilia and HIV: Group Leader Contact: CSG Enterprises, 301 N Harrison St Ste 156, Princeton, NJ, 08540. Summary: This manual is part of a set of materials designed to implement structured role play simulations. This manual teaches women whose partners may have hemophila and/or Human immunodeficiency virus (HIV) infection how to deal with the disease. Each of 20 encounters includes goals, resources, activities, a plan for an encouter period,
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and a discussion period. They address such topics as fear, safer sexual conduct, parenthood, planning, children, schools, talking with physicians, and dealing with inlaws. This manual is for the Group leader. •
Handi Staff Introduction to Hemophilia and HIV/AIDS Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This manual offers answers to frequently asked questions about hemophilia, von Willebrand disease, and HIV/AIDS. It defines different types of calls, categorizing them by caller; suggests basic listening techniques; and describes ways to gather information from callers. It offers reference source information on the HIV/AIDS population in the hemophilia community. The manual discusses dealing with callers in need of psychosocial support, proposes a number of role-playing scenarios, and lists NHF directories, indexes, and referral sources. It includes a statistics sheet on hemophilia in the United States and an AIDS update from the Hemophilia Information Exchange.
•
HIV Risk Reduction Within the Hemophilia Community: A National Program Planning Manual Contact: US Department of Health and Human Services, Public Health Service, Health Resources and Services Administration, Office of Communications, HIV/AIDS Bureau, 5600 Fishers Ln 7-46, Rockville, MD, 20857, (301) 443-6652, http://www.hrsa.dhhs.gov/hab. Summary: This manual provides guidance in developing goals and objectives for reducing risk for Human immunodeficiency virus (HIV) in the National Hemophilia Comprehensive Care Program. It includes a description of the National Agenda, and concomitant goals and objectives. It provides instructions on how to write a management plan including goals and HIV risk-reduction objectives; inventory of community resources; development of protocols for outreach, patient services and evaluation; and determining staff requirements. Supplements to the manual include new goals and objectives; a KABB questionnaire; community outreach model programs; and comprehensive care. It also provides information on resources and materials available to enhance program development and implementation.
•
Adolescents, Hemophilia, & HIV: Group Leader Contact: CSG Enterprises, 301 N Harrison St Ste 156, Princeton, NJ, 08540. Summary: This manual, written for group leaders, gives instructions on a program of structured role play simulations. It is designed to teach adolescents with hemophilia, or those associated with someone who has hemophilia, about the connection between hemophilia and the Human immunodeficiency virus (HIV). The first section of the manual explains the program and provides a time schedule for each activity. The program consists of preparation, the encounter, a small group discussion, and a large group discussion. Each encounter consists of before, during, and after instructions, and a role-play scenario. Subjects addressed include parental role, safer sex, family situations, physician patient relations, and condom use. This program is supposed to help people talk about problems in a safe, caring and fun way; and get new ideas about how to solve problems.
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•
Adolescents, Hemophilia, & HIV: Operator's Manual Contact: CSG Enterprises, 301 N Harrison St Ste 156, Princeton, NJ, 08540. Summary: This manual, written for operator's of the program, gives instructions on a program of structured role play simulations (encounters). The program is designed to teach adolescents with hemophilia, or those associated with someone who has hemophilia, about the connection between hemophilia and the Human immunodeficiency virus (HIV). An overview of the subject matter and purpose, the simulation in operation, advantages of a simulation approach, and a summary of the encounter issues are given. Also provided for the operator are practical considerations, step-by-step instructions on running the simulation, and guidelines for leading the discussions. Subjects addressed include parental role, safer sex, family situations, physician patient relations, and condom use. An appendix provides a list of additional readings, information about the authors, and instructions for introducing the session.
•
How Do HIV and Hemophilia Affect Health Insurability and Existing Group Insurance? Contact: Great Lakes Hemophilia Foundation, PO Box 704, Milwaukee, WI, 53201-0704, (414) 257-0200, http://www.glhf.org. Summary: This paper briefly describes the impact of hemophilia and HIV, on an individual's insurability for new insurance programs and status in existing group policies.
•
A New Decade: Hopes and Challenges. XIX International Congress of the World Federation of Hemophilia: Washington, D.C., August 14-19, 1990 Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This program lists the workshops, posters, and special programs presented at this conference on hemophilia. The presentations cover a wide range of diseases and psychosocial issues that confront persons with hemophilia, one of which is Acquired immunodeficiency syndrome (AIDS), caused by Human immunodeficiency virus (HIV). Some of the issues discussed include the need for increased patient support, the development of new treatment programs for hemophilia and AIDS, and the inadequate health service accessibility that faces many individuals.
•
Hemophilia Treatment in New York State; Status Report and Recommendations Contact: New York Department of Health, Hemophilia Advisory Panel, PO Box 509, Albany, NY, 12201-0509. Summary: This report discusses many issues associated with hemophilia and its treatment, specifically in New York State. Following an overview of the disease, the report describes blood products, a regional consortium for purchasing and distributing clotting factor concentrate, health insurance trends, and transfusion-associated diseases, including Human immunodeficiency virus (HIV), the etiologic agent of Acquired immunodeficiency syndrome (AIDS).
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Survey Report of Hemophilia and HIV Programs for Adolescents Contact: National Hemophilia Foundation, Hemophilia and AIDS/HIV Network for Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (800) 424-2634, http://www.hemophilia.org. Summary: This report presents the results of a survey of local HIV prevention and support programs for adolescents with hemophilia. The purposes of the survey were to determine the availability of such programs, to determine trends in program development, to select model programs to serve as a basis for recommendations for the development of new programs, and to improve networking and communication. The review process consisted of a short preliminary survey, a longer written survey, and a telephone survey. The report presents an analysis of survey results, suggests model programs, and summarizes selected HIV prevention and support programs directed at other adolescents. A number of recommendations and conclusions are included.
•
Condom Use to Prevent HIV in Wives of Men With Hemophilia Who Are HIV Seropositive Contact: University of Georgia, College of Education, Department of Health Promotion and Behavior, 300 River Rd, Athens, GA, 30602-6522, (706) 542-3313, http://www.coe.uga.edu/health/. Summary: This report summarizes a study conducted to examine condom use during 1993 and 1994 in a selected sample of married couples when the husband has hemophilia and is HIV seropositive and all wives are seronegative. The study attempted to identify psychosocial variables which differentiated couples that consistently and inconsistently used condoms. The study results suggest that condom use is consistent in most such couples. This may reflect actual changes in condom use or that the nature of the current sample differed from earlier studies. Men who were consistent condom users also reported a higher level of general psychological stress. These husbands are more anxious and more uncertain about the future of their illness.
•
Safety of Therapeutic Products Used for Hemophilia Patients Source: Morbidity and Mortality Weekly Report; Vol. 37, no. 29. 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 summarizes information discussed at a January 11, 1988, meeting sponsored by the Centers for Disease Control and Prevention (CDC) to discuss the safety of therapeutic products used for treating hemophilia patients, focusing specifically on the transmission of Human immunodeficiency virus (HIV) and non-A, non-B hepatitis viruses. The purpose of the meeting was to share current epidemiologic and clinical trial data, to address therapeutic issues, and to review the safety of the manufactured blood components used for treating hemophilia patients. An editorial note reports that epidemiologic and laboratory data indicate that processed plasma derivatives currently available in North America, Europe, and Australia have a high degree of safety with regard to HIV transmission. It also presents the National Hemophilia Foundation's recommendations for United States physicians, developed after a review of the data presented at the CDC-sponsored meeting.
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•
Guidelines to Fight/End Discrimination Within the Hemophilia Community Contact: National Hemophilia Foundation, Hemophilia and AIDS/HIV Network for Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (800) 424-2634, http://www.hemophilia.org. Summary: This statement lists National Hemophilia Foundation guidelines for hemophiliacs and members of their families who have experienced discrimination by schools, in the workplace, from insurance companies, and other sources. Guidelines are classified as safe, probably safe, and unsafe for legal recourse, sources of support, and maintenance of confidentiality.
•
Hemophilia and Acquired Immune Deficiency Syndrome (AIDS): Intimacy and Sexual Behavior Contact: National Hemophilia Foundation, AIDS Task Force and Mental Health Committee, 110 Greene St Rm 406, New York, NY, 10012, (212) 219-8180. Summary: This update discusses the implications of the high risk of Human immunodeficiency virus (HIV) infection among hemophiliacs and its implications for their sexual activities. The risk associated with a variety of sexual activities is discussed, and alternatives and strategies for minimizing the risk of transmission to a sexual partner are described. The possibility of transmission of infection to a fetus is discussed. Advice on sexual intimacy for adolescents with hemophilia and their parents is also provided.
The NLM Gateway16 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.17 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “hemophilia” (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. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
16 17
Items Found 14862 350 270 675 10 16167
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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HSTAT18 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.19 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.20 Simply search by “hemophilia” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
Coffee Break: Tutorials for Biologists21 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.22 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.23 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/.
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/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
18
Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html.
19
The HSTAT URL is http://hstat.nlm.nih.gov/.
20
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. 21 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 22 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. 23 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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The Genome Project and Hemophilia In the following section, we will discuss databases and references which relate to the Genome Project and hemophilia. 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).24 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 “hemophilia” (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 hemophilia: •
Hemophilia A Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?306700
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Hemophilia A with Vascular Abnormality Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?306800
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Hemophilia B Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?306900 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: •
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
24 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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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 “hemophilia” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database25 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. The Genome Database26 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 25
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 26 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.
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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 “hemophilia” (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).
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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 hemophilia 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 hemophilia. 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 hemophilia. 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 “hemophilia”:
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Other guides AIDS http://www.nlm.nih.gov/medlineplus/aids.html AIDS and Infections http://www.nlm.nih.gov/medlineplus/aidsandinfections.html Alpha-1 Antitrypsin Deficiency http://www.nlm.nih.gov/medlineplus/alpha1antitrypsindeficiency.html Anemia http://www.nlm.nih.gov/medlineplus/anemia.html Bleeding Disorders http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html Genes and Gene Therapy http://www.nlm.nih.gov/medlineplus/genesandgenetherapy.html Genetic Testing/Counseling http://www.nlm.nih.gov/medlineplus/genetictestingcounseling.html Hemophilia http://www.nlm.nih.gov/medlineplus/hemophilia.html Hepatitis http://www.nlm.nih.gov/medlineplus/hepatitis.html Hepatitis A http://www.nlm.nih.gov/medlineplus/hepatitisa.html Hepatitis B http://www.nlm.nih.gov/medlineplus/hepatitisb.html Immune System and Disorders http://www.nlm.nih.gov/medlineplus/immunesystemanddisorders.html Pneumocystis Carinii Infections http://www.nlm.nih.gov/medlineplus/pneumocystiscariniiinfections.html Pulmonary Embolism http://www.nlm.nih.gov/medlineplus/pulmonaryembolism.html
Within the health topic page dedicated to hemophilia, the following was listed: •
General/Overviews Frequently Asked Questions: Hemophilia Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=28&Document=42&IndLangue=2 Hemophilia in Pictures Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=31&Document=181&IndLangue=2 Hemophilia: Facts for Families Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=31&Document=180&IndLangue=2
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Treatment New Recombinant Antihemophilic Factor Licensed Source: Food and Drug Administration http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01241.html
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Coping Information for Teachers and Childcare Providers Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_providers.htm Tips for Travellers Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=26&Document=53&IndLangue=2
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Specific Conditions/Aspects Bleeding Disorders: Financial and Insurance Issues Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_issues.htm Factor I Deficiency (Afibrinogenemia) Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_types4.htm Factor II Deficiency (Prothrombin) Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_types5.htm Factor V Deficiency Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00378 Factor VII Deficiency (Proconvertin or Stable Factor) Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_types7.htm Hemophilia A (Factor VIII Deficiency) Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_types1.htm Hemophilia B (Factor IX Deficiency) Source: National Hemophilia Foundation http://www.hemophilia.org/bdi/bdi_types2.htm
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Children Growing up with Hemophilia - Babies Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=31&Document=216&IndLangue=2 Growing up with Hemophilia - Going to School Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=31&Document=218&IndLangue=2
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Growing up with Hemophilia - Toddlers and Preschool Children Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=31&Document=217&IndLangue=2 How to Deal with Hemophilia Source: Nemours Foundation http://kidshealth.org/kid/health_problems/blood/hemophilia.html •
Law and Policy Ricky Ray Hemophilia Relief Fund: Frequently Asked Questions Source: Health Resources and Services Administration http://bhpr.hrsa.gov/rickyray/faq.htm
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Organizations National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/ National Hemophilia Foundation http://www.hemophilia.org/home.htm World Federation of Hemophilia http://www.wfh.org/
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Teenagers Growing up with Hemophilia - Adolescence Source: World Federation of Hemophilia http://www.wfh.org/ShowDoc.asp?Rubrique=31&Document=219&IndLangue=2
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 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 hemophilia. 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:
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History of the National Hemophilia Foundation's Opposition to AIDS Litigation in the Hemophilia Community Contact: Committee of Ten Thousand, 918 Pennslyvania Ave SE, Washington, DC, 20003, (202) 543-0988, http://www.cott.org. Summary: In this fact sheet, the author examines the role of the National Hemophilia Foundation (NHF) in opposing AIDS litigation, particularly in the form of class action suits, against fractionators of blood products. The reasons given by the NHF in opposing class action lawsuits are confidentiality issues and failure rates of individual lawsuits. The author states the failure rates are due to NHF physicians testifying on behalf of the fractionators. The fact sheet explains the four qualifying conditions for a class action lawsuit and how the NHF argued against the issues of commonality and numerosity. At the least, the NHF discourages families from filing lawsuits or supporting class action suits.
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HIV Seroprevalence in the Hemophilia Community Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This AIDS update fact sheet on HIV seroprevalence in the hemophilia community provides information obtained from the Seroconversion Surveillance Project (SSP). The data, collected during 1985-1989, from SSP indicates that half of all persons with hemophilia and other coagulation disorders were HIV-infected. It also illustrates the rate of seropositivity increases with the severity of the coagulation disorder. It suggests the significant regional differences in seropositivity rates require further investigation.
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Hemophilia and Sports Contact: American Red Cross National Headquarters, American Red Cross, National Headquarters, Health and Safety Services, Office of HIV/AIDS Education, 8111 Gatehouse Rd 6th Fl, Falls Church, VA, 22042-1203, (703) 206-6707, http://www.redcross.org/. National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This booklet reviews common attitudes and make recommendations concerning participation in sports and games by children and adults with severe hemophilia. Participation related to sports by a child with hemophilia presents certain risks, but is vital to his physical and psychological development. The general body build of the person, past clinical history, and present conditions of joints should all be considered when choosing a sport, with appropriate precautions taken in all cases. A list of various sports includes evaluative ratings on their safety. The booklet briefly discusses sports activities for persons with mild hemophilia.
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Comprehensive Care for People With Hemophilia Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This brochure addresses comprehensive care for people with hemophilia; that is, continuing supervision by a multidisciplinary team of professionals overseeing
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all medical and psychosocial factors affecting persons and their families. The brochure discusses the functions of a comprehensive care center, the components of the team, essential resources, HIV infection and hemophilia, implementation of the treatment plan, and the benefits of comprehensive care. •
Living With HIV: For Adolescents With Hemophilia Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This brochure answers questions about HIV that might be asked by adolescents with hemophilia. The brochure discusses symptoms of AIDS, modes of HIV transmission, the HIV-antibody test, studies regarding casual contact transmission, and the need for sexually active adolescents to engage in safer sexual conduct. Other issues that are explored include AIDS-related discrimination, the benefits and drawbacks of informing schools of seropositive results, infection-control procedures, health practices for HIV-positive persons, and available treatment programs.
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National Hemophilia Foundation: The Tex Cen Chapter Contact: National Hemophilia Foundation, Texas Central Chapter, 3530 Forest Ln Ste 116, Dallas, TX, 75234, (214) 351-4595, http://www.hemophilia.org. Summary: This brochure describes hemophilia, which is a genetic disease; treatment programs for hemophiliacs; activities of the National Hemophilia Foundation; and suggestions for community support. Hemophiliacs who received blood clotting factor before 1985 are at high risk of exposure to Human immunodeficiency virus (HIV), the etiologic agent of Acquired immunodeficiency syndrome (AIDS).
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Hemophilia, AIDS and Family Planning Contact: Great Lakes Hemophilia Foundation, PO Box 704, Milwaukee, WI, 53201-0704, (414) 257-0200, http://www.glhf.org. Summary: This brochure discusses the risks and ramifications of parenthood for hemophiliacs. It looks at evaluating risks related to Human immunodeficiency virus (HIV) infection, pros and cons of deciding to postpone or attempt pregnancy, and making an informed decision.
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What You Should Know About Hemophilia Contact: National Hemophilia Foundation, Hemophilia and AIDS Network for the Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (212) 328-3700, http://www.infonhf.org. Summary: This brochure gives detailed information about hemophilia. It mentions that many persons with hemophilia became infected with the Human immunodeficiency virus (HIV) through blood transfusions.
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Let's Talk About Hemophilia and AIDS Contact: Hemophilia Council of California, 1507 21st St, Suite 206, Sacramento, CA, 95814, (916) 448-7444. Summary: This brochure presents basic information about Acquired immunodeficiency syndrome (AIDS) and Human immunodeficiency virus (HIV) infection for children who
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have hemophilia. It explains the pathogenesis of hemophilia and the alit-hemophilia factor in blood transfusions in relation to HIV transmission through blood. •
Questions and Answers About HIV and AIDS for Parents of Children With Hemophilia Contact: Great Lakes Hemophilia Foundation, PO Box 704, Milwaukee, WI, 53201-0704, (414) 257-0200, http://www.glhf.org. Summary: This brochure provides advice to parents of hemophiliacs about Human immunodeficiency virus (HIV) and Acquired immunodeficiency syndrome (AIDS). It covers the risk of infection through contaminated blood products, emotional and sexual issues, testing, talking with teenage sons about AIDS, coping with emotions of fear and anxiety, and the lack of risk through casual contact.
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Research Priorities in Hemophilia : HCV and HIV Disease : A Blueprint for Action Contact: National Hemophilia Foundation, Hemophilia and AIDS/HIV Network for Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (800) 424-2634, http://www.hemophilia.org. Summary: This brochure provides information concerning the need to study the impact of medical treatments for the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) on persons with hemophilia. The brochure describes HCV and the available treatments, noting the lack of real knowledge about how HCV interacts with hemophilia. The brochure makes recommendations for research to discover more about HCV in hemophiliacs. It examines HIV/AIDS, its history among hemophiliacs, and the development of combination therapies to treat persons with this infection/disease. The brochure calls for research to be done concerning the impact and effectiveness of combination therapies on persons with HIV/AIDS and hemophilia. It supplies the readers with similar information concerning persons with hemophilia who are co-infected with HIV/AIDS and HCV. The brochure suggests an order for research priorities concerning people with all three of these afflictions.
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Health Insurance Options for Persons With Hemophilia and HIV/ARC/AIDS Contact: Great Lakes Hemophilia Foundation, PO Box 704, Milwaukee, WI, 53201-0704, (414) 257-0200, http://www.glhf.org. Summary: This brochure provides insurance information to hemophiliacs, particularly those infected with HIV/AIDS. Health-insurance options and assistance programs that may provide health benefits are listed and briefly described.
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Questions and Answers About HIV and AIDS for Young People With Hemophilia Contact: Great Lakes Hemophilia Foundation, PO Box 704, Milwaukee, WI, 53201-0704, (414) 257-0200, http://www.glhf.org. Summary: This brochure provides young hemophiliacs with information on Acquired immunodeficiency syndrome (AIDS) and Human immunodeficiency virus (HIV), including forms of transmission and preventive measures. It explains the meaning of positive results on the HIV-antibody test.
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Spanish Hemophilia/HIV Resource: A Listing of Materials Available From the HANDI Information Center Contact: National Hemophilia Foundation, Hemophilia and AIDS/HIV Network for Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (800) 424-2634, http://www.hemophilia.org. Summary: This directory lists educational materials available from the HANDI resource center. Resources include articles, books, brochures, children's stories, and fliers; and address a wide variety of topics, including genetic screening for hemophilia, HIV transmission, children living with hemophilia, viral hepatitis, home infusion therapy, nutritional guidelines for people with hemophilia, and self esteem.
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Hemophilia Source: Kansas City, MO: University of Missouri, School of Dentistry. 1990. 1 p. Contact: Available from University of Missouri, Kansas City. School of Dentistry, 650 East 25th Street, Kansas City, MO 64108. (816) 235-2111; http://www.umkc.edu/dentistry. PRICE: Single copy free. Summary: This fact sheet, part of a series on oral health and various disabling conditions, discusses hemophilia. Dental concerns associated with hemophilia arise from problems with control of bleeding during or following dental treatment or home injuries. Common dental problems are discussed, including an increased caries rate, increased periodontal disease rate, missing teeth, and complications with the natural loss of primary teeth. Preventive management issues discussed include the need for good daily oral hygiene, protection against bleeding during dental treatment, frequent professional cleanings to control disease, and fluoride therapy.
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The National Hemophilia Foundation Resources Contact: National Hemophilia Foundation, Hemophilia and AIDS/HIV Network for Dissemination of Information, 116 W 32nd St Fl 11, New York, NY, 10001-3212, (800) 424-2634, http://www.hemophilia.org. Summary: This resource guide describes materials distributed by the Hemophilia and AIDS/HIV Network for the Dissemination of Information (HANDI). Listings cover the following topics: hemophilia, Von Willebrand disease and other bleeding disorders, hepatitis, HIV/AIDS, bereavement, and finance and reimbursement. Also included are directories, resources listings and indexes, and a Spanish materials index. Each entry contains the publisher's address, an abstract, date of publication, target audiences, and descriptions of format and length.
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:
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Factor XI Deficiency (Hemophilia C) Summary: A general overview about Factor XI Deficiency -- the most common of all bleeding disorder affecting females. The brochure includes treatment options. Source: National Hemophilia Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=3078
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Hemophilia Summary: This consumer health information document provides general information about hemophilia -- the oldest known hereditary bleeding disorder -- includes information about the safety of current treatment Source: National Heart, Lung, and Blood Institute, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=3079 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 hemophilia. 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 hemophilia 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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WebMD®Health: http://my.webmd.com/health_topics
Associations and Hemophilia The following is a list of associations that provide information on and resources relating to hemophilia: •
Canadian Hemophilia Society Telephone: (514) 848-0503 Toll-free: (800) 668-2686 Fax: (514) 848-9661 Email:
[email protected] Web Site: www.hemophilia.ca Background: The Canadian Hemophilia Society (CHS) is a registered charity dedicated to improving the quality of life for all persons with hemophilia and other inherited bleeding disorders. Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that enable the blood to clot. Hemophilia may be classified as mild, moderate, or severe. The level of severity is determined by the percentage of active clotting factor in the blood (normal percentage ranges from 50 to 150 percent). People who have severe hemophilia have less than one percent of active clotting factor in their blood. CHS was established in 1953 and its goals and objectives are to assure that all persons with hemophilia have ready access to the highest possible level of care; assure that the hemophilia community is made aware of issues that affect every aspect of hemophilia and that the general public be informed on matters deemed appropriate; initiate and promote research that will continue to improve care and result in a cure for hemophilia; encourage peer support and social interaction among the hemophilia community; assist persons with hemophilia in being aware of their rights and ensure that no discrimination occurs; and assist persons with hemophilia living in third world countries to improve their quality of care. CHS publishes a quarterly newsletter entitled 'Hemophilia Today' in both English and French. An extensive list of educational material includes 'Helping Others Is In Our Blood - Canadian Hemophilia Society,' 'We re All Related By Blood,' 'What You Should Know About Blood Transfusion,' 'Hemophilia In Perspective,' and 'A Vision of Comprehensive Care for Persons with Inherited Bleeding Disorders.' All materials are available in both English and French. Relevant area(s) of interest: Antihemophilic Factor Deficiency, Antihemophilic Globulin Deficiency, Hemophilia
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Hemophilia Federation of America Telephone: (337) 991-0067 Toll-free: (800) 203-9797 Fax: (337) 991-0087 Email:
[email protected] Web Site: www.hemophiliafed.org Background: The Hemophilia Federation of America exists for the sole purpose of serving its constituents as a patient advocate for, but not limited to, product safety, treatment, insurance, and quality of life issues in a positive and proactive manner. It
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serves all people with coagulation disorders and complications of treatment, including HIV. •
National Hemophilia Foundation Telephone: (212) 328-3700 Toll-free: (800) 424-2634 Fax: (212) 328-3799 Email:
[email protected] Web Site: http://www.hemophilia.org Background: Founded in 1948, the National Hemophilia Foundation is a national, notfor-profit organization dedicated to the treatment and cure of hemophilia, related bleeding disorders and complications of those disorders, including HIV and HCV. NHF also strives to support people with bleeding disorders, their families, and healthcare professionals; increase public awareness of bleeding disorders; and advocate on behalf of affected individuals. NHF is also committed to disseminating current information on bleeding disorders; raising funds for medical research; and promoting legislation beneficial to affected individuals and family members. Relevant area(s) of interest: Hemophilia
•
Swedish Hemophilia Society Telephone: 46 08 661 9455 Fax: 46 08 661 9465 Email:
[email protected] Web Site: http://www.xpress.se/fbis/ Background: The Swedish Hemophilia Society (FBIS) is a nonprofit organization for individuals affected by hemophilia in Sweden. Hemophilia is a group of hereditary bleeding disorders characterized by deficiency of one of the blood factors necessary for blood clotting (coagulation). Affected individuals may experience bleeding episodes that occur for no apparent reason or due to surgery, dental extractions, or injuries. Recurrent bleeding into the joints and muscles may cause painful inflammation of the joints (arthritis) and associated deformities. The Swedish Hemophilia Society, which was established in 1964, currently serves as an umbrella organization consisting of eight local societies. The FBIS disseminates information and provides assistance to these local societies. On the national level, the Society establishes contacts with authorities and other government-supported organizations for disabled individuals. The Swedish Hemophilia Society has several primary objectives, including informing the general public, the community, and governmental institutions about hemophilia disease and improving the quality of life of affected individuals by arranging conferences and meetings where current issues are discussed. The Society offers several programs and services, including providing summer and winter camps for affected children and youths and recreation trips that provide physical training opportunities. The Swedish Hemophilia Society also maintains a web site on the Internet.
•
World Federation of Hemophilia Telephone: 514-875-7944 Fax: 514-875-8916
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Email:
[email protected] Web Site: http://www.wfh.org Background: The World Federation of Hemophilia is an international not-for-profit organization in Canada that was founded in 1963 to promote the care of individuals with hemophilia throughout the world. Hemophilia is a group of hereditary bleeding disorders characterized by deficiency of one of the blood factors necessary for blood clotting (coagulation). Affected individuals may experience bleeding episodes that occur for no apparent reason or due to surgery, dental extractions, or injuries. Recurring bleeding into the joints and muscles may cause painful inflammation of the joints (arthritis) and associated deformities. The primary objective of the World Federation of Hemophilia is to help bring treatment to individuals with hemophilia throughout the world. To help fulfill its objective, the Federation conducts international symposia, offers educational materials for affected individuals and family members, and maintains a web site on the Internet. The Federation's web site discusses the organization's mission, goals, and services; offers information concerning hemophilia product notifications, withdrawals, and medical advisories; provides access to educational materials on hemophilia; and offers an FAQ ('frequently asked questions') area entitled 'Ask the Expert' with answers to questions submitted by individuals with hemophilia, family members, health care professionals, and other organizational members. The FAQ includes sections on general guidelines, information for parents, specific hemophilia topics, blood-related topics, hemophilia carriers, musculoskeletal and surgical issues, von Willebrand's disease, gene therapy, hepatitis, HIV/AIDS and hemophilia, inhibitors, product information/queries, and issues/reports from developing countries. Relevant area(s) of interest: Hemophilia
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to hemophilia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with hemophilia. 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 hemophilia. 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.
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The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “hemophilia” (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 “hemophilia”. 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 “hemophilia” (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 “hemophilia” (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.27
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
27
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)28: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
•
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)
•
California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
•
California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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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/
28
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
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
•
Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
•
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
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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
•
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/
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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/
242 Hemophilia
•
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
243
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 hemophilia: •
Basic Guidelines for Hemophilia Christmas disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000539.htm Hemophilia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000537.htm Hemophilia - resources Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002204.htm Hemophilia A Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000538.htm Hemophilia B Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000539.htm
244 Hemophilia
•
Signs & Symptoms for Hemophilia Bleeding disorder Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001304.htm Bleeding disorders Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001304.htm Blood in the urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003138.htm Bruising Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Hematomas Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Hematuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003138.htm Nosebleed - symptom Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003106.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm
•
Diagnostics and Tests for Hemophilia Bleeding time Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003656.htm Factor I Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003650.htm Fibrinogen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003650.htm Partial thromboplastin time Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003653.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm Prothrombin time Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm PT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm
Online Glossaries 245
PTT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003653.htm Serum factor IX Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003679.htm Serum factor VIII antigen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003678.htm •
Nutrition for Hemophilia Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm Vitamin K Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002407.htm
•
Surgery and Procedures for Hemophilia Synovectomy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002972.htm
•
Background Topics for Hemophilia Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Hemophilia - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002204.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Intrauterine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002389.htm Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.htm X-linked recessive Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002051.htm
246 Hemophilia
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
247
HEMOPHILIA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [NIH] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] 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] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [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] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [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] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases
248 Hemophilia
catecholamines. [NIH] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
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 antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [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] Alexia: The inability to recognize or comprehend written or printed words. [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
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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]
Allo: A female hormone. [NIH] Allografts: A graft of tissue obtained from the body of another animal of the same species but with genotype differing from that of the recipient; tissue graft from a donor of one genotype to a host of another genotype with host and donor being members of the same species. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [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] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Aluminum Hydroxide: Hydrated aluminum. A compound with many biomedical applications: as a gastric antacid, an antiperspirant, in dentifrices, as an emulsifier, as an adjuvant in bacterins and vaccines, in water purification, etc. [NIH] Amber: A yellowish fossil resin, the gum of several species of coniferous trees, found in the alluvial deposits of northeastern Germany. It is used in molecular biology in the analysis of organic matter fossilized in amber. [NIH] 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] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [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]
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Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]
Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] 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] 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] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anergy: Absence of immune response to particular substances. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [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] Aniridia: A congenital abnormality in which there is only a rudimentary iris. This is due to the failure of the optic cup to grow. Aniridia also occurs in a hereditary form, usually autosomal dominant. [NIH] Ankle: That part of the lower limb directly above the foot. [NIH] Ankle Joint: The joint that is formed by the inferior articular and malleolar articular surfaces of the tibia, the malleolar articular surface of the fibula, and the medial malleolar, lateral
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malleolar, and superior surfaces of the talus. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anomalies: Birth defects; abnormalities. [NIH] Anterior chamber: The space in front of the iris and behind the cornea. [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] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidiuretic: Suppressing the rate of urine formation. [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] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antilymphocyte Serum: Serum containing gamma-globulins which are antibodies for lymphocyte antigens. It is used both as a test for histocompatibility and therapeutically in transplantation. [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 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] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH]
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Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Apheresis: Components plateletpheresis. [NIH]
being
separated
out,
as
leukapheresis,
plasmapheresis,
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] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Argipressin: Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2, cyclic 1-6 disulfide. The usual mammalian antidiuretic hormone, it is a cyclic nonapeptide with arginine in position 8 of the chain. Argipressin is used to treat diabetes insipidus and as hemostatic because of its vasoconstrictor action. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Arthrography: Roentgenography of a joint, usually after injection of either positive or negative contrast medium. [NIH] Arthropathy: Any joint disease. [EU] Arthroplasty: Surgical reconstruction of a joint to relieve pain or restore motion. [NIH] Articular: Of or pertaining to a joint. [EU] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Aspartic Endopeptidases: A sub-subclass of endopeptidases that depend on an aspartic acid residue for their activity. EC 3.4.23. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the
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biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [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] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] 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] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] 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] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axilla: The underarm or armpit. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]
Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls,
254 Hemophilia
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] 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] Bacteriophage lambda: A temperate inducible phage and type species of the genus lambdalike Phages, in the family Siphoviridae. Its natural host is E. coli K12. Its virion contains linear double-stranded DNA, except for 12 complementary bases at the 5'-termini of the polynucleotide chains. The DNA circularizes on infection. [NIH] 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] Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous. [NIH] Barium Sulfate: Sulfuric acid, barium salt (1:1). A compound used as an x-ray contrast medium that occurs in nature as the mineral barite. It is also used in various manufacturing applications and mixed into heavy concrete to serve as a radiation shield. [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 Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [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]
Bereavement: Refers to the whole process of grieving and mourning and is associated with a deep sense of loss and sadness. [NIH] Beta-Thalassemia: A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley's anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe complications and even death, hemoglobin A synthesis is absent. [NIH]
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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] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [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] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] 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] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bleeding Time: Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Disorders: Hemorrhagic and thrombotic disorders that occur as a consequence of abnormalities in blood coagulation due to a variety of factors sych as coagulation protein disorders, blood platelet disorders, blood protein disorders or nutritional conditions. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelet Disorders: Disorders caused by abnormalities in platelet count or function. [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]
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Blood Proteins: Proteins that are present in blood serum, including serum albumin, blood coagulation factors, and many other types of proteins. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [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] Blood-Borne Pathogens: Infectious organisms in the blood, of which the predominant medical interest is their contamination of blood-soiled linens, towels, gowns, bandages, other items from individuals in risk categories, needles and other sharp objects, and medical and dental waste, all of which health workers are exposed to. This concept is differentiated from the clinical conditions of bacteremia, viremia, and fungemia where the organism is present in the blood of a patient as the result of a natural infectious process. [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 Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood 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] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Plexus: The large network of nerve fibers which distributes the innervation of the upper extremity. The brachial plexus extends from the neck into the axilla. In humans, the nerves of the plexus usually originate from the lower cervical and the first thoracic spinal cord segments (C5-C8 and T1), but variations are not uncommon. [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] 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] Brain Neoplasms: Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]
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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] 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] 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] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Busulfan: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]
Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [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 Chloride: A salt used to replenish calcium levels, as an acid-producing diuretic, and as an antidote for magnesium poisoning. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [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 become pathologic when the environment is favorable and the host resistance is weakened. [NIH]
Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [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
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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] Carboxy: Cannabinoid. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] 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] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [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] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [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] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. [NIH] Catecholamines: A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH]
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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 Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [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 motility: The ability of a cell to move. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [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 Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [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] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Central retinal vein: The blood vessel that carries blood from the retina. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [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]
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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] 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] 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] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chloroplasts: Plant cell inclusion bodies that contain the photosynthetic pigment chlorophyll, which is associated with the membrane of thylakoids. Chloroplasts occur in cells of leaves and young stems of higher plants. [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] Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [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 leukemia: A slowly progressing cancer of the blood-forming tissues. [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]
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Chymotrypsin: A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. [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] Citric Acid: A key intermediate in metabolism. It is an acid compound found in citrus fruits. The salts of citric acid (citrates) can be used as anticoagulants due to their calcium chelating ability. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [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 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] Clonal Deletion: Removal, via cell death, of immature lymphocytes that interact with antigens during maturation. For T-lymphocytes this occurs in the thymus and ensures that mature T-lymphocytes are self tolerant. B-lymphocytes may also undergo clonal deletion. [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] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [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] Coagulation Protein Disorders: Hemorrhagic and thrombotic disorders resulting from abnormalities or deficiencies of coagulation proteins. [NIH]
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Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [NIH] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] 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] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Coliphages: Viruses whose host is Escherichia coli. [NIH] Colitis: Inflammation of the colon. [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 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] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [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] 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.
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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 3: The fourth component to attach in the complement reaction sequence. It is a beta-globulin with a sedimentation coefficient of 5.5, a molecular weight of 185,000 and a serum concentration of 1.3 micrograms/ml. Its fragments have anaphylatoxic, chemotactic, and histaminic action and affect smooth muscle. [NIH] 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] Complement Factor D: A serum protein which during the alternate pathway of complement activation converts the inactive factor B to complement 3 convertase. EC 3.4.21.46. [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 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] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [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 axial 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 CAT scan, computed tomography (CT scan), or computerized
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tomography. [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] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Condoms: A sheath that is worn over the penis during sexual behavior in order to prevent pregnancy or spread of sexually transmitted disease. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] 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] 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 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] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted
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beyond normal dimensions. [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] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] 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] 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] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [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] Corneum: The superficial layer of the epidermis containing keratinized cells. [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] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] 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] Coumarins: Synthetic or naturally occurring substances related to coumarin, the deltalactone of coumarinic acid. Coumarin itself occurs in the tonka bean. The various coumarins have a wide range of proposed actions and uses including as anticoagulants, pharmaceutical aids, indicators and reagents, photoreactive substances, and antineoplastic agents. [NIH] Coxsackieviruses: A heterogeneous group of the genus enterovirus found in association with various diseases in man and other animals. Two groups (A and B) have been identified with a number of serotypes in each. The name is derived from a village in New York State where the virus was first identified. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH]
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Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cryosurgery: The use of freezing as a special surgical technique to destroy or excise tissue. [NIH]
Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteine Endopeptidases: Endopeptidases which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by sulfhydryl reagents. EC 3.4.22. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Retinitis: Infection of the retina by cytomegalovirus characterized by retinal necrosis, hemorrhage, vessel sheathing, and retinal edema. Cytomegalovirus retinitis is a major opportunistic infection in AIDS patients and can cause blindness. [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] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]
Cytotoxic: Cell-killing. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [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]
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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] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dental Staff: Personnel who provide dental service to patients in an organized facility, institution or agency. [NIH] Dental Waste: Any waste product generated by a dental office, surgery, clinic, or laboratory including amalgams, saliva, and rinse water. [NIH] Dentifrices: Any preparations used for cleansing teeth; they usually contain an abrasive, detergent, binder and flavoring agent and may exist in the form of liquid, paste or powder; may also contain medicaments and caries preventives. [NIH] Dentists: Individuals licensed to practice dentistry. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [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] Dermatosis: Any skin disease, especially one not characterized by inflammation. [EU] 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] Desmopressin: A synthetic analog of the natural hormone 8-arginine vasopressin (argipressin). Its action is mediated by the vasopressin receptor V2. It has prolonged antidiuretic activity, but little pressor effects. It also modulates levels of circulating factor VIII and von Willebrand factor. [NIH] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] 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]
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Diagnostic procedure: A method used to identify a disease. [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] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diathesis: 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 person more than usually susceptible to certain diseases. [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] Dilatation: The act of dilating. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [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 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] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] 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 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] 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
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its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Drug Costs: The amount that a health care institution or organization pays for its drugs. It is one component of the final price that is charged to the consumer (fees, pharmaceutical or prescription fees). [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [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] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyslexia: Partial alexia in which letters but not words may be read, or in which words may be read but not understood. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectopic: Pertaining to or characterized by ectopia. [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] 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] Ejaculation: The release of semen through the penis during orgasm. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding 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] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] 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]
Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to
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prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Ellagic Acid: A fused four ring compound occurring free or combined in galls. Isolated from the kino of Eucalyptus maculata Hook and E. Hemipholia F. Muell. Activates Factor XII of the blood clotting system which also causes kinin release; used in research and as a dye. [NIH]
Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [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] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous Retroviruses: Retroviruses that have integrated into the germline (Proviruses) that have lost infectious capability but retained the capability to transpose. [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] 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, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH]
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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] Enhancer: Transcriptional element in the virus genome. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [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]
Environmental Pollutants: Substances which pollute the environment. Use environmental pollutants in general or for which there is no specific heading. [NIH]
for
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemics: A period of increased prevalence of a particular disease in a population. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [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] Epidural: The space between the wall of the spinal canal and the covering of the spinal cord. An epidural injection is given into this space. [NIH] Epiphyseal: Pertaining to or of the nature of an epiphysis. [EU] 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] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or 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]
Equine Infectious Anemia: Viral disease of horses caused by the equine infectious anemia virus (EIAV). It is characterized by intermittent fever, weakness, and anemia. Chronic infection consists of acute episodes with remissions. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks
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containing hemoglobin whose function is to transport oxygen. [NIH] Erythroleukemia: Cancer of the blood-forming tissues in which large numbers of immature, abnormal red blood cells are found in the blood and bone marrow. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Escalation: Progressive use of more harmful drugs. [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] 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] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of 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] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [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] Extracorporeal: Situated or occurring outside the body. [EU] Extraction: The process or act of pulling or drawing out. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] Extravascular: Situated or occurring outside a vessel or the vessels. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH]
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Facial: Of or pertaining to the face. [EU] 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] Family Relations: Behavioral, psychological, and social relations among various members of the nuclear family and the extended family. [NIH] Fat: Total lipids including phospholipids. [NIH] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Femoral Vein: The vein accompanying the femoral artery in the same sheath; it is a continuation of the popliteal vein and becomes the external iliac vein. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibrinolytic Agents: Fibrinolysin or agents that convert plasminogen to fibrinolysin (plasmin). [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] Fibula: The bone of the lower leg lateral to and smaller than the tibia. In proportion to its length, it is the most slender of the long bones. [NIH] Filariasis: Infections with nematodes of the superfamily Filarioidea. The presence of living worms in the body is mainly asymptomatic but the death of adult worms leads to granulomatous inflammation and permanent fibrosis. Organisms of the genus Elaeophora infect wild elk and domestic sheep causing ischaemic necrosis of the brain, blindness, and dermatosis of the face. [NIH]
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Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] 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] 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] 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] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [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] Fulminant Hepatic Failure: Liver failure that occurs suddenly in a previously healthy person. The most common causes of FHF are acute hepatitis, acetaminophen overdose, and liver damage from prescription drugs. [NIH] Fungemia: The presence of fungi circulating in the blood. Opportunistic fungal sepsis is seen most often in immunosuppressed patients with severe neutropenia or in postoperative patients with intravenous catheters and usually follows prolonged antibiotic therapy. [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]
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Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gametogenesis: The first phase of sexual reproduction which involves the transforming of certain cells in the parent into specialized reproductive cells. [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] 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] 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 Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Duplication: It encodes the major envelope protein and includes all the specifications for HBsAg. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [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 Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of
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fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [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] 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] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [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]
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] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] 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 health-
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related institutions and organizations. [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] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [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] Haematuria: Blood in the urine. [EU] Haemophilia: A haemorrhagic diathesis occurring in two main forms: 1. Haemophilia A (classic haemophilia, factor VIII deficiency), an X-linked disorder due to deficiency of coagulation factor VIII; 2. Haemophilia B (factor IX deficiency, Christmas disease), also Xlinked, due to deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but a different loci, and are characterized by subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. [EU] Haemostasis: The arrest of bleeding, either by the physiological properties of vasoconstriction and coagulation or by surgical means. [EU] 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] Hand, Foot and Mouth Disease: A mild, highly infectious viral disease of children, characterized by vesicular lesions in the mouth and on the hands and feet. It is caused by coxsackieviruses A. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [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] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH]
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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] Hemarthrosis: Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [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] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparan Sulfate Proteoglycan: A substance released by astrocytes, which is critical in stopping nervous fibers in their tracks. [NIH] Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [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] Hepatitis Viruses: Any of the viruses that cause inflammation of the liver. They include both DNA and RNA viruses as well viruses from humans and animals. [NIH]
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Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hepatoma: A liver tumor. [NIH] Hepatomegaly: Enlargement of 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] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimer: Zippered pair of nonidentical proteins. [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]
Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Home Infusion Therapy: Use of any infusion therapy on an ambulatory, outpatient, or other non-institutionalized basis. [NIH] 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] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human Genome Project: A coordinated effort of researchers to map and sequence the human genome. [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
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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] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrocephalus: Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial hypertension; headache; lethargy; urinary incontinence; and ataxia (and in infants macrocephaly). This condition may be caused by obstruction of cerebrospinal fluid pathways due to neurologic abnormalities, intracranial hemorrhages; central nervous system infections; brain neoplasms; craniocerebral trauma; and other conditions. Impaired resorption of cerebrospinal fluid from the arachnoid villi results in a communicating form of hydrocephalus. Hydrocephalus ex-vacuo refers to ventricular dilation that occurs as a result of brain substance loss from cerebral infarction and other conditions. [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 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [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] 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] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH]
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Hypnotic: A drug that acts to induce sleep. [EU] Hypothyroidism: Deficiency of thyroid activity. In adults, it is most common in women and is characterized by decrease in basal metabolic rate, tiredness and lethargy, sensitivity to cold, and menstrual disturbances. If untreated, it progresses to full-blown myxoedema. In infants, severe hypothyroidism leads to cretinism. In juveniles, the manifestations are intermediate, with less severe mental and developmental retardation and only mild symptoms of the adult form. When due to pituitary deficiency of thyrotropin secretion it is called secondary hypothyroidism. [EU] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] 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] Iliac Vein: A vein on either side of the body which is formed by the union of the external and internal iliac veins and passes upward to join with its fellow of the opposite side to form the inferior vena cava. [NIH] Immune Complex Diseases: Group of diseases mediated by the deposition of large soluble complexes of antigen and antibody with resultant damage to tissue. Besides serum sickness and the arthus reaction, evidence supports a pathogenic role for immune complexes in many other systemic immunologic diseases including glomerulonephritis, systemic lupus erythematosus and polyarteritis nodosa. [NIH] 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 system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [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] 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]
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]
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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] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [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 psychological, physiological, or anatomical structure or function. [NIH] Impetigo: A common superficial bacterial infection caused by staphylococcus aureus or group A beta-hemolytic streptococci. Characteristics include pustular lesions that rupture and discharge a thin, amber-colored fluid that dries and forms a crust. This condition is commonly located on the face, especially about the mouth and nose. [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] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] 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] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indinavir: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability. [NIH]
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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] Induction therapy: Treatment designed to be used as a first step toward shrinking the cancer and in evaluating response to drugs and other agents. Induction therapy is followed by additional therapy to eliminate whatever cancer remains. [NIH] 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]
Infectious Mononucleosis: A common, acute infection usually caused by the Epstein-Barr virus (Human herpesvirus 4). There is an increase in mononuclear white blood cells and other atypical lymphocytes, generalized lymphadenopathy, splenomegaly, and occasionally hepatomegaly with hepatitis. [NIH] Inferior vena cava: A large vein that empties into the heart. It carries blood from the legs and feet, and from organs in the abdomen and pelvis. [NIH] 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] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]
Infuse: To pour (a liquid) into something. [EU] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] 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] 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] Inorganic: Pertaining to substances not of organic origin. [EU] 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]
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Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] 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] Integrase: An enzyme that inserts DNA into the host genome. It is encoded by the pol gene of retroviruses and also by temperate bacteriophages, the best known being bacteriophage lambda. EC 2.7.7.-. [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 Alfa-2b: A recombinant alfa interferon consisting of 165 amino acid residues with arginine in position 23 and histidine in position 34. It is used extensively as an antiviral and antineoplastic agent. [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 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-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] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] 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] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH]
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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] Intracellular: Inside a cell. [NIH] Intracranial Hemorrhages: Bleeding within the intracranial cavity, including hemorrhages in the brain and within the cranial epidural, subdural, and subarachnoid spaces. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intramuscular injection: IM. Injection into a muscle. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [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] Intrinsic Factor: A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12. Deficiency of intrinsic factor results in pernicious anemia. [NIH]
Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] 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] 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] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [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] Joint: The point of contact between elements of an animal skeleton with the parts that
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surround and support it. [NIH] Juvenile Delinquency: The antisocial acts of children or persons under age which are illegal or lawfully interpreted as constituting delinquency. [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] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [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] 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] Kilobase: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [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] 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] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [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]
Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [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] Library Services: Services offered to the library user. They include reference and circulation.
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[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] Linkage: The tendency of two or more genes in the same chromosome to remain together 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] 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] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [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] Litter: Appliance consisting of an oblong frame over which is stretched a canvas or other material, used for carrying an injured or disabled person. [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 cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]
Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [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] 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] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [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
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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]
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] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [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] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [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] Lysosomal Storage Diseases: Inborn errors of metabolism characterized by defects in specific lysosomal hydrolases and resulting in intracellular accumulation of unmetabolized substrates. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] 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] Magnesium Hydroxide: Magnesium hydroxide (Mg(OH)2). An inorganic compound that occurs in nature as the mineral brucite. It acts as an antacid with cathartic effects. [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] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malabsorption syndrome: A group of symptoms such as gas, bloating, abdominal pain, and diarrhea resulting from the body's inability to properly absorb nutrients. [NIH] 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]
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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] 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] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [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 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 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] 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]
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Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [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] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metalloendopeptidases: Endopeptidases which use a metal, normally zinc, in the catalytic mechanism. This group of enzymes is inactivated by metal chelators. EC 3.4.24. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from 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] 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] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Micelles: Electrically charged colloidal particles or ions consisting of oriented molecules; aggregates of a number of molecules held loosely together by secondary bonds. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [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] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]
labeled
with
Milligram: A measure of weight. A milligram is approximately 450,000-times smaller than a pound and 28,000-times smaller than an ounce. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [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] Mitotic: Cell resulting from mitosis. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired
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from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular mass: The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16). [NIH] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] 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] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucopolysaccharidoses: Group of lysosomal storage diseases each caused by an inherited deficiency of an enzyme involved in the degradation of glycosaminoglycans (mucopolysaccharides). The diseases are progressive and often display a wide spectrum of clinical severity within one enzyme deficiency. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multicenter Studies: Controlled studies which are planned and carried out by several cooperating institutions to assess certain variables and outcomes in specific patient populations, for example, a multicenter study of congenital anomalies in children. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [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]
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Musculoskeletal Diseases: Diseases of the muscles and their associated ligaments and other connective tissue and of the bones and cartilage viewed collectively. [NIH] Musculoskeletal System: Themuscles, bones, and cartilage of the body. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] 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] 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] 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] 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] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [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] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] 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] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and
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ganglia. [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] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] 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] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [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] Night Blindness: Anomaly of vision in which there is a pronounced inadequacy or complete absence of dark-adaptation. [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] 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] Nuclear Family: A family composed of spouses and their children. [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] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Obstetrics: A medical-surgical specialty concerned with management and care of women during pregnancy, parturition, and the puerperium. [NIH]
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Occult: Obscure; concealed from observation, difficult to understand. [EU] Occult Bleeding: Blood in stool that is not visible to the naked eye. May be a sign of disease such as diverticulosis or colorectal cancer. [NIH] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Oligo: Chemical and mineral elements that exist in minimal (oligo) quantities in the body, in foods, in the air, in soil; name applied to any element observed as a microconstituent of plant or animal tissue and of beneficial, harmful, or even doubtful significance. [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] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [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] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Optic cup: The white, cup-like area in the center of the optic disc. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH] Oral Manifestations: Disorders of the mouth attendant upon non-oral disease or injury. [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] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [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] Ornithine: An amino acid produced in the urea cycle by the splitting off of urea from arginine. [NIH]
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Orofacial: Of or relating to the mouth and face. [EU] Orthopaedic: Pertaining to the correction of deformities of the musculoskeletal system; pertaining to orthopaedics. [EU] Osteoarthritis: Degeneration of articular cartilage. Primary osteoarthritis is very common in older persons, especially affecting weight-bearing joints. Articular cartilage becomes soft, frayed and thinned. [NIH] Osteonecrosis: Death of a bone or part of a bone, either atraumatic or posttraumatic. [NIH] 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] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [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]
Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] 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] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] 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] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Partial Thromboplastin Time: Test of the intrinsic (factors VIII, IX, XI, and XII) and common (fibrinogen, prothrombin, factors V and X) pathways of coagulation in which a mixture of plasma and phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides) is recalcified and the time required for the appearance of fibrin strands measured. Activation may be provided by contact with the glass tube or exposure to activators (e.g., ellagic acid, particulate silicates such as diatomaceous earth or kaolin) before
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addition of the calcium chloride. It is used as a screening test and to monitor heparin therapy. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Parvovirus: A genus of the family Parvoviridae, subfamily Parvovirinae, infecting a variety of vertebrates including humans. Parvoviruses are responsible for a number of important diseases but also can be non-pathogenic in certain hosts. The type species is mice minute virus. [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] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Pediatric Dentistry: The practice of dentistry concerned with the dental problems of children, proper maintenance, and treatment. The dental care may include the services provided by dental specialists. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [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] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [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] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously
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defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral blood: Blood circulating throughout the body. [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] Pernicious: Tending to a fatal issue. [EU] Pernicious anemia: A type of anemia (low red blood cell count) caused by the body's inability to absorb vitamin B12. [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] 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] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] 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] Pharyngitis: Inflammation of the throat. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [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] 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] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [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
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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] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] 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] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] 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] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [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 Exchange: Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (PPF), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. [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] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH]
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Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [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] Platelet Count: A count of the number of platelets per unit volume in a sample of venous blood. [NIH] Platelet Transfusion: The transfer of blood platelets from a donor to a recipient or reinfusion to the donor. [NIH] Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [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]
Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] 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] Polyarthritis: An inflammation of several joints together. [EU] 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]
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] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH]
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Popliteal: Compression of the nerve at the neck of the fibula. [NIH] Popliteal Vein: The vein formed by the union of the anterior and posterior tibial veins; it courses through the popliteal space and becomes the femoral 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] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] 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] 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] 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] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Diagnosis: Determination of the nature of a pathological condition or disease in the postimplantation embryo, fetus, or pregnant female before birth. [NIH] Prescription Fees: The charge levied on the consumer for drugs or therapy prescribed under written order of a physician or other health professional. [NIH] 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] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [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]
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Proenzymes: 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] 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]
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] Proinsulin: The substance made first in the pancreas that is then made into insulin. When insulin is purified from the pancreas of pork or beef, all the proinsulin is not fully removed. When some people use these insulins, the proinsulin can cause the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin is injected. The purified insulins have less proinsulin and other impurities than the other types of insulins. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [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] 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] 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 Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [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
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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 Engineering: Procedures by which nonrandom single-site changes are introduced into structural genes (site-specific mutagenesis) in order to produce mutant genes which can be coupled to promoters that direct the synthesis of a specifically altered protein, which is then analyzed for structural and functional properties and then compared with the predicted and sought-after properties. The design of the protein may be assisted by computer graphic technology and other advanced molecular modeling techniques. [NIH] Protein Folding: A rapid biochemical reaction involved in the formation of proteins. It begins even before a protein has been completely synthesized and proceeds through discrete intermediates (primary, secondary, and tertiary structures) before the final structure (quaternary structure) is developed. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [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] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [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] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
Prothrombin Time: Measurement of clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen, prothrombin, and factors V, VII, and X. It is used for monitoring anticoagulant therapy with coumarins. [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] 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] Provirus: Virus that is integrated into the chromosome of a host cell and is transmitted in that form from one host cell generation to another without leading to the lysis of the host cells. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pseudogenes: Genes bearing close resemblance to known genes at different loci, but rendered non-functional by additions or deletions in structure that prevent normal transcription or translation. When lacking introns and containing a poly-A segment near the downstream end (as a result of reverse copying from processed nuclear RNA into double-
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stranded DNA), they are called processed genes. [NIH] Pseudotumor Cerebri: A condition marked by raised intracranial pressure and characterized clinically by headaches; nausea; papilledema, peripheral constriction of the visual fields, transient visual obscurations, and pulsatile tinnitus. Obesity is frequently associated with this condition, which primarily affects women between 20 and 44 years of age. Chronic papilledema may lead to optic nerve injury (optic nerve diseases) and visual loss (blindness). [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 Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Puerperium: Period from delivery of the placenta until return of the reproductive organs to their normal nonpregnant morphologic state. In humans, the puerperium generally lasts for six to eight weeks. [NIH] Pulmonary: Relating to the lungs. [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]
Purified Insulins: Insulins with much less of the impure proinsulin. It is thought that the use of purified insulins may help avoid or reduce some of the problems of people with diabetes such as allergic reactions. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [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] Pustular: Pertaining to or of the nature of a pustule; consisting of pustules (= a visible collection of pus within or beneath the epidermis). [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] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quiescent: Marked by a state of inactivity or repose. [EU] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the
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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] 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] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] 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] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [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
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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] 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] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [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] Remission Induction: Therapeutic act or process that initiates a response to a complete or partial remission level. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Repopulation: The replacement of functional cells, usually by proliferation, following or during irradiation. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] 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] 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] 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] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative
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enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Vein: Central retinal vein and its tributaries. It runs a short course within the optic nerve and then leaves and empties into the superior ophthalmic vein or cavernous sinus. [NIH]
Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve (neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] Retinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [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] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rheumatic Diseases: Disorders of connective tissue, especially the joints and related structures, characterized by inflammation, degeneration, or metabolic derangement. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Ribavirin: 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [NIH] Ribonuclease: RNA-digesting enzyme. [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] 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] 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] Rituximab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Role-play: In this method, a conflict is artificially constructed, and the trainee is given a strategic position in it. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [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] Scarlet Fever: Infection with group A streptococci that is characterized by tonsillitis and pharyngitis. An erythematous rash is commonly present. [NIH] 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] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [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] 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] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [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] 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] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH]
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Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [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] Serine Endopeptidases: Any member of the group of endopeptidases containing at the active site a serine residue involved in catalysis. EC 3.4.21. [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] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sexual Partners: Married or single individuals who share sexual relations. [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]
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] 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] 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] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH]
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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 Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Problems: Situations affecting a significant number of people, that are believed to be sources of difficulty or threaten the stability of the community, and that require programs of amelioration. [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] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [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] 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] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [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] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes,
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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] Splenectomy: An operation to remove the spleen. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Staphylococcus: A genus of gram-positive, facultatively anaerobic, coccoid bacteria. Its organisms occur singly, in pairs, and in tetrads and characteristically divide in more than one plane to form irregular clusters. Natural populations of Staphylococcus are membranes of warm-blooded animals. Some species are opportunistic pathogens of humans and animals. [NIH] Staphylococcus aureus: Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. [NIH] Steady state: Dynamic equilibrium. [EU] Stem cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Sternum: Breast bone. [NIH] Steroid: A group name for lipids that contain a hydrogenated 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] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
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] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [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]
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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] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [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] Sublingual: Located beneath the tongue. [EU] Submandibular: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [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]
Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [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] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [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]
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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 joint. It is loosely attached to the external fibrous capsule and secretes synovial fluid. [NIH] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole 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] Talus: The second largest of the tarsal bones and occupies the middle and upper part of the tarsus. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [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, 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] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [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] 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] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thoracic: Having to do with 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] Thrombasthenia: A congenital bleeding disorder with prolonged bleeding time, absence of aggregation of platelets in response to most agents, especially ADP, and impaired or absent
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clot retraction. Platelet membranes are deficient in or have a defect in the glycoprotein IIbIIIa complex (platelet glycoprotein GPIIB-IIIA complex). [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombolytic Therapy: Use of infusions of fibrinolytic agents to destroy or dissolve thrombi in blood vessels or bypass grafts. [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]
Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Thrombopoietin: A humoral factor that controls blood platelet production through stimulation of megakaryocyte populations. Bone marrow megakaryocytes increase in both size and number in response to exposure to thrombopoietin. [NIH] Thromboses: The formation or presence of a blood clot within a blood vessel during life. [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] 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] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [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] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [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]
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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] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonsillitis: Inflammation of the tonsils, especially the palatine tonsils. It is often caused by a bacterium. Tonsillitis may be acute, chronic, or recurrent. [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] Toxicity Tests: An array of tests used to determine the toxicity of a substance to living systems. These include tests on clinical drugs, foods, and environmental pollutants. [NIH] 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] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] 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] 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] 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] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]
Translating: Conversion from one language to another language. [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]
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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] Transposase: An enzyme that binds to single-stranded DNA. It is thought to recognize the repetitive ends of a transposon and to participate in the cleavage of the recipient site into which the new transposon copy inserts. EC 2.7.7.-. [NIH] Transposons: Discrete genetic elements capable of inserting, in a non-permuted fashion, into the chromosomes of many bacteria. [NIH] Trans-Splicing: The joining of RNA from two different genes. One type of trans-splicing is the "spliced leader" type (primarily found in protozoans such as trypanosomes and in lower invertebrates such as nematodes) which results in the addition of a capped, noncoding, spliced leader sequence to the 5' end of mRNAs. Another type of trans-splicing is the "discontinuous group II introns" type (found in plant/algal chloroplasts and plant mitochondria) which results in the joining of two independently transcribed coding sequences. Both are mechanistically similar to conventional nuclear pre-mRNA cis-splicing. Mammalian cells are also capable of trans-splicing. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trauma Centers: Specialized hospital facilities which provide diagnostic and therapeutic services for trauma patients. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] 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] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulnar Nerve: A major nerve of the upper extremity. In humans, the fibers of the ulnar nerve originate in the lower cervical and upper thoracic spinal cord (usually C7 to T1), travel via the medial cord of the brachial plexus, and supply sensory and motor innervation to parts of the hand and forearm. [NIH] 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]
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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] Untranslated Regions: The parts of the messenger RNA sequence that do not code for product, i.e. the 5' untranslated regions and 3' untranslated regions. [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] 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, and mental confusion. [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] 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] 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] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [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] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]
Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Vena: A vessel conducting blood from the capillary bed to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH]
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Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventricles: Fluid-filled cavities in the heart or brain. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] 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 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] Viremia: The presence of viruses in the blood. [NIH] Virion: The infective system of a virus, composed of the viral genome, a protein core, and a protein coat called a capsid, which may be naked or enclosed in a lipoprotein envelope called the peplos. [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] 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] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] 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 together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Weight-Bearing: The physical state of supporting an applied load. This often refers to the weight-bearing bones or joints that support the body's weight, especially those in the spine, hip, knee, and foot. [NIH]
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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]
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] 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] 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]
319
INDEX A Abdominal, 88, 92, 247, 285, 288, 295, 297 Abdominal Pain, 247, 288 Aberrant, 74, 169, 247 Ablation, 60, 247 Accommodation, 16, 247 Acetaminophen, 247, 274 Acquired Immunodeficiency Syndrome, 107, 247 Acute lymphoblastic leukemia, 187, 247 Acute lymphocytic leukemia, 247 Adenine, 247, 303 Adenocarcinoma, 247, 279 Adenosine, 34, 247, 297 Adenosine Deaminase, 34, 247 Adenovirus, 7, 8, 36, 46, 66, 72, 76, 120, 153, 173, 205, 247 Adjustment, 94, 247 Adjuvant, 140, 247, 249, 275 Adrenal Medulla, 150, 247 Adsorption, 156, 248 Adsorptive, 248 Adverse Effect, 26, 248, 308 Aerosol, 41, 248 Affinity, 19, 21, 24, 46, 62, 64, 156, 248, 253, 309 Affinity Chromatography, 156, 248 Agonist, 172, 248, 269 Airway, 14, 29, 42, 248 Alanine, 73, 248 Albumin, 248, 295, 298, 312 Alexia, 248, 269 Algorithms, 248, 255 Alimentary, 248, 295 Alkaline, 248, 249, 254, 257 Alkaloid, 248, 262 Alkylating Agents, 248, 257 Allo, 44, 249 Allografts, 249, 279 Alopecia, 249, 266 Alpha-1, 67, 224, 249 Alternative medicine, 199, 249 Aluminum, 158, 249 Aluminum Hydroxide, 158, 249 Amber, 249, 282 Amino Acid Motifs, 249, 264 Amino Acid Sequence, 166, 171, 249, 251, 264, 272, 275
Amino Acid Substitution, 120, 166, 172, 249 Amino-terminal, 161, 249 Ammonia, 247, 249, 316 Amnion, 250 Amniotic Fluid, 126, 250 Amphetamines, 250, 262 Amplification, 8, 47, 175, 176, 250 Anaesthesia, 250, 283 Analog, 10, 250, 267 Analogous, 15, 250, 314 Anaphylatoxins, 250, 263 Anatomical, 250, 253, 264, 282, 307 Anemia, 43, 67, 169, 187, 189, 200, 219, 224, 250, 254, 271, 288, 297, 312 Anergy, 37, 250 Anesthesia, 81, 82, 117, 248, 250, 270 Angina, 142, 250 Angioplasty, 142, 250 Anions, 248, 250, 285, 308, 311 Aniridia, 95, 250 Ankle, 113, 250 Ankle Joint, 113, 250 Annealing, 30, 176, 251 Anomalies, 185, 251, 291 Anterior chamber, 251, 285 Antibacterial, 251, 309 Antibiotic, 55, 70, 185, 251, 274, 296, 306, 309 Antibodies, 8, 12, 15, 21, 24, 26, 30, 35, 37, 39, 40, 41, 44, 47, 48, 61, 76, 77, 79, 107, 140, 141, 143, 146, 156, 159, 165, 167, 171, 251, 253, 277, 280, 288, 298, 307 Anticoagulant, 9, 184, 189, 251, 301, 302 Antidiuretic, 251, 252, 267 Antigen, 12, 33, 37, 40, 46, 50, 109, 150, 154, 245, 248, 251, 263, 279, 281, 282, 283 Antigen-Antibody Complex, 251, 263 Anti-inflammatory, 247, 251, 252, 276, 300 Anti-Inflammatory Agents, 251, 252 Antilymphocyte Serum, 251, 288 Antimetabolite, 251, 306 Antimicrobial, 251, 267 Antineoplastic, 249, 251, 265, 266, 284 Antioxidant, 34, 251 Antiviral, 34, 251, 284, 296, 306 Anus, 251, 256, 304 Anxiety, 229, 252
320 Hemophilia
Aorta, 92, 252 Apheresis, 69, 93, 252 Apolipoproteins, 252, 287 Apoptosis, 65, 67, 169, 252 Applicability, 76, 252 Aqueous, 141, 144, 252, 254, 266, 280 Arginine, 166, 250, 252, 267, 284, 294, 315 Argipressin, 252, 267 Aromatic, 252, 261 Arterial, 18, 45, 252, 259, 260, 280, 302 Arteries, 92, 142, 252, 255, 256, 265, 287, 290, 292 Arterioles, 252, 256, 257 Arteriovenous, 129, 252 Arthrography, 186, 252 Arthropathy, 35, 86, 162, 163, 252 Arthroplasty, 88, 252 Articular, 250, 252, 295 Aspartic, 149, 157, 252, 270 Aspartic Acid, 149, 252 Aspartic Endopeptidases, 252, 270 Aspirin, 185, 252 Assay, 19, 24, 30, 44, 46, 60, 104, 175, 252, 307 Astrocytes, 253, 278 Asymptomatic, 253, 254, 273 Ataxia, 219, 253, 280, 312 Atrial, 172, 173, 253 Atrial Fibrillation, 172, 173, 253 Atrium, 253 Atrophy, 219, 253 Attenuated, 76, 120, 170, 253 Atypical, 253, 283 Autoantibodies, 44, 97, 253 Autoantigens, 253 Autoimmune disease, 253, 298 Autoimmunity, 55, 253 Autologous, 25, 60, 253 Autosuggestion, 253, 281 Axilla, 253, 256 Axillary, 82, 253 B Bacteremia, 253, 256 Bacteria, 34, 69, 248, 251, 253, 254, 264, 271, 272, 290, 298, 309, 310, 314, 315, 316 Bacterial Infections, 189, 254, 259 Bactericidal, 254, 272 Bacteriophage, 149, 254, 284, 298, 314 Bacteriophage lambda, 254, 284 Bacterium, 254, 264, 278, 314 Barbiturate, 254, 312 Barium, 158, 254
Barium Sulfate, 158, 254 Basal Ganglia, 253, 254, 256 Basal Ganglia Diseases, 253, 254 Base, 13, 30, 68, 205, 247, 254, 267, 274, 275, 286, 299, 312 Base Sequence, 254, 274, 275 Basophils, 254, 277, 286 Benign, 254, 256, 277, 292, 304 Bereavement, 230, 254 Beta-Thalassemia, 121, 254 Bilateral, 255, 306 Bile, 255, 275, 279, 287, 310 Binding Sites, 11, 24, 35, 255 Bioavailability, 255, 282 Biochemical, 22, 30, 48, 86, 251, 255, 257, 274, 276, 297, 302 Biological response modifier, 255, 284 Biopsy, 189, 255, 296 Biosynthesis, 10, 255, 301, 308 Biotechnology, 15, 16, 38, 70, 73, 183, 199, 211, 218, 219, 220, 255 Bladder, 255, 282, 301, 316 Blastocyst, 255, 264, 298 Bleeding Time, 153, 255, 312 Bloating, 255, 288 Blood Coagulation Disorders, 153, 255 Blood Coagulation Factors, 149, 255, 256 Blood Glucose, 255, 278, 284 Blood Platelet Disorders, 255 Blood Platelets, 255, 289, 299, 313 Blood pressure, 255, 258, 280, 291, 309 Blood Proteins, 232, 256 Blood transfusion, 228, 229, 256 Blood-Borne Pathogens, 70, 256 Body Fluids, 52, 256, 257, 269, 309 Bone Marrow, 32, 40, 48, 61, 169, 189, 247, 256, 272, 281, 288, 289, 309, 310, 311 Bone Marrow Cells, 40, 48, 61, 256, 289 Bone scan, 186, 256 Bowel, 256, 268, 283, 285, 310 Bowel Movement, 256, 268, 310 Brachial, 82, 256, 315 Brachial Plexus, 82, 256, 315 Brachytherapy, 256, 284, 285, 304, 318 Bradykinin, 256, 298 Brain Neoplasms, 256, 280, 312 Branch, 241, 256, 288, 296, 303, 309, 312 Breakdown, 172, 257, 268, 275 Breeding, 14, 45, 55, 257 Bronchi, 257 Bronchial, 41, 257 Bronchoalveolar Lavage, 41, 257
Index 321
Bronchoalveolar Lavage Fluid, 41, 257 Buccal, 257, 287 Busulfan, 60, 257 Bypass, 70, 146, 165, 257, 313 C Calcium, 10, 141, 142, 143, 151, 161, 174, 257, 261, 262, 273, 296, 302, 308 Calcium Chloride, 257, 296 Callus, 257, 270 Candidiasis, 187, 257 Candidosis, 257 Capillary, 58, 71, 131, 255, 256, 257, 316, 317 Capsid, 8, 51, 257, 317 Capsules, 155, 257, 275 Carbohydrate, 257, 276, 299 Carbon Dioxide, 258, 298, 305, 316 Carboxy, 174, 258 Carcinogenic, 249, 258, 283, 294, 301, 310 Carcinogens, 258, 294 Carcinoma, 258 Cardiac, 87, 183, 193, 253, 258, 270, 292, 310 Cardiomyopathy, 87, 258 Cardiovascular, 6, 23, 89, 258 Cardiovascular disease, 6, 23, 258 Carrier Proteins, 258, 298 Case report, 4, 72, 81, 103, 106, 126, 129, 258, 261 Case series, 102, 258, 261 Catabolism, 11, 258 Catalytic Domain, 8, 258 Catecholamines, 248, 258, 268 Catheterization, 250, 258 Catheters, 55, 258, 274, 282, 284 Cations, 258, 285 Cause of Death, 85, 258 Cell Count, 77, 98, 109, 259, 297 Cell Cycle, 44, 259 Cell Death, 252, 259, 261, 292 Cell Differentiation, 259, 308 Cell Division, 218, 254, 259, 289, 290, 298, 301, 307 Cell membrane, 24, 258, 259, 267, 269, 297 Cell motility, 259, 279 Cell proliferation, 48, 142, 169, 259, 284, 308 Cell Size, 259, 274 Cell Transplantation, 259 Cellulose, 259, 274, 298 Central Nervous System, 248, 250, 256, 259, 262, 276, 277, 280, 294
Central Nervous System Infections, 259, 277, 280 Central retinal vein, 81, 259, 306 Cerebellar, 253, 259, 305 Cerebral, 55, 253, 254, 256, 259, 260, 280, 289 Cerebral Infarction, 259, 280 Cerebrospinal, 259, 280 Cerebrospinal fluid, 259, 280 Cerebrovascular, 254, 258, 260, 312 Cerebrum, 259, 260, 315 Cervical, 256, 260, 315 Chemokines, 87, 260 Chemotactic Factors, 260, 263 Chemotherapy, 169, 260 Chimera, 64, 260 Chloroplasts, 260, 315 Cholera, 260, 308 Cholesterol, 56, 255, 260, 265, 280, 287, 310 Cholesterol Esters, 260, 287 Chorioretinitis, 260, 306 Choroid, 260, 305, 306 Chromatin, 44, 252, 260, 271, 293, 309 Chromosomal, 20, 31, 58, 175, 185, 250, 260, 291, 298, 306, 312 Chronic leukemia, 185, 260 Chronic renal, 200, 260, 299 Chylomicrons, 260, 287 Chymotrypsin, 157, 261 CIS, 41, 49, 170, 261, 306, 315 Citric Acid, 158, 261 Citrus, 261 Clathrin, 149, 261, 262 Clear cell carcinoma, 261, 267 Cleave, 10, 261 Clinical Medicine, 261, 300 Clinical study, 7, 197, 261 Clonal Deletion, 37, 261 Clone, 65, 261 Cloning, 10, 15, 31, 34, 58, 255, 261, 283 Clot Retraction, 261, 298, 313 Coagulation Protein Disorders, 255, 261 Coated Vesicles, 261, 262 Coca, 262 Cocaine, 186, 262 Codon, 70, 148, 165, 174, 262, 275 Cofactor, 15, 22, 54, 62, 64, 150, 262, 302, 313 Coliphages, 254, 262 Colitis, 262, 283 Collagen, 21, 64, 150, 262, 273, 275, 299, 301
322 Hemophilia
Collapse, 257, 262 Colloidal, 248, 262, 269, 290, 308 Colorectal, 262, 294 Colorectal Cancer, 262, 294 Combination Therapy, 3, 262 Combinatorial, 10, 262 Communicable disease, 262, 316 Complement, 28, 160, 250, 262, 263, 275, 298 Complement 3, 263 Complement Activation, 250, 263 Complement Factor D, 28, 263 Complementary and alternative medicine, 125, 132, 263 Complementary medicine, 125, 263 Complementation, 170, 263 Complete remission, 263, 305 Computational Biology, 211, 218, 263 Computed tomography, 263, 264 Computerized axial tomography, 263, 264 Computerized tomography, 186, 263, 264 Conception, 149, 264, 273, 310 Concomitant, 81, 213, 264 Condoms, 192, 215, 264 Confounding, 26, 264 Confusion, 264, 316 Conjugated, 264 Conjugation, 147, 264 Connective Tissue, 256, 262, 264, 273, 275, 288, 290, 292, 306, 311, 312 Consciousness, 264, 267, 268 Consensus Sequence, 10, 249, 264 Conserved Sequence, 249, 264 Constitutional, 264, 306 Constriction, 151, 264, 285, 303, 316 Constriction, Pathologic, 264, 316 Consultation, 18, 265 Consumption, 265, 267, 305 Contamination, 171, 256, 265, 278, 279 Contraindications, ii, 265 Control group, 17, 265, 300 Conventional therapy, 265 Conventional treatment, 141, 265 Coordination, 53, 265 Corneum, 265, 271 Coronary, 9, 116, 142, 172, 258, 265, 290, 292 Coronary heart disease, 258, 265 Coronary Thrombosis, 265, 290, 292 Cortex, 253, 265, 301, 305 Cortisone, 265, 300 Coumarins, 265, 302
Coxsackieviruses, 265, 277 Cranial, 265, 273, 277, 285, 294 Craniocerebral Trauma, 254, 265, 277, 280, 312 Crossing-over, 266, 304 Cryosurgery, 95, 266 Curative, 20, 32, 33, 43, 59, 196, 266, 312 Cutaneous, 20, 257, 266, 287, 316 Cyclophosphamide, 60, 266 Cysteine, 10, 260, 266, 270 Cysteine Endopeptidases, 266, 270 Cystine, 266 Cytokine, 30, 84, 266, 312 Cytomegalovirus, 81, 266 Cytomegalovirus Retinitis, 81, 266 Cytoplasm, 252, 254, 259, 266, 271, 277, 293, 306 Cytoskeletal Proteins, 261, 266 Cytotoxic, 20, 34, 36, 38, 153, 266, 282, 304, 308 D Databases, Bibliographic, 211, 266 De novo, 26, 266 Decidua, 266, 298 Defense Mechanisms, 35, 266 Degenerative, 267, 278 Deletion, 29, 151, 152, 252, 261, 267, 275 Dementia, 247, 267 Denaturation, 15, 267 Density, 11, 34, 44, 267, 274, 287, 294, 299 Dental Care, 130, 189, 267, 296 Dental Staff, 189, 267 Dental Waste, 256, 267 Dentifrices, 249, 267 Dentists, 185, 267 Deoxyribonucleotides, 149, 267 Depolarization, 267, 308 Dermatosis, 267, 273 DES, 121, 250, 267 Desmopressin, 83, 86, 121, 122, 204, 206, 267 Detergents, 176, 267 Detoxification, 56, 267 Developing Countries, 80, 101, 234, 267 Diabetes Mellitus, 187, 267, 276, 278 Diagnostic procedure, 139, 199, 268 Dialyzer, 268, 278 Diarrhea, 268, 288 Diathesis, 17, 25, 51, 75, 144, 268, 277 Digestion, 248, 255, 256, 268, 285, 287, 310, 316 Digestive system, 137, 268
Index 323
Dilatation, 250, 268 Dilation, 256, 268, 280 Dimerization, 28, 57, 268 Diploid, 263, 268, 298 Direct, iii, 9, 10, 16, 18, 23, 24, 35, 49, 98, 100, 153, 190, 203, 261, 268, 269, 302, 305 Discrimination, 216, 228, 232, 268 Disease Progression, 31, 38, 52, 109, 268, 317 Disinfectant, 268, 272 Dissociation, 56, 248, 268 Dissociative Disorders, 268 Distal, 21, 84, 175, 268, 302 Dopamine, 262, 268 Drug Costs, 115, 269 Drug Interactions, 204, 205, 269 Drug Tolerance, 269, 313 Duct, 174, 175, 258, 269, 288, 307 Duodenum, 255, 261, 269, 295, 310 Dyslexia, 187, 269 Dysplasia, 219, 269 Dystrophy, 29, 219, 269 E Ectopic, 57, 269 Edema, 144, 266, 269, 285 Effector, 262, 269 Ejaculation, 269, 307 Elastin, 262, 269 Electrocoagulation, 261, 269 Electrolyte, 269, 309 Electrons, 251, 254, 269, 285, 295, 304 Electrophoresis, 72, 156, 269 Electroporation, 90, 269 Ellagic Acid, 270, 295 Emaciation, 247, 270 Embryo, 250, 255, 259, 270, 283, 300 Embryogenesis, 30, 270 Emphysema, 67, 270 Encapsulated, 49, 155, 270, 287 Endarterectomy, 250, 270 Endemic, 260, 270, 288, 310 Endocarditis, 257, 270 Endocytosis, 15, 270 Endogenous Retroviruses, 87, 270 Endopeptidases, 157, 252, 266, 270, 290, 296, 301, 308 Endothelial cell, 9, 22, 26, 47, 58, 64, 66, 117, 145, 150, 270, 313 Endothelium, 61, 270, 299 Endothelium, Lymphatic, 270 Endothelium, Vascular, 270 Endotoxin, 271, 315
End-stage renal, 260, 271, 299 Enhancer, 28, 46, 168, 271 Enteropeptidase, 271, 315 Environmental Exposure, 271, 294 Environmental Health, 210, 212, 271 Environmental Pollutants, 271, 314 Enzymatic, 54, 55, 142, 257, 258, 263, 271, 273, 306 Enzyme, 8, 22, 24, 34, 41, 54, 60, 67, 142, 145, 146, 149, 157, 160, 161, 172, 247, 249, 258, 269, 271, 284, 290, 291, 298, 301, 302, 306, 308, 311, 313, 314, 315, 317, 318 Enzyme Inhibitors, 271, 298 Eosinophils, 271, 277, 286 Epidemics, 12, 271 Epidemiological, 95, 271 Epidermal, 271, 286, 289 Epidermis, 20, 265, 271, 279, 286, 300, 303 Epidural, 74, 271, 285 Epiphyseal, 186, 271 Epithelial, 41, 61, 247, 266, 271, 279 Epithelial Cells, 61, 271, 279 Epithelium, 37, 41, 42, 270, 271, 285 Epitope, 12, 15, 271 Equine Infectious Anemia, 42, 271 Erythrocytes, 250, 256, 271, 304 Erythroleukemia, 43, 272 Erythropoietin, 160, 175, 272 Escalation, 7, 35, 51, 272 Esophagus, 268, 272, 310 Essential Tremor, 219, 272 Ethanol, 158, 272 Ethnic Groups, 180, 272 Eukaryotic Cells, 266, 272, 282, 294 Excitation, 250, 272, 274 Excitatory, 272, 276 Exhaustion, 272, 288 Exogenous, 148, 154, 159, 164, 248, 272, 275, 301 Exon, 29, 50, 87, 272 External-beam radiation, 272, 285, 304, 318 Extracellular, 253, 264, 270, 272, 273, 309 Extracellular Matrix, 264, 272, 273 Extracorporeal, 87, 156, 272 Extraction, 188, 272 Extravasation, 272, 278 Extravascular, 121, 151, 272 Extremity, 256, 272, 315 Eye Infections, 247, 272
324 Hemophilia
F Facial, 188, 273, 295 Facial Nerve, 273, 295 Family Planning, 211, 228, 273 Family Relations, 178, 191, 273 Fat, 256, 265, 273, 287, 309, 312 Femoral, 25, 273, 300 Femoral Artery, 273 Femoral Vein, 25, 273, 300 Femur, 273 Fetus, 55, 216, 272, 273, 281, 298, 300 Fibrin, 11, 62, 101, 142, 145, 146, 151, 160, 172, 255, 261, 273, 295, 298, 313 Fibrinogen, 10, 142, 145, 146, 151, 154, 155, 158, 160, 172, 244, 273, 295, 298, 302, 313 Fibrinolysis, 84, 99, 120, 172, 273 Fibrinolytic, 273, 313 Fibrinolytic Agents, 273, 313 Fibroblasts, 16, 197, 273 Fibrosis, 14, 29, 36, 42, 55, 65, 67, 72, 181, 219, 273, 307 Fibula, 250, 273, 300 Filariasis, 55, 273 Filtration, 158, 274 Flow Cytometry, 13, 54, 274 Fluorescence, 9, 274 Fluorescent Dyes, 274 Fold, 15, 18, 41, 46, 62, 63, 64, 154, 165, 274 Forearm, 255, 274, 315 Fractionation, 146, 158, 159, 274 Frameshift, 70, 274 Frameshift Mutation, 70, 274 Fulminant Hepatic Failure, 63, 274 Fungemia, 256, 274 Fungi, 264, 272, 274, 290, 318 Fungus, 257, 274 G Gallbladder, 89, 247, 268, 275 Gametogenesis, 30, 275 Gangrenous, 275, 308 Gas, 249, 258, 275, 280, 288, 293, 311, 316 Gastric, 249, 275, 285 Gastrointestinal, 111, 155, 256, 272, 275, 289, 311 Gastrointestinal tract, 155, 272, 275 Gelatin, 275, 276, 312 Gene Deletion, 37, 275 Gene Duplication, 29, 275 Gene Expression, 18, 21, 26, 29, 41, 48, 49, 56, 59, 61, 76, 120, 220, 275 Gene Targeting, 67, 275 Genetic Code, 275, 293
Genetic Counseling, 87, 275 Genetic Engineering, 255, 261, 275 Genetic Screening, 230, 275 Genetics, 23, 27, 50, 66, 67, 74, 87, 111, 145, 153, 161, 198, 247, 264, 275, 291 Genotype, 31, 92, 95, 101, 114, 196, 249, 275, 297 Gestation, 275, 297, 298 Gestational, 39, 276 Gland, 148, 164, 174, 175, 200, 247, 265, 276, 288, 289, 295, 301, 307, 311, 313 Glomerular, 276, 305 Glomeruli, 276, 303 Glucocorticoid, 276, 300 Glucose, 56, 219, 255, 259, 267, 276, 278, 284, 307 Glucose Intolerance, 267, 276 Glucuronic Acid, 276, 278 Glutamate, 276 Glutamic Acid, 10, 149, 276, 301 Glycerol, 276, 297 Glycerophospholipids, 276, 297 Glycine, 158, 276, 308 Glycoprotein, 150, 154, 161, 174, 272, 273, 276, 277, 285, 291, 313, 315 Glycosaminoglycans, 276, 291 Glycosylation, 58, 71, 276 Gonadal, 276, 310 Governing Board, 276, 300 Gp120, 277, 296 Grade, 14, 69, 277 Graft, 142, 198, 249, 277, 279, 282 Graft Rejection, 277, 282 Grafting, 20, 277, 282 Granulocytes, 51, 69, 277, 286, 308, 318 H Habitat, 277, 293 Haematuria, 277 Haemophilia, 113, 114, 122, 123, 152, 162, 277 Half-Life, 15, 17, 120, 147, 154, 277 Hand, Foot and Mouth Disease, 187, 277 Haploid, 277, 298 Haptens, 248, 277 Headache, 96, 277, 280 Health Services, 4, 277 Health Status, 15, 178, 278 Heart attack, 258, 278 Hemarthrosis, 73, 114, 189, 278 Hematoma, 72, 74, 89, 111, 278 Hematopoiesis, 6, 278
Index 325
Hematopoietic Stem Cells, 17, 39, 41, 42, 43, 60, 278 Hemodialysis, 185, 268, 278 Hemoglobin, 169, 250, 254, 272, 278, 286, 312 Hemoglobinuria, 219, 278 Hemolytic, 278, 282, 312 Hemorrhage, 45, 79, 99, 104, 125, 158, 162, 265, 266, 269, 277, 278, 303, 311 Heparan Sulfate Proteoglycan, 11, 278 Heparin, 11, 143, 278, 296 Hepatic, 25, 33, 37, 39, 42, 49, 56, 63, 72, 81, 168, 248, 278 Hepatitis A, 167, 171, 179, 186, 204, 224, 278 Hepatitis Viruses, 215, 278 Hepatocellular, 73, 149, 279 Hepatocellular carcinoma, 73, 279 Hepatocyte, 13, 26, 28, 56, 66, 71, 279 Hepatocyte Growth Factor, 26, 279 Hepatoma, 59, 279 Hepatomegaly, 279, 283 Hepatovirus, 278, 279 Hereditary, 153, 155, 181, 231, 233, 234, 250, 279, 306, 312 Heredity, 275, 279 Herpes, 187, 279 Herpes Zoster, 187, 279 Heterodimer, 62, 174, 279 Heterogeneity, 31, 248, 279 Histidine, 279, 284 Histocompatibility, 19, 30, 251, 279 Home Infusion Therapy, 230, 279 Homologous, 13, 29, 88, 149, 176, 266, 275, 279, 307, 311 Hormonal, 169, 253, 279 Hormone, 249, 252, 265, 267, 272, 279, 284, 289, 301, 308, 313 Horny layer, 271, 279 Human Genome Project, 65, 221, 279 Humoral, 20, 46, 121, 277, 279, 313 Humour, 279 Hybrid, 13, 33, 46, 47, 48, 66, 145, 160, 261, 280 Hybridization, 47, 280, 291 Hybridomas, 270, 280 Hydrocephalus, 185, 280, 285 Hydrogen, 254, 257, 267, 280, 291, 293, 295, 297, 311 Hydrogen Peroxide, 280, 311 Hydrolases, 280, 288
Hydrolysis, 247, 252, 280, 296, 297, 299, 302, 315 Hydrophilic, 267, 280 Hydrophobic, 64, 156, 267, 276, 280, 287 Hydroxylation, 149, 280 Hydroxylysine, 262, 280 Hydroxyproline, 262, 280 Hypercholesterolemia, 14, 280 Hypertension, 258, 280, 285 Hypnotic, 128, 254, 281, 312 Hypothyroidism, 186, 281 I Iatrogenic, 188, 281 Id, 123, 130, 225, 231, 240, 242, 281 Idiopathic, 68, 96, 188, 281 Iliac Vein, 273, 281 Immune Complex Diseases, 251, 281, 298 Immune function, 82, 281, 282 Immune system, 169, 253, 281, 282, 288, 292, 316, 318 Immune Tolerance, 27, 37, 71, 76, 79, 97, 103, 114, 165, 281 Immunity, 12, 37, 38, 76, 120, 247, 248, 281, 282 Immunization, 281, 282 Immunodeficiency syndrome, 177, 178, 179, 191, 212, 214, 228, 229, 281 Immunodominant Epitopes, 36, 281 Immunogenic, 40, 48, 98, 282 Immunoglobulin, 30, 251, 282, 291 Immunologic, 7, 33, 52, 94, 97, 260, 281, 282, 304 Immunology, 19, 39, 41, 77, 79, 247, 248, 274, 282 Immunosuppressant, 51, 249, 282 Immunosuppressive, 12, 37, 60, 75, 112, 122, 146, 153, 266, 276, 282 Immunosuppressive Agents, 153, 282 Immunosuppressive therapy, 75, 112, 122, 146, 282 Immunotherapy, 75, 282 Impairment, 187, 253, 272, 282, 289, 290 Impetigo, 187, 282 Implant radiation, 282, 284, 285, 304, 318 Implantation, 25, 163, 197, 264, 282 In situ, 13, 47, 282 In Situ Hybridization, 47, 282 Incontinence, 280, 282 Incubation, 161, 282, 286 Incubation period, 282, 286 Indicative, 180, 282, 296, 316 Indinavir, 17, 282
326 Hemophilia
Induction, 37, 40, 48, 60, 67, 71, 85, 94, 97, 98, 103, 110, 114, 283 Induction therapy, 85, 283 Infarction, 259, 283 Infectious Mononucleosis, 186, 283 Inferior vena cava, 25, 281, 283 Inflammatory bowel disease, 200, 283 Infuse, 146, 283 Infusion, 7, 37, 60, 76, 105, 120, 141, 145, 155, 174, 279, 283, 314 Ingestion, 37, 283 Inhalation, 248, 283 Initiation, 16, 23, 31, 142, 283, 314 Innervation, 256, 273, 283, 315 Inorganic, 283, 288 Insertional, 29, 283 Insight, 11, 21, 56, 283 Instillation, 121, 283 Insulator, 44, 284 Insulin, 60, 284, 301 Insulin-dependent diabetes mellitus, 284 Integrase, 67, 284 Interferon, 3, 13, 31, 34, 44, 85, 95, 99, 110, 284, 288 Interferon Alfa-2b, 3, 95, 284 Interferon-alpha, 99, 284 Interleukin-1, 13, 284 Interleukin-10, 13, 284 Interleukin-2, 284 Interleukins, 282, 284 Intermittent, 96, 271, 284 Internal Medicine, 25, 31, 51, 85, 120, 127, 278, 284 Internal radiation, 284, 285, 304, 318 Interstitial, 256, 257, 284, 285, 305, 318 Intestinal, 155, 201, 271, 284, 288 Intestine, 155, 256, 262, 285, 286, 310 Intracellular, 47, 52, 261, 283, 285, 288, 289, 308 Intracranial Hemorrhages, 280, 285, 312 Intracranial Hypertension, 96, 277, 280, 285 Intrahepatic, 12, 285 Intramuscular, 18, 23, 35, 37, 40, 51, 147, 152, 153, 197, 277, 285, 295 Intramuscular injection, 18, 23, 40, 153, 285 Intraperitoneal, 41, 42, 285 Intravascular, 28, 44, 285 Intrinsic, 22, 62, 63, 142, 154, 158, 161, 166, 248, 285, 295 Intrinsic Factor, 22, 285
Introns, 171, 285, 302, 315 Invasive, 281, 285, 288 Invertebrates, 285, 315 Involuntary, 254, 272, 285, 292 Ions, 141, 142, 254, 268, 269, 280, 285, 290, 302 Iris, 95, 250, 251, 285 Irradiation, 60, 169, 285, 305, 318 Ischemia, 253, 285 J Joint, 68, 78, 79, 81, 88, 109, 162, 163, 189, 250, 252, 285, 311, 312 Juvenile Delinquency, 185, 286 K Kb, 27, 46, 148, 164, 170, 175, 210, 286 Keratin, 286 Keratinocytes, 16, 20, 286 Kidney Disease, 137, 200, 210, 219, 286 Kilobase, 148, 164, 286 Kinetic, 9, 31, 286 L Labile, 167, 262, 273, 286 Large Intestine, 262, 268, 285, 286, 304, 309 Latent, 8, 173, 286, 300 Lentivirus, 29, 41, 42, 44, 286 Lesion, 172, 286, 287, 315 Lethargy, 280, 281, 286 Leucine, 166, 286 Leucocyte, 249, 286, 288 Leukapheresis, 252, 286 Leukemia, 60, 103, 186, 189, 200, 218, 286 Leukocytes, 142, 254, 256, 260, 271, 277, 284, 286, 293, 315 Library Services, 240, 286 Ligament, 287, 301 Ligands, 63, 147, 149, 287 Linkage, 30, 78, 87, 105, 287 Lip, 185, 287 Lipid, 15, 165, 252, 276, 284, 287 Lipoprotein, 11, 287, 317 Liposomal, 15, 287 Liposomes, 155, 287 Litter, 42, 287 Liver cancer, 287 Liver Transplantation, 101, 115, 122, 287 Localization, 47, 57, 287 Localized, 10, 270, 278, 283, 287, 298, 315 Locomotion, 287, 298 Loop, 22, 103, 287 Low-density lipoprotein, 287 Lupus, 76, 287, 312
Index 327
Lymph, 37, 253, 260, 270, 279, 283, 287, 288, 311 Lymph node, 37, 253, 260, 287, 288 Lymphadenopathy, 283, 288 Lymphatic, 55, 270, 283, 287, 288, 290, 299, 309, 313 Lymphatic system, 287, 288, 309, 313 Lymphoblastic, 288 Lymphoblasts, 247, 288 Lymphocyte, 13, 37, 38, 77, 153, 247, 251, 288 Lymphocyte Count, 247, 288 Lymphocyte Depletion, 77, 288 Lymphoid, 251, 286, 288 Lymphoma, 218, 288 Lysine, 280, 288, 315 Lysosomal Storage Diseases, 15, 288, 291 Lytic, 173, 288 M Macrophage, 284, 288 Magnesium Hydroxide, 158, 288 Magnetic Resonance Imaging, 186, 288 Malabsorption, 185, 219, 288 Malabsorption syndrome, 185, 288 Malaria, 55, 288, 289 Malaria, Falciparum, 288, 289 Malaria, Vivax, 288, 289 Malformation, 129, 289 Malignant, 218, 247, 251, 256, 287, 289, 292, 304 Malnutrition, 248, 253, 289, 291 Mammary, 148, 164, 289 Mastitis, 131, 289, 308 Medial, 250, 289, 315 Mediate, 35, 67, 76, 117, 268, 289 Medicament, 152, 156, 289 MEDLINE, 211, 218, 219, 289 Medullary, 150, 289 Megakaryocytes, 17, 256, 289, 313 Meiosis, 289, 311 Melanin, 285, 289 Melanocytes, 289 Melanoma, 218, 289 Membrane, 10, 19, 24, 48, 54, 62, 87, 142, 154, 158, 161, 250, 253, 259, 260, 262, 263, 267, 268, 270, 272, 277, 287, 289, 291, 294, 297, 300, 305, 306, 308, 312, 314, 317 Membrane Proteins, 287, 289 Memory, 36, 267, 289 Mental Disorders, 137, 289
Mental Health, iv, 4, 5, 137, 180, 191, 210, 216, 217, 289, 303 Mental Processes, 268, 289, 303 Mental Retardation, 21, 65, 220, 290 Mercury, 274, 290 Mesenchymal, 39, 290 Metabolic disorder, 28, 290 Metalloendopeptidases, 270, 290 Metastasis, 24, 290, 292 MI, 88, 145, 166, 246, 290 Mice Minute Virus, 290, 296 Micelles, 24, 290 Microbe, 290, 314 Microorganism, 262, 290, 296, 317 Microspheres, 55, 290 Milligram, 143, 290 Milliliter, 144, 290 Mitochondria, 290, 294, 315 Mitosis, 44, 252, 290 Mitotic, 27, 41, 290 Modeling, 290, 302 Modification, 10, 28, 147, 275, 290, 303 Molecular mass, 161, 291 Molecular Probes, 269, 291 Monitor, 9, 52, 106, 291, 293, 296 Monoclonal, 22, 25, 68, 83, 120, 280, 285, 291, 304, 307, 318 Monocyte, 51, 291 Mononuclear, 13, 34, 36, 38, 283, 291, 315 Morphology, 29, 278, 291 Mosaicism, 72, 111, 291 Mucolytic, 257, 291 Mucopolysaccharidoses, 186, 291 Mucosa, 287, 291, 311 Multicenter Studies, 4, 291 Multicenter study, 122, 291 Muscle Fibers, 291 Muscular Atrophy, 219, 291 Muscular Dystrophies, 185, 269, 291 Musculoskeletal Diseases, 177, 292 Musculoskeletal System, 292, 295 Mutagenesis, 29, 35, 57, 292, 302 Mutagenic, 49, 249, 292 Mutagens, 274, 292 Myocardial infarction, 44, 142, 172, 173, 265, 290, 292 Myocardium, 290, 292 Myotonic Dystrophy, 219, 292 N Naive, 17, 20, 292 Nausea, 292, 303, 316 NCI, 1, 7, 31, 136, 209, 261, 292
328 Hemophilia
Necrosis, 252, 259, 266, 273, 283, 290, 292 Neonatal, 26, 37, 68, 292 Neoplasia, 186, 218, 292 Neoplasms, 247, 251, 256, 258, 292, 304 Neoplastic, 280, 288, 292 Nephropathy, 286, 292 Nerve, 104, 128, 250, 253, 256, 273, 283, 292, 293, 294, 300, 303, 307, 315 Nerve Fibers, 256, 292 Nervous System, 219, 259, 292, 293, 311 Neural, 6, 279, 293 Neurologic, 280, 293 Neuronal, 293 Neurons, 262, 272, 292, 293, 311 Neuropeptides, 55, 293 Neuroretinitis, 293, 306 Neutrons, 285, 293, 304 Neutropenia, 51, 274, 293 Neutrophils, 277, 286, 293 Niche, 7, 59, 293 Night Blindness, 293, 306 Nitrogen, 248, 266, 291, 293, 315 Nuclear, 56, 71, 254, 264, 269, 272, 273, 292, 293, 302, 315 Nuclear Family, 273, 293 Nuclei, 264, 269, 275, 285, 288, 290, 293, 294 Nucleic Acid Hybridization, 280, 293 Nucleus, 252, 254, 260, 266, 271, 272, 289, 291, 293, 301, 310, 312 O Obstetrics, 68, 293 Occult, 188, 294 Occult Bleeding, 188, 294 Odds Ratio, 294, 305 Oligo, 13, 294 Oncogene, 218, 279, 294 Oncogenic, 286, 294 On-line, 15, 243, 294 Opacity, 267, 294 Open Reading Frames, 286, 294 Opportunistic Infections, 247, 294 Optic cup, 250, 294 Optic Nerve, 293, 294, 303, 305, 306 Oral Health, 185, 186, 188, 230, 294 Oral Hygiene, 230, 294 Oral Manifestations, 187, 189, 294 Organ Culture, 294, 313 Organ Transplantation, 186, 294 Organelles, 261, 266, 289, 294 Ornithine, 14, 294 Orofacial, 188, 295
Orthopaedic, 86, 107, 128, 184, 193, 295 Osteoarthritis, 189, 295 Osteonecrosis, 189, 295 Outpatient, 68, 182, 279, 295 Ovalbumin, 37, 295 Overdose, 274, 295 Oxidation, 251, 266, 295 Oxygenation, 87, 295 P Palate, 185, 295 Palliative, 295, 312 Pancreas, 247, 261, 268, 284, 295, 301, 315 Pancreatic, 218, 261, 295 Pancreatic cancer, 218, 295 Pancreatic Juice, 261, 295 Parenteral, 12, 295 Parotid, 175, 295 Paroxysmal, 219, 295 Partial remission, 295, 305 Partial Thromboplastin Time, 115, 141, 295 Particle, 296, 314 Parturition, 293, 296 Parvovirus, 8, 100, 173, 290, 296 Pathogen, 282, 296 Pathogenesis, 9, 34, 38, 55, 142, 229, 296 Pathologic, 252, 255, 257, 265, 296, 305 Pathologic Processes, 252, 296 Pathophysiology, 13, 51, 185, 296 Patient Education, 226, 238, 240, 246, 296 Pediatric Dentistry, 187, 188, 296 Pelvic, 296, 301 Penicillin, 296, 316 Penis, 264, 269, 296 Peptide, 10, 20, 60, 64, 65, 142, 148, 156, 157, 161, 270, 271, 280, 286, 296, 299, 301, 302, 313 Peptide Hydrolases, 270, 280, 296 Peptide T, 65, 296 Percutaneous, 25, 296 Perfusion, 296, 313 Pericardium, 296, 312 Perinatal, 53, 106, 296 Periodontal disease, 230, 297 Peripheral blood, 34, 36, 38, 39, 284, 297 Peritoneal, 285, 297 Peritoneal Cavity, 285, 297 Pernicious, 285, 297 Pernicious anemia, 285, 297 PH, 51, 71, 111, 297 Pharmaceutical Preparations, 143, 259, 272, 275, 297
Index 329
Pharmacodynamics, 81, 297 Pharmacokinetic, 15, 17, 44, 105, 297 Pharmacologic, 9, 33, 250, 277, 297, 313, 314 Pharyngitis, 297, 307 Phenotype, 13, 17, 28, 30, 47, 56, 95, 105, 114, 149, 263, 275, 297 Phospholipases, 297, 308 Phospholipids, 15, 24, 54, 99, 140, 146, 273, 287, 297 Phosphorus, 257, 297 Phosphorylate, 151, 297 Phosphorylated, 151, 297 Phosphorylation, 151, 297 Photocoagulation, 261, 297 Physical Examination, 189, 298 Physiologic, 22, 24, 41, 64, 66, 248, 255, 277, 298, 304, 305 Physiology, 9, 188, 278, 298 Pigment, 260, 289, 298 Placenta, 24, 298, 301, 303 Plants, 34, 248, 252, 257, 258, 260, 261, 262, 276, 291, 298, 307, 314, 315 Plaque, 250, 298 Plasma cells, 251, 298 Plasma Exchange, 68, 298 Plasma protein, 22, 24, 56, 63, 248, 270, 298, 302, 308 Plasmapheresis, 68, 252, 298 Plasmid, 16, 28, 40, 49, 55, 59, 67, 81, 90, 298, 316 Plasmin, 151, 273, 298, 299 Plasminogen, 273, 298, 299 Plasminogen Activators, 298, 299 Platelet Activation, 299, 308 Platelet Aggregation, 17, 160, 250, 299 Platelet Count, 51, 68, 255, 299 Platelet Transfusion, 69, 299 Plateletpheresis, 252, 299 Platelets, 9, 17, 24, 47, 51, 62, 64, 69, 142, 145, 150, 151, 161, 169, 172, 299, 312, 313 Platinum, 287, 299 Plexus, 256, 299 Point Mutation, 8, 22, 48, 62, 65, 174, 299 Polyarthritis, 186, 299 Polycystic, 219, 299 Polyethylene, 158, 299 Polymers, 11, 55, 62, 147, 299, 302 Polymorphic, 30, 299 Polymorphism, 50, 105, 106, 299
Polypeptide, 147, 156, 157, 169, 173, 174, 249, 262, 264, 273, 280, 298, 299, 301, 302, 312, 318 Polysaccharide, 251, 259, 299 Popliteal, 273, 300 Popliteal Vein, 273, 300 Posterior, 253, 260, 285, 295, 300 Postnatal, 300, 310 Postoperative, 188, 274, 300 Postsynaptic, 300, 308 Post-translational, 10, 23, 149, 300 Potentiates, 284, 300 Potentiation, 300, 308 Practice Guidelines, 217, 300 Preclinical, 14, 26, 28, 33, 35, 43, 44, 46, 66, 197, 198, 300 Precursor, 144, 161, 172, 266, 268, 269, 271, 298, 300, 302, 315, 316 Predisposition, 114, 185, 300 Prednisolone, 300 Prednisone, 68, 300 Prenatal, 78, 106, 126, 270, 275, 300 Prenatal Diagnosis, 78, 126, 300 Prescription Fees, 269, 300 Prevalence, 3, 33, 73, 106, 107, 127, 168, 185, 271, 294, 300 Prickle, 286, 300 Primary endpoint, 69, 300 Proenzymes, 142, 160, 301 Progeny, 29, 43, 44, 61, 264, 301 Progesterone, 301, 310 Program Development, 213, 215, 301 Progression, 12, 31, 34, 38, 52, 71, 85, 97, 107, 250, 301 Progressive, 38, 129, 189, 259, 260, 267, 269, 272, 277, 291, 292, 299, 301, 305, 306 Progressive disease, 189, 301 Proinsulin, 60, 301, 303 Projection, 266, 294, 301, 305 Proline, 166, 262, 280, 301 Promoter, 9, 17, 23, 28, 37, 42, 44, 46, 47, 51, 52, 57, 148, 152, 164, 168, 174, 301 Prophase, 301, 311 Prophylaxis, 53, 107, 117, 135, 155, 301, 316 Prospective study, 32, 301 Prostate, 218, 301 Protease, 17, 62, 65, 68, 142, 145, 155, 157, 161, 172, 262, 282, 301 Protease Inhibitors, 157, 301 Protein Binding, 301, 313
330 Hemophilia
Protein C, 15, 19, 24, 62, 142, 148, 149, 150, 154, 164, 167, 248, 249, 252, 254, 262, 286, 287, 301, 302, 316, 317 Protein Conformation, 249, 286, 302 Protein Engineering, 15, 302 Protein Folding, 56, 302 Protein Kinases, 56, 302 Protein S, 15, 35, 56, 70, 183, 219, 220, 255, 264, 275, 302, 306 Proteolytic, 62, 107, 145, 146, 151, 157, 160, 249, 263, 271, 273, 298, 299, 302 Prothrombin Time, 83, 302 Protocol, 9, 13, 17, 19, 28, 32, 53, 69, 97, 103, 123, 302 Protozoa, 264, 290, 302 Provirus, 160, 173, 302 Proximal, 21, 176, 268, 302 Pseudogenes, 30, 302 Pseudotumor Cerebri, 285, 303 Psychology, 82, 94, 107, 268, 303 Public Health, 93, 120, 128, 130, 213, 217, 303 Public Policy, 211, 303 Publishing, 5, 70, 188, 215, 231, 303 Puerperium, 293, 303 Pulmonary, 14, 29, 224, 255, 257, 265, 303 Pulse, 291, 303 Purified Insulins, 301, 303 Purifying, 157, 267, 303 Purines, 254, 303, 308 Purpura, 33, 68, 188, 303 Pustular, 282, 303 Pyelonephritis, 55, 303 Q Quality of Life, 38, 82, 92, 232, 233, 303 Quaternary, 302, 303 Quiescent, 60, 303 R Radiation, 254, 271, 272, 274, 281, 284, 285, 303, 304, 318 Radiation therapy, 272, 274, 284, 285, 304, 318 Radioactive, 256, 277, 280, 282, 284, 285, 291, 293, 294, 304, 318 Radiography, 186, 304 Radiolabeled, 285, 304, 318 Radiological, 296, 304 Radiotherapy, 256, 285, 304, 318 Randomized, 3, 32, 67, 68, 69, 95, 269, 304 Randomized clinical trial, 67, 304 Receptor, 10, 11, 13, 30, 34, 37, 41, 44, 57, 64, 251, 267, 268, 277, 279, 296, 304, 308
Recombinant Proteins, 10, 304 Recombination, 13, 29, 88, 100, 175, 264, 275, 304 Reconstitution, 12, 15, 304 Rectal, 111, 304 Rectum, 251, 256, 262, 268, 275, 282, 283, 286, 301, 304 Red blood cells, 169, 271, 272, 278, 304, 307 Red Nucleus, 253, 304 Refer, 1, 257, 262, 274, 279, 287, 292, 293, 305 Refraction, 305, 309 Refractory, 19, 51, 85, 269, 305 Regeneration, 304, 305 Regimen, 4, 13, 269, 305, 306 Relapse, 68, 305 Relative risk, 32, 305 Remission, 68, 305 Remission Induction, 68, 305 Renal failure, 169, 278, 305 Repopulation, 48, 305 Reproductive cells, 275, 305 Resorption, 280, 305 Respiration, 258, 290, 291, 305 Response rate, 4, 31, 305 Restoration, 304, 305 Retina, 41, 42, 259, 260, 266, 293, 294, 305, 306, 317 Retinal, 266, 294, 305, 306 Retinal Vein, 306 Retinitis, 15, 266, 306 Retinitis Pigmentosa, 15, 306 Retinoblastoma, 218, 306 Retreatment, 6, 306 Retrospective, 31, 306 Retroviral vector, 25, 40, 43, 61, 160, 306 Retrovirus, 14, 60, 71, 306 Rheumatic Diseases, 186, 189, 306 Rhinitis, 306, 308 Ribavirin, 3, 13, 31, 32, 95, 306 Ribonuclease, 34, 306 Ribose, 247, 306 Ribosome, 306, 314 Rigidity, 298, 306 Risk factor, 19, 79, 110, 113, 186, 301, 305, 306 Ristocetin, 150, 306 Rituximab, 51, 68, 307 Role-play, 212, 213, 307 Rubella, 109
Index 331
S Saline, 257, 298, 307 Salivary, 266, 268, 273, 295, 307, 311 Salivary glands, 266, 268, 273, 307 Saponins, 307, 310 Scarlet Fever, 187, 307 Sclerosis, 34, 219, 307 Screening, 30, 31, 53, 95, 172, 261, 275, 296, 307 Secondary tumor, 290, 307 Secretion, 13, 23, 25, 56, 164, 167, 279, 281, 284, 307, 316 Secretory, 20, 23, 174, 175, 307 Segregation, 304, 307 Seizures, 295, 307 Self Care, 129, 307 Semen, 35, 39, 269, 301, 307 Septic, 186, 307 Septicaemia, 307, 308 Sequence Homology, 296, 307 Sequencing, 31, 50, 58, 98, 108, 308 Serine, 24, 54, 62, 142, 157, 161, 261, 270, 308, 315 Serine Endopeptidases, 270, 308 Serotypes, 8, 18, 28, 265, 308 Serous, 270, 308 Serum, 23, 31, 62, 141, 245, 248, 250, 251, 256, 262, 263, 281, 287, 304, 308, 315 Serum Albumin, 256, 308 Sex Determination, 219, 308 Sexual Partners, 4, 179, 308 Sexually Transmitted Diseases, 192, 308 Shock, 308, 315 Side effect, 44, 48, 58, 68, 98, 146, 203, 205, 248, 266, 308, 314 Signal Transduction, 34, 308 Signs and Symptoms, 185, 189, 200, 305, 308 Skeletal, 6, 8, 18, 74, 153, 291, 308 Skeleton, 273, 285, 308 Skull, 169, 265, 308 Small intestine, 260, 269, 279, 285, 309, 315, 317 Smallpox, 309, 316 Social Environment, 303, 309 Social Problems, 185, 309 Sodium, 144, 309 Soft tissue, 162, 187, 188, 200, 256, 308, 309 Solid tumor, 189, 309 Solvent, 62, 272, 276, 309 Soma, 309
Somatic, 7, 16, 30, 71, 72, 111, 270, 279, 289, 290, 309 Somatic cells, 7, 30, 289, 290, 309 Specialist, 53, 234, 268, 309 Specificity, 16, 25, 43, 54, 60, 157, 248, 270, 281, 309, 313 Spectrum, 33, 36, 291, 309 Sperm, 260, 305, 309 Spermatozoa, 307, 309 Spinal cord, 253, 256, 259, 260, 271, 292, 309, 315 Spinous, 271, 286, 309 Spleen, 63, 80, 266, 288, 309, 310 Splenectomy, 51, 310 Splenomegaly, 283, 310 Sporadic, 306, 310 Stabilization, 20, 55, 310 Standard therapy, 68, 310 Staphylococcus, 282, 310 Staphylococcus aureus, 282, 310 Steady state, 9, 310 Stem cell transplantation, 38, 67, 189, 310 Stem Cells, 16, 39, 48, 60, 61, 272, 310 Sterility, 266, 310 Sternum, 169, 310 Steroid, 21, 84, 265, 307, 310 Stimulant, 310, 316 Stomach, 247, 268, 272, 275, 279, 292, 297, 309, 310 Stool, 282, 286, 294, 310 Strand, 28, 30, 310 Streptococci, 282, 307, 310 Stress, 56, 127, 177, 188, 191, 215, 244, 292, 300, 310 Stroke, 137, 142, 172, 173, 210, 258, 311 Stroma, 285, 311 Stromal, 256, 311 Stromal Cells, 256, 311 Subacute, 283, 311 Subclinical, 283, 307, 311 Subcutaneous, 12, 121, 122, 147, 152, 269, 275, 277, 295, 311 Sublingual, 175, 311 Submandibular, 175, 311 Subspecies, 309, 311 Substance P, 304, 306, 307, 311 Substrate, 22, 24, 29, 54, 60, 64, 149, 157, 258, 271, 280, 311 Suction, 274, 311 Superoxide, 34, 311 Superoxide Dismutase, 34, 311 Supplementation, 153, 311
332 Hemophilia
Support group, 129, 191, 245, 311 Suppression, 19, 37, 46, 70, 311 Symphysis, 301, 311 Symptomatic, 31, 113, 311 Synapsis, 311 Synaptic, 16, 308, 311 Synergistic, 145, 146, 311 Synovial, 189, 312 Synovial Fluid, 189, 312 Synovial Membrane, 312 Systemic disease, 186, 187, 189, 200, 312 Systemic lupus erythematosus, 75, 281, 312 T Talus, 251, 312 Telangiectasia, 219, 312 Telomere, 175, 277, 312 Terminator, 262, 312 Thalamic, 253, 312 Thalamic Diseases, 253, 312 Thalassemia, 43, 67, 189, 254, 312 Thalidomide, 185, 312 Therapeutics, 7, 23, 25, 40, 49, 64, 141, 205, 312 Thermal, 268, 293, 312 Thigh, 273, 312 Thoracic, 89, 256, 288, 312, 315 Threonine, 296, 308, 312 Thrombasthenia, 188, 312 Thrombin, 8, 11, 24, 58, 142, 143, 145, 146, 151, 160, 161, 167, 172, 174, 273, 299, 301, 302, 313 Thrombocytes, 299, 313 Thrombocytopenia, 9, 51, 68, 69, 117, 185, 189, 313 Thrombolytic, 142, 298, 313 Thrombolytic Therapy, 142, 313 Thrombomodulin, 301, 313 Thromboplastin, 24, 143, 144, 151, 158, 244, 302, 313 Thrombopoietin, 51, 313 Thromboses, 188, 313 Thrombus, 89, 142, 172, 265, 283, 299, 313, 317 Thymus, 261, 281, 288, 313 Thyroid, 281, 313 Thyrotropin, 281, 313 Tissue Culture, 67, 313 Tissue Distribution, 63, 313 Tolerance, 12, 19, 37, 39, 40, 50, 93, 94, 96, 97, 276, 313 Tomography, 186, 314
Tonic, 154, 314 Tonsillitis, 307, 314 Topical, 272, 280, 314 Toxic, iv, 34, 41, 48, 56, 60, 146, 249, 264, 271, 281, 314 Toxicity, 9, 18, 21, 23, 26, 28, 35, 48, 49, 51, 52, 56, 57, 60, 269, 290, 306, 314 Toxicity Tests, 48, 314 Toxicology, 7, 212, 314 Toxins, 251, 276, 283, 314 Transcriptase, 306, 314 Transcription Factors, 56, 314 Transduction, 8, 18, 26, 29, 33, 34, 42, 48, 60, 61, 65, 174, 308, 314 Transfection, 16, 23, 28, 55, 255, 269, 314 Transferases, 276, 314 Transgenes, 6, 16, 20, 23, 42, 48, 49, 170, 314 Translating, 29, 314 Translation, 29, 56, 59, 63, 302, 314 Translational, 63, 70, 314 Translocation, 29, 314 Transposase, 16, 59, 315 Transposons, 59, 315 Trans-Splicing, 28, 57, 105, 315 Trauma, 68, 86, 102, 107, 172, 188, 189, 193, 278, 292, 315 Trauma Centers, 68, 315 Tropism, 28, 46, 315 Trypsin, 46, 48, 67, 157, 261, 271, 301, 315, 318 Tryptophan, 262, 315 Tuberculosis, 187, 265, 287, 315 Tuberous Sclerosis, 219, 315 Tumor Necrosis Factor, 13, 34, 36, 312, 315 Tumor suppressor gene, 70, 315 U Ulcer, 111, 315 Ulnar Nerve, 81, 315 Ultrasonography, 186, 315 Unconscious, 266, 281, 316 Universal Precautions, 179, 316 Untranslated Regions, 50, 152, 316 Urea, 294, 316 Uremia, 153, 305, 316 Urethra, 296, 301, 316 Urinary, 280, 282, 316 Urine, 244, 251, 255, 277, 278, 282, 316 V Vaccination, 170, 316 Vaccine, 38, 52, 204, 247, 302, 316 Vaccinia, 34, 316
Index 333
Vacuoles, 270, 294, 316 Vagina, 257, 267, 316 Vaginitis, 257, 316 Valine, 73, 166, 316 Variola, 316 Vascular, 23, 55, 66, 99, 185, 188, 189, 218, 260, 270, 283, 298, 299, 313, 316 Vasoconstriction, 142, 277, 316 Vein, 49, 67, 252, 273, 281, 283, 285, 293, 295, 300, 306, 316, 317 Vena, 25, 316 Venous, 68, 78, 84, 172, 252, 259, 299, 302, 316, 317 Venous blood, 259, 299, 316 Venous Thrombosis, 78, 84, 172, 317 Ventricles, 259, 280, 317 Ventricular, 280, 317 Venules, 256, 257, 270, 317 Vertebrae, 169, 309, 317 Vesicular, 277, 279, 309, 316, 317 Veterinary Medicine, 211, 317 Villi, 280, 317 Viral Hepatitis, 189, 230, 317 Viral Load, 52, 77, 98, 108, 112, 317 Viral vector, 6, 16, 21, 27, 29, 33, 40, 41, 49, 54, 65, 66, 90, 113, 117, 152, 160, 165, 205, 317 Viremia, 256, 317
Virion, 174, 254, 317 Virulence, 253, 314, 317 Viscera, 309, 317 Visual field, 303, 306, 317 Vitreous Body, 260, 305, 317 Vitro, 11, 13, 16, 19, 24, 25, 29, 36, 39, 44, 46, 47, 48, 49, 55, 57, 58, 60, 64, 66, 144, 147, 148, 149, 164, 278, 282, 307, 313, 317 Vivo, 6, 7, 8, 10, 11, 13, 14, 16, 19, 21, 23, 24, 26, 27, 29, 30, 33, 38, 39, 41, 42, 43, 44, 46, 47, 48, 49, 57, 58, 60, 61, 63, 64, 66, 67, 71, 72, 142, 147, 153, 163, 165, 170, 278, 282, 288, 317 W Weight-Bearing, 295, 317 White blood cell, 169, 247, 251, 283, 286, 288, 291, 293, 298, 318 X Xenograft, 44, 250, 318 X-ray, 193, 254, 263, 264, 274, 285, 293, 304, 318 X-ray therapy, 285, 318 Y Yeasts, 257, 274, 297, 318 Z Zygote, 264, 291, 318 Zymogen, 149, 161, 261, 301, 318
334 Hemophilia
Index 335
336 Hemophilia
