Fibrosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

FIBROSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES J AMES N. P ...

Author: ICON Health Publications

15 downloads 1392 Views 5MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

FIBROSIS 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

ii

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., 1960Fibrosis: 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: 0-597-84281-7 1. Fibrosis-Popular works. I. Title.

iii

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: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

iv

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 fibrosis. 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.

v

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.

vi

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

vii

Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON FIBROSIS .................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Fibrosis........................................................................................ 10 E-Journals: PubMed Central ....................................................................................................... 67 The National Library of Medicine: PubMed ................................................................................ 94 Academic Periodicals covering Fibrosis ..................................................................................... 139 Dissertations on Fibrosis............................................................................................................ 140 CHAPTER 2. NUTRITION AND FIBROSIS ........................................................................................ 141 Overview.................................................................................................................................... 141 Finding Nutrition Studies on Fibrosis....................................................................................... 141 Federal Resources on Nutrition ................................................................................................. 147 Additional Web Resources ......................................................................................................... 148 CHAPTER 3. ALTERNATIVE MEDICINE AND FIBROSIS .................................................................. 151 Overview.................................................................................................................................... 151 The Combined Health Information Database............................................................................. 151 National Center for Complementary and Alternative Medicine................................................ 152 Additional Web Resources ......................................................................................................... 173 General References ..................................................................................................................... 176 CHAPTER 4. CLINICAL TRIALS AND FIBROSIS ............................................................................... 177 Overview.................................................................................................................................... 177 Recent Trials on Fibrosis............................................................................................................ 177 Keeping Current on Clinical Trials ........................................................................................... 197 CHAPTER 5. PATENTS ON FIBROSIS ............................................................................................... 199 Overview.................................................................................................................................... 199 Patents on Fibrosis..................................................................................................................... 199 Patent Applications on Fibrosis ................................................................................................. 214 Keeping Current ........................................................................................................................ 228 CHAPTER 6. BOOKS ON FIBROSIS................................................................................................... 229 Overview.................................................................................................................................... 229 Book Summaries: Federal Agencies............................................................................................ 229 Book Summaries: Online Booksellers......................................................................................... 234 Chapters on Fibrosis................................................................................................................... 234 Directories.................................................................................................................................. 236 CHAPTER 7. MULTIMEDIA ON FIBROSIS ........................................................................................ 239 Overview.................................................................................................................................... 239 Video Recordings ....................................................................................................................... 239 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 241 Overview.................................................................................................................................... 241 U.S. Pharmacopeia..................................................................................................................... 241 Commercial Databases ............................................................................................................... 242 Researching Orphan Drugs ....................................................................................................... 243 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 249 Overview.................................................................................................................................... 249 NIH Guidelines.......................................................................................................................... 249 NIH Databases........................................................................................................................... 251 Other Commercial Databases..................................................................................................... 256 The Genome Project and Fibrosis............................................................................................... 256 APPENDIX B. PATIENT RESOURCES ............................................................................................... 261 Overview.................................................................................................................................... 261

viii Contents

Patient Guideline Sources.......................................................................................................... 261 News Services and Press Releases.............................................................................................. 265 Newsletter Articles .................................................................................................................... 267 Associations and Fibrosis........................................................................................................... 269 Finding Associations.................................................................................................................. 272 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 275 Overview.................................................................................................................................... 275 Preparation................................................................................................................................. 275 Finding a Local Medical Library................................................................................................ 275 Medical Libraries in the U.S. and Canada ................................................................................. 275 ONLINE GLOSSARIES................................................................................................................ 281 Online Dictionary Directories ................................................................................................... 281 FIBROSIS DICTIONARY ............................................................................................................ 283 INDEX .............................................................................................................................................. 389

1

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 fibrosis 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 fibrosis, 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 fibrosis, 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 fibrosis. 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 fibrosis, 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 fibrosis. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

3

CHAPTER 1. STUDIES ON FIBROSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on fibrosis.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and fibrosis, 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 “fibrosis” (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: •

Regression of Liver Fibrosis After Biliary Drainage in Patients with Chronic Pancreatitis and Stenosis of the Common Bile Duct Source: New England Journal of Medicine. 344(6): 418-423. February 8, 2001. Summary: Chronic obstruction of the common bile duct may cause hepatic (liver) fibrosis and secondary biliary cirrhosis (scarring). This article reports on a study of liver biopsy specimens from 11 patients with chronic stenosis (narrowing) of the common bile duct due to chronic pancreatitis (inflammation of the pancreas). All the patients had undergone liver biopsy before or at the time of surgical biliary decompression and all underwent a subsequent liver biopsy for various clinical reasons. The patients were followed as part of a prospective study of 501 patients who had been treated for chronic pancreatitis. Two pathologists, who were unaware of the sequence of specimens, graded fibrosis on a scale of 0 (none) to 3 (cirrhosis). The 11 patients were all men. Chronic

4

Fibrosis

pancreatitis was due to alcohol abuse in 10 of the men; 1 had idiopathic disease. The median age at diagnosis was 38 years. The median interval between the first and second liver biopsies was 2.5 years (range of 0.3 to 9.0 years). The two patients who had restenosis of the biliary anastomosis were excluded from the analysis. In the remaining group of nine patients, the second specimen showed significant improvement in fibrosis. The fibrosis improved by two grades in two patients and by one grade in four patients; in three patients, the grade did not change. The pathologists agreed on the grading of specimens from 10 of the 11 patients. The authors conclude that, in patients with chronic pancreatitis and stenosis of the common bile duct, liver fibrosis may regress after biliary drainage. 1 figure. 2 tables. 24 references. •

Cystic Fibrosis-Related Diabetes and Abnormal Glucose Tolerance: Overview and Medical Nutrition Therapy Source: Diabetes Spectrum. 15(2): 124-127. 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Cystic fibrosis (CF) is an autosomal recessively inherited disease the results in thick, sticky secretions in many organs, including lung, liver, gastrointestinal tract, and pancreas. Eighty-five percent of CF patients have exocrine pancreatic insufficiency. This article reviews CF-related diabetes (CFRD) and abnormal glucose tolerance, focusing on the use of medical nutrition therapy (MNT) to manage these problems. Maintaining optimal nutritional status and weight in patients with CF is the goal of treatment and can dramatically improve longevity. A high-calorie, high-fat, highsodium diet is essential to maintaining weight and nutritional status in CF. However, patients with CFRD are at risk for diabetes microvascular disease, so optimal control of blood glucose is important to prevention complications and to normalize metabolism of nutrients. The authors stress that a team approach to these patients is recommended, ideally with the pulmonary (lung) team working closely with an endocrinologist and other diabetes team members who are well acquainted with CFRD. 3 tables. 33 references.

•

Long-Term Impact of Renal transplantation on Liver Fibrosis During Hepatitis C Virus Infection Source: Gastroenterology. 123(5): 1494-1499. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.gastrojournal.org. Summary: During hepatitis C virus (HCV) infection, liver fibrosis progression after renal (kidney) transplantation remains controversial. This article reports on a cohort study that compared liver histopathologic features during HCV infection between kidney transplant recipients and matched groups of hemodialysis patients or controls without renal disease and untreated for HCV> Each kidney transplant recipients (group 1, n = 30) was matched at first liver biopsy (LB) using the main factors known to influence progression of fibrosis, with one HCV hemodialyzed patient (group 2, n = 30) and one HCV-infected patients (nonhemodialyzed, nontransplanted; group 3, n = 30). The rate of fibrosis progression per year between the first and second liver biopsies was significantly lower in group 1 than group 3. The authors conclude that liver fibrosis progression is low in most HCV-infected kidney transplant recipients with moderate liver disease at baseline. 3 tables. 21 references.

Studies

•

5

Management Dilemmas in the Individual with Cystic Fibrosis and Diabetes Source: Journal of the American Dietetic Association. 94(1): 78-80. January 1994. Summary: In this article, glucose tolerance in patients with cystic fibrosis (CF) and the program of intensive insulin therapy recommended for them by the Diabetes Management Center of University Hospitals of Cleveland, Ohio, are reviewed. The authors note that, as their life expectancy has improved, patients with CF have experienced an increasing incidence of diabetes. The authors describe the use of a flexible meal-planning system to establish individualized carbohydrate targets with specific insulin boluses titrated to each meal to control postprandial blood glucose excursions. The records of 22 patients followed for more than 1 year are reviewed. The authors conclude that strict metabolic control is an attainable goal in patients with CF and is associated with positive weight gain. 26 references.

•

Liver Disease in Cystic Fibrosis: A Prospective Study on Incidence, Risk Factors, and Outcome Source: Hepatology. 36(6): 1374-1382. December 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. The authors of this article assessed prospectively the incidence and risk factors of this complication, and its impact of the clinical course of CF. Between 1980 and 1990, the authors enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10 year duration. During a 14 year median follow (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5 patients. Incidence rate (number of cases per 100 patient-years) was 1.8 percent, with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus, male sex, or severe mutations. Incidence of cirrhosis (liver scarring) was 4.5 percent during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, and 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality or higher incidence of other clinically relevant outcomes. The authors conclude that LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation. 2 figures. 4 tables. 46 references.

•

Liver and Biliary Problems in Cystic Fibrosis Source: Seminars in Liver Disease. 18(3): 227-235. 1998. Contact: Available from Thieme Medical Publishers, Inc. 333 Seventh Avenue, New York, NY 10001. (212) 760-0888. Fax (212) 947-1112. Website: www.thieme.com. Summary: Liver disease associated with cystic fibrosis (CF) has been increasingly diagnosed during recent years, probably due to the combined effect of systemic hepatic assessment and fewer deaths of CF patients from extra hepatic causes. This article reports on liver and biliary problems in CF. The authors note that in a group of 173 patients regularly followed at their center, cumulative incidence of liver disease was 17 percent over a mean period of 10 years. Although it generally runs a mild course, it is

6

Fibrosis

considered a major complication of CF which may limit survival and quality of life of affected patients. CF associated liver disease should be considered as the first inherited liver disorder in which the primary defect affects cholangiocyte transport systems. Although data assessing the effects of defective CF transmembrane regulator (CFTR) on cholangiocyte pathobiology are not yet available, the impaired secretory function of the biliary epithelium is considered responsible for reduced biliary fluidity and alkalinity and for subsequent bile duct damage by cytotoxic compounds or infectious agents. No clear association with specific CFTR mutations has been observed. Treatment with ursodeoxycholic acid, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is the most useful therapeutic approach in CF associated liver disease. Beneficial effects on liver biochemistry, hepatic excretory function, liver histology, and essential fatty acid status have been reported, but there are no long term data on its effects on clinically relevant outcomes, such as death or need for transplantation. The effectiveness of bile acid therapy may be higher if started in patients with early stage liver disease, before symptoms have become clinically evident. The authors conclude that early diagnosis and identification of CF patients who are more liable to develop liver disease should be actively pursued. 2 figures. 1 table. 84 references. (AA-M). •

Liver Disease in Pediatric Patients with Cystic Fibrosis is Associated with Glutathione S-Transferase P1 Polymorphism Source: Hepatology. 36(4 Part 1): 913-917. 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: Liver disease in patients with cystic fibrosis (CF) is inconstant and has not yet been clearly related to any specific risk factor. Among liver detoxifying enzymes, the glutathione S-transferases (GSTs) play a key role in the protection against oxidative stress. This article reports on a study that provides the first demonstration of a significant association between GST gene polymorphism and the development of liver disease in patients with CF. The authors hypothesize that the major role of GSTs as detoxifying enzymes is probably emphasized in CF disease by the frequent use of antibiotics and other drugs in these patients. Identification of GSTP1 polymorphism may have prognostic significant in pediatric patients with CF and may direct more targeted therapy toward children with an increased risk of liver disease. 3 tables. 25 references.

•

Energy Expenditure and Substrate Utilization in Adults with Cystic Fibrosis and Diabetes Mellitus Source: American Journal of Clinical Nutrition. 69(1): 64-69. January 1999. Contact: Available from American Journal of Clinical Nutrition. Production Office, 9650 Rockville Pike, Bethesda, MD 20814. (301) 530-7038. Fax (301) 571-8303. Website: www.ajcn.org. Summary: The onset of cystic fibrosis-related diabetes mellitus (CFDM) is often associated with a decline in clinical and nutritional status. This article reports on a study undertaken to characterize energy expenditure (EE) and substrate utilization during rest, exercise, and recovery from exercise in patients with CF diagnosed with diabetes mellitus. The study included 10 people with CF, 7 with CFDM, and 10 control subjects; all were between 18 and 45 years of age. In all 3 periods, minute ventilation was higher in the CF and CFDM groups than in the control subjects. During rest and exercise, the

Studies

7

CF and CFDM groups maintained EE values at the high end of the normal range of the control subjects. However, during recovery, EE was higher in the CF and CFDM groups than in the control group. The authors conclude that EE may be higher than usual for the patients with CF and CFDM during periods of recovery from mild exercise or activity because of increased work of breathing consistent with higher ventilatory requirements. This information may be useful for patients receiving nutritional counseling who may choose to exercise regularly, but are concerned about possible weight loss. 4 tables. 33 references. •

Cystic-Fibrosis-Related Diabetes Mellitus Source: Diabetes Educator. 28(5): 768, 770-771, 774-775. September-October 2002. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article describes the care of patients with cystic-fibrosis-related diabetes mellitus (CFRD). The authors present a case report of a patient with CFRD in order to describe the patient care issues that need to be managed. The authors note that alone, cystic fibrosis requires a complicated treatment regimen. The diabetes treatment plan must complement this regimen without unnecessary burden. The authors describe the challenges of providing diabetes education for a 30 year old woman with newly diagnosed CFRD. She presented an opportunity for collaboration between pulmonologists, endocrinologists, nurses, and dietitians in the inpatient and outpatient practice settings. Topics include the patient background and history, the use of carbohydrate counting, capillary blood glucose monitoring (SMBG), insulin therapy, hypoglycemia (low blood glucose), and hospital discharge and follow up. The authors conclude that as the life expectancy for persons with CF increases, so does the likelihood of CFRD. As for all patients with diabetes, optimal glucose control is a worthwhile goal in this already high-risk population. 1 figure. 10 references.

•

Hepatitis Fibrosis Caused By Alcohol Source: Seminars in Liver Disease. 10(1): 66-74. 1990. Summary: This article discusses hepatic fibrosis caused by alcohol. Fibrosis is one of a group of histologic features that characterize alcoholic liver disease. The author focuses on fibrosis because it represents a potentially irreversible form of injury for which there is little therapy. The author discusses the histology and natural history of alcoholic fibrosis; the cells implicated in alcoholic fibrogenesis; the cellular mechanisms of fibrosis; genetic and environmental factors in alcoholic cirrhosis; and the diagnosis of alcoholic fibrosis. The author concludes that the past decade of research has brought a better understanding of the mechanisms whereby alcohol promotes fibrosis in the liver. The perivenular and perisinusoidal fibrosis that characterizes alcoholic cirrhosis suggests that it is a unique entity distinct from other types of fibrotic liver disease. The understanding of alcoholic fibrosis is still incomplete, but a framework now exists on which additional hypotheses, such as those dealing with the regulation of fibrogenesis, can be based. 1 figure. 2 tables. 104 references.

•

Diabetes Secondary to Cystic Fibrosis: An Increasing Clinical Problem Source: Diabetes Educator. 16(6): 478-482. November-December 1990. Summary: This article discusses the clinical management of diabetes when it arises secondarily to cystic fibrosis (CF). As children with CF survive longer, some who reach

8

Fibrosis

young adulthood are developing diabetes. The challenge to diabetes educators in managing these patients is to incorporate basic diabetes treatment into a life-style that includes chronic infections, variable food intakes, multiple demands on time for selfcare procedures, and the psychosocial problems caused by cystic fibrosis. Of particular concern is a meal plan that will attain and maintain a desirable body weight and yet control blood glucose levels. 1 table. 7 references. (AA-M). •

Fibrosis and Disease Progression in Hepatitis C Source: Hepatology. 36(5 Supplemental 1): S47-S56. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: This article discusses the progression of fibrosis in chronic hepatitis C, which determines the ultimate prognosis and thus the need and urgency of therapy. Fibrogenesis is a complex dynamic process, which is mediated by necroinflammation and activation of stellate cells. The liver biopsy remains the gold standard to assess fibrosis. Scoring systems allow a semiquantitative assessment and are useful for crosssectional and cohort studies and in treatment trials. The rate at which fibrosis progresses varies markedly between patients. The major factors known to be associated with fibrosis progression are older age at infection, male gender, and excessive alcohol consumption. Viral load and genotype do not seem to influence significantly the progression rate. Progression of fibrosis is more rapid in immunocompromised patients. Hepatic steatosis (fatty liver), obesity, and diabetes may also contribute to more rapid progression of fibrosis. There are no tests that reliably predict the rate of progression of fibrosis in an individual patient. Serum markers for fibrosis are not reliable and need to be improved and validated. Liver biopsy provides the most accurate information on the stage of fibrosis and grade of necroinflammation, both of which have prognostic significance. Repeating the liver biopsy, 3 to 5 years after an initial biopsy, is the most accurate means of assessing the progression of fibrosis. 4 figures. 2 tables. 63 references.

•

Patient with Cystic Fibrosis: A Case Study Source: Access. 15(8): 58-59,65. September-October 2001. Contact: Available from American Dental Hygienists' Association. 444 North Michigan Avenue, Chicago, IL 60611. Summary: This article summarizes a case report of a 33 year old Caucasian male who presented with the chief complaint of 'needing to have his teeth cleaned.' The patient had been last seen in a private dental office approximately 18 months previously; a history of annual prophylaxes since adulthood was reported. The medical history was significant for cystic fibrosis, for which the patient was taking 2.5 milligrams of Pulmozyme through a nebulizer once daily. He was also taking 4,000 units of Creon, a pancreatic enzyme, before meals and snacks, as well as fat-soluble vitamins (A, E, K) daily. The author describes the patient's oral health history, extraoral findings, intraoral findings, dental hygiene care planning, radiographic findings, implementation of the care plan, patient education and oral hygiene instructions, and prognosis. The author concludes with a brief description of cystic fibrosis and the implications of this disease for dental hygiene practice. 1 figure.

Studies

•

9

Diabetes Mellitus in Cystic Fibrosis Source: European Journal of Gastroenterology and Hepatology. 8(8): 744-747. August 1996. Summary: This article updates readers on diabetes mellitus (DM) in patients with cystic fibrosis (CF). Diabetes mellitus in cystic fibrosis (CF-DM) increases in prevalence with age; develops insidiously; and is characterized by insulinopenia, normal insulin sensitivity, increased insulin clearance rate, and concomitant exocrine pancreatic insufficiency. Since CF-DM impairs overall CF clinical status, including lung function, and may result in late diabetes complications, the condition should be screened through annual oral glucose tolerance tests (OGTTs) beginning at age 10, and be treated with insulin from the time of diagnosis of CF-DM. In patients with CF-DM, self-care modifications and compromises are often necessary to help the patients obtain a life as normal as possible while managing both diseases. 42 references. (AA-M).

•

Pancreatic Insufficiency in Cystic Fibrosis and Pancreatic Exocrine Enzyme Replacement Source: Practical Gastroenterology. 20(1): 37-42. January 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, one in a series on cystic fibrosis (CF), considers pancreatic insufficiency in CF and the use of pancreatic exocrine enzyme replacement. Pancreatic insufficiency in CF results in maldigestion of nutrients, which can, in turn, result in vitamin and trace element deficiencies, intussusception, distal intestinal obstruction, rectal prolapse, and growth retardation. In patients with CF and pancreatic insufficiency, the improvement in nutritional status following therapy with pancreatic enzymes reduced morbidity and mortality. The currently available pancreatic enzyme extracts decrease fecal nutrient losses, but they fail to fully correct maldigestion and malabsorption. In addition, there are several problems with the current preparations. The pancreatic extracts have fixed enzyme ratios, nonphysiologic route of administration, and variation in their content and manufacture. The normal pancreas secretes about 600,000 units of lipase a day, equivalent to 150 capsules a day of a lowdose, enteric-coated microsphere product (containing 4,000 units of lipase). On the other hand, high-dose enzyme is associated with strictures in the ascending colon. The pancreatic enzymes are delivered as rapid-release enzyme preparations, at times with acid-reducing compounds, and as enteric-coated tablets or microspheres containing the enzymes. 1 table. 26 references. (AA-M).

•

Clinical Factors in Progressive Renal Damage: The Role of Interstitial Fibrosis Source: American Journal of Kidney Diseases. 17(5 Supplement 1): 62-64. May 1991. Summary: This brief article discusses the role of interstitial fibrosis in progressive renal damage. The authors consider two main aspects: the correlation of interstitial fibrosis with the behavior of renal function over time; and the most appropriate definition of fibrosis and the mechanisms that lead to its formation. 19 references.

•

Renal Tubulointerstitial Fibrosis: New Thoughts On Its Development and Progression Source: Postgraduate Medicine. 108(1): 159-162, 165, 171-172. July 2000.

10

Fibrosis

Contact: Available from McGraw-Hill, Inc. 1221 Avenue of the Americas, New York, NY 10020. (612) 832-7869. Summary: Tubulointerstitial (between the tissues of the kidney tubules) fibrosis, characterized by the accumulation of extracellular matrix proteins, is a morphologic hallmark of chronic renal (kidney) disease, as well as a component of normal aging in the kidney and of chronic allograft nephropathy (kidney disease in a transplanted kidney). In this article, the author describes patterns that have recently been proposed to explain the pathogenesis (development) of tubulointerstitial injury. In addition, the author discusses available and experimental pharmacologic (drug) interventions that may reduce renal fibrosis. Several new antifibrotic agents are already being tested in experimental models of renal disease and in some cases have been tried in patients with clinical disease. The author concludes that current research shows that both interstitial fibroblasts and renal tubular epithelial cells promote extracellular matrix accumulation. Two peptides (TGF beta and angiotensin II) produced locally or delivered in the circulation, appear to play a central role in renal fibrosis. Drug therapy for renal fibrosis may require methods directed at multiple factors involved in the fibrotic process, including angiotensin II, TGF beta, and the proliferation and activitation of interstitial fibroblasts. 1 figure. 3 tables. 30 references.

Federally Funded Research on Fibrosis The U.S. Government supports a variety of research studies relating to fibrosis. 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 fibrosis. 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 fibrosis. The following is typical of the type of information found when searching the CRISP database for fibrosis: •

Project Title: A CILIATED CELL-SPECIFIC PROMOTER FOR GENE THERAPY OF CF Principal Investigator & Institution: Ostrowski, Lawrence E.; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): The long-term objective of this research is to develop a ciliated cell-specific promoter that will improve the effectiveness of gene therapy or cystic fibrosis (CF). In normal airways, the cystic fibrosis transmembrane conductance regulator (CFTR) protein is expressed primarily at the apical surface of ciliated cells and

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).

Studies 11

in the submucosal glands. For gene therapy of CF to be successful, the normal CFTR protein must be expressed in the proper location. However, many of the gene therapy vectors currently under investigation have no specificity for the differentiated airway epithelium. In addition, these vectors frequently use viral promoter elements or promoters of constitutively expressed genes to drive high-level expression of reporter genes. A major drawback to the use of these vectors therefore is that they may result in high levels of CFTR expression in unwanted cell types (e.g., macrophages, basal cells). These promoters may also be less efficient at providing stable, long-term expression in the non-dividing ciliated cell population. Our hypothesis is that the use of a specific promoter to direct expression of the CFTR protein to the ciliated cells located at the apical surface of the airways will correct the CF phenotype. In addition, we hypothesize that by using an endogenous promoter in an integrating vector, we will achieve stable long-term expression of the CFTR protein. The use of a ciliated cell-specific promoter will also increase the safety of gene therapy for CF by preventing potentially deleterious expression of CFTR in the wrong cell types. To test our hypothesis, we propose the following specific aims: Specific Aim 1: To identify and clone the promoter regions of ciliated cell-specific genes. Specific Aim 2: To identify the essential regulatory elements responsible for ciliated cell specific gene expression. Specific Aim 3: To demonstrate correction of the CF phenotype in both in vitro and in vivo models by targeted expression of the normal CFTR gene in ciliated cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A LINKAGE STUDY IN FAMILIAL PULMONARY FIBROSIS Principal Investigator & Institution: Schwartz, David A.; Professor of Medicine and Genetics; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 20-AUG-2000; Project End 31-JUL-2005 Summary: (Adapted from Investigator's Abstract) The overall goal of this project is to investigate inherited genetic factors that play a role in the development of pulmonary fibrosis. The overall hypothesis of this investigation is that inherited genetic factors predispose individuals to develop pulmonary fibrosis. The goal of this investigation is to identify a group of genetic loci that play a role in the development of familial pulmonary fibrosis. The overall hypothesis is supported by the following observations: familial pulmonary fibrosis is indistinguishable pathologically from idiopathic pulmonary fibrosis and appears to be inherited as an autosomal dominant trait with variable penetrance; pulmonary fibrosis is associated with pleiotropic genetic disorders, such as Hermansky-Pudlak syndrome, neuofibromatosis, tuberous sclerosis, NeimannPick disease, Gaucher's disease, and familial hypocalciuric hypercalcemia; pulmonary fibrosis is frequently observed in autoimmune disease, including rheumatoid arthritis and systemic sclerosis; variable susceptibility is evident among workers who are reported to be exposed occupationally to similar concentrations of fibrogenic dusts; and inbred strains of mice differ in their susceptibility to fibrogenic dust. In conjunction with the exponential growth of human molecular genetics, the investigators state that these clinical observations suggest that a well organized approach to define the genetic determinants of pulmonary fibrosis is scientifically feasible and justified. This project proposes to use standard genetic methodology (linkage analysis) to investigate the distribution of polymorphisms for anonymous genetic markers in families with familial pulmonary fibrosis. The investigators state that their comprehensive genome-wide study, using standard genetic markers, will allow them to identify loci which subsequently may prove to contain novel genes that play a role in the pathogenesis of pulmonary fibrosis. Once genetic loci are defined in familial pulmonary fibrosis,

12

Fibrosis

candidate genes can be identified on the basis of both positional and functional criteria. Moreover, they note that this approach will provide basic information on high priority loci that will be applicable to the rapidly evolving dense human transcript map for pulmonary fibrosis in families with two or more cases of pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A PROMOTER-SPECIFIC TFO PREVENTS LIVER FIBROSIS Principal Investigator & Institution: Guntaka, Ramareddy V.; Molecular Sciences; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): In response to injury, an evolutionarily conserved wound healing process occurs. This response, if gone awry, can result in a pathologic process known as fibrosis, which is due to abnormal accumulation of extra cellular matrix (ECM) and is responsible for causing structural alterations and loss of function of the involved organ. Hepatic fibrosis, if not checked, can progress into cirrhosis and cause irreversible damage to the liver. The main component of the ECM is type I collagen, which, in the case of hepatic fibrosis, is synthesized by the activated stellate cells of the liver. Upon activation, stellate cells become more active in that they are proliferative, contractile due to a -smooth muscle actin and synthesize increased amounts of type I collagen. In our laboratory we have developed a triplex-forming oligodeoxyribonueleotide (TFO), which forms a triple helix structure with the C1 region (-170 to -141) of the a1(I) collagen gene promoter and inhibits transcription. Further we have shown that this TFO inhibits liver fibrosis, induced by administration of the chemical, dimethyl-nitorosamine (DMN), in rats. Now we would like to develop this antigene TFO as a potential antifibrotic agent. We hypothesize that this TFO selectively inhibits collagen synthesis in activated stellate cells. In this proposal, we describe experiments to address the mechanism by which the TFO inhibits collagen gene transcription. Whether the TFO blocks transcription by forming triplexes or by blocking events that lead to inflammation and activation of stellate cells will be studied. Experiments to develop a most efficacious TFO and to study its toxicity, stability, and biodistribution have been proposed. Further, the uptake by different tissues in rats and by different cell types, such as hepatocytes, stellate and Kupffer cells of the liver will also be studied. In these studies we will be using histochemical methods to monitor fibrosis, immunohistochemical methods to examine toxicity and inflammation and various biochemical and nucleic acid hybridization techniques to quantitate the levels of collagen mRNA in the liver tissues. In addition, we will assay for liver function to assess the extent of damage to the liver by the DMN and prevention by the TFO. The data generated from this project may lead to Phase I trials in humans for the treatment of liver fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ALPHA ADRENOCEPTORS IN VASCULAR WALL GROWTH Principal Investigator & Institution: Faber, James E.; Professor; Cellular/Molecular Physiology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAY-2003 Summary: This proposal will determine if local sympathetic activation of alpha1adrenergic receptors (AR) worsens the neointimal and adventitial growth responses to balloon angioplasty, as a model of vascular wall fibroproliferative disease. Evidence

Studies 13

suggests that angioplasty augments local adrenergic neurotransmission. Furthermore, alpha1AR activation induces growth of smooth muscle cells (SMC) and adventitial fibroblasts (AFB). Although alpha1AR stimulation has been proposed to contribute to hypertensive wall hypertrophy and fibrosis, exacerbate atherosclerosis, and to worsen restenosis after angioplasty and stenting, no studies have directly examined these hypotheses because of absence of local drug delivery systems that prevent confounding systemic hemodynamic and humoral actions. We have devised a novel system that overcomes this problem. This, plus recently developed highly selective alpha1AR subtype antagonists, knockout mice and antisense strategies, will be used to investigate the hypothesis that stimulation of a specific alpha1AR subtype on SMCs and/or adventitial fibroblasts (AFB) may contribute importantly to intimal lesion growth and adventitial fibrosis. A possible key role for AFBs in vascular wall disease is just now emerging. We have developed a unique model system for study of these cells in vivo and in vitro, and have made the intriguing finding that AFBs cells differ from other fibroblasts in the array of cytoskeletal proteins that they express, and in their unexpected expression of multiple alphaAR subtypes. Moreover, AFBs undergo a remarkable phenotypic transformation that may be important in vascular wall disease. Aim 1 will determine if alpha1AR stimulation directly induces growth of the normal vascular wall, and importantly, if it worsens neointimal growth and adventitial fibrosis after injury. Aim 2 will determine how injury alters alphaAR expression in the intima, media and adventitia; and which alpha1-AR subtype(s) on SMCs and AFBs augments normal and injured wall growth. Aim 3 will examine if alpha1AR stimulation worsens neointimal or adventitial growth by augmenting SMC and/or AFB proliferation, migration, or matrix elaboration in vivo. Aim 4 will use cultured SMCs and AFBs to test our hypothesis that alpha1AR stimulation adds to-or synergizes with- a specific peptide growth factor(s) to promote SMC and AFB phenotypic transformation, proliferation, migration and/or matrix accumulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALTERED EPITHELIAL STAT1 DEPENDENT SIGNALING IN CYSTIC F Principal Investigator & Institution: Kelley, Thomas J.; Assistant Professor; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from the Applicant's Abstract): Cystic fibrosis (CF) is an inflammatory disease initiated by the loss of cystic fibrosis transmembrane conductance regulator (CFTR) function in epithelial cells. CFTR is a chloride channel whose activity is stimulated by PKA-mediated phosphorylation, and how a loss of this single chloride channel leads to the variety of symptoms associated with CF remains a mystery. The investigators have previously shown that nitric oxide (NO) production and the expression of the inducible form of nitric oxide synthase (NOS2) are reduced in CF airway epithelium. NO is known to regulate several transepithelial ion transport properties and act as a powerful anti-microbial agent, which may have biological significance in CF since CF is partially characterized by altered non-CFTR ion transport abnormalities and susceptibility to airway bacterial infections. Airway epithelium from other inflammatory airway diseases such as asthma have been shown to have increased expression of NOS2, but the mechanisms responsible for decreased NOS2 expression in the presence of such a robust inflammatory response seen in CF remain unclear. The investigators believe that alterations in the signal transducer and activator of transcription-1 (Stat 1) signaling pathway in CF epithelium are responsible for the

14

Fibrosis

puzzling lack of NOS2 expression. Their data indicate that increased levels of the protein inhibitor of activated Stat1 (PIAS1) bind the available activated phosphorylatedStat1 (p-Stat1) in CF epithelial cells preventing Stat1 signaling which is necessary for NOS2 expression. This hypothesis also suggests that portions of interferon-y (IFN-y) dependent signaling would be lost in CF. This conclusion is supported by recently published data by Schwiebert et al. demonstrating reduced RANTES expression in response to IFN-y in CF epithelial cells compared to non-CF controls. Understanding the link between lost CFTR function and overexpression of PIASI will be a focus of this proposal, as will be determining the influence of IFN-y signaling on characteristics of CF-related disease. The aims of this proposal are: 1) to determine the influence of CFTR activity and function of PIAS1 expression and Stat1 pathway activity in epithelial cells; and 2) to determine the role of IFN-y/Stat1-dependent pathways and the effects of PIAS1 in regulating cellular responses with respect to known CF-related abnormalities. Learning how a loss of CFTR function leads to altered cell signaling processes and how these processes unfluence disease may increase our understanding of CF and lead to more precise therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANGIOGENESIS IN HYPEROXIC LUNG FIBROSIS Principal Investigator & Institution: Douglas, Ivor S.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): This 5-year training program proposes the development plan for a career as an independent biomedical researcher in the area of lung injury and angiogenesis. The principal investigator, has completed Pulmonary and Critical Care Fellowship training through the ABIM Research Pathway. With the sponsors and experienced collaborators he will expand on his scientific skills in preparation for career progression as an independent physician-scientist. The program will emphasize skills in molecular biology of angiogenesis and macrophage regulation of fibrosis using a murine hyperoxia model. To advance his knowledge in computational biology he will attend courses in applied statistics. Steven Greenberg M.D. a macrophage biologist, and Paul Rothman M.D., a renowned immunologist in the area of molecular regulation of cytokine signaling, will provide sponsorship. The program will benefit from collaborative expertise of Jan Kitajewski PhD, an expert in angiogenesis and Patty Lee, M.D. who will provide consultative support for the hyperoxia studies. Additionally, George Yancopoulos, a world renowned investigator, will collaborate and serve with the sponsors, Drs. Kitajewski and Lee on an advisory committee every 8 weeks. This committee will review progress and provide close scientific support and career advice. Prolonged hyperoxia results in lung fibrosis in humans and mice. The accompanying vascular remodeling contributes to pulmonary hypertension, right heart failure, and premature death. This program addresses the questions: Do macrophage-derived angiogenic regulatory factors, particularly angiopoietin-2 (Ang-2), contribute to vascular remodeling in response to prolonged sublethal hyperoxia. Do these vascular alterations contribute, independently, to the development of lung fibrosis? And does macrophage-derived Ang-2 directly inhibit endothelial cell survival in response to hyperoxia? The role of macrophage-derived mediators in hyperoxic lung injury remains unclear. We demonstrate in preliminary experiments, increased Ang-2 mRNA and protein in response to hyperoxic exposure in RAW 264.7 and in a mouse model of sublethal hyperoxic lung fibrosis. These mice develop macrophage-predominant cellular infiltration, collagen deposition and

Studies 15

pulmonary vascular regression that recapitulates features of subacute lung fibrosis in humans. The following specific aims will be accomplished: 1) The characterization of fibrotic and vascular remodeling responses in hyperoxia-exposed mice by immunohistochemistry, Western and Northern blotting and ELISA to quantify changes in markers of lung fibrosis, angiogenesis and expression of angiogenic regulators and their receptors. The effects on pulmonary vasculature will be evaluated by confocal microscopy. 2) Functional changes in response to altered expression of macrophagederived angiogenic regulators by angiogenesis assays. Macrophage-depleted mice will be used to assess the contribution of lung macrophages. 3) Lung targeted overexpression of Ang-1 or 2 by adenovirus transfection or blocking antibodies prior to hyperoxia to determine the contribution of Ang-2 to pulmonary vascular remodeling and fibrosis during prolonged sublethal hyperoxia. 4) Determine if Ang-2 mediated endothelial survival inhibition is PI3K/Akt dependent. Columbia University has an established record of successful mentorship and training for K08 Career awardees in their preparation for careers as independent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIVIRAL & ANTIFIBROTIC LIVER THERAPY OF HCV+ DRINKERS Principal Investigator & Institution: Lieber, Charles S.; Professor of Medicine & Pathology; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-MAY-2005 Summary: We plan to evaluate a combined antiviral, antifibrotic and antioxidant treatment in the progression of liver disease of heretofore excluded patients with hepatitis C namely alcohol drinkers. Abstainers or alcohol consumers will be given state- of-the-art antiviral treatment (pegylated interferon + ribavirin) for 24-48 weeks. Another innovative aspect of this proposal is the supplemention with an anti-fibrotic agent, namely polyenylphosphatidylcholine (PPC) extracted from soybeans, or placebo, administered for 3 years (concomitantly with the antiviral treatment and thereafter). Current therapy neglects the fact that what causes the major medical symptoms and eventually the demise of the patient is liver fibrosis, resulting cirrhosis and associated complications, including hepatocellular carcinoma. If the fibrotic process could be stopped or even prevented, the hepatitis C virus would lose much of its impact on health. Available anti-fibrotic agents are too toxic to be used in patients, except for one, namely PPC, which has been shown in various experimental models to have striking anti-fibrotic actions, and which was found recently to be beneficial in HCV+ patients in terms of their circulating levels of transaminases. Fibrosis was not assessed, but documentation of the effects of PPC on fibrosis in HCV+ patients is being proposed here. It is noteworthy that PPC was discovered to have also significant anti- oxidant effects. This may be important in HCV+ patients since various studies have now indicated that HCV is associated with an oxidative stress. Another innovative aspect is the inclusion of drinkers who thus far were excluded from standard antiviral treatment, mainly because of concerns about exacerbation of mental disorders, reliability and compliance. However, the latter objection has now been overcome by the availability of pegylated interferon which can be administered once a week by the therapist in a controlled fashion. For both PPC and ribavirin, compliance will be monitored by incorporation of markers, such as riboflavin, that can be measured in the urine. Spot checks of blood levels of dilinoleoylphosphatidylcholine (DLPC, the main phosphatidylcholine species of PPC) will also be performed. Accordingly, support is

16

Fibrosis

requested for a a double-blind, randomized placebo controlled study to assess the efficacy of this novel approach for the treatment of liver disease in HCV+ alcohol consumers or abstainers. Funds are requested for special laboratory tests, study nurses, travel to meetings, patient monitoring expenses and a core office. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APOPTOSIS CARDIOMYOPATHY

AND

CONTRACTILITY

IN

ISCHEMIC

Principal Investigator & Institution: Canty, John M.; Professor; Medicine; State University of New York at Buffalo Suite 211 Ub Commons Amherst, Ny 14228 Timing: Fiscal Year 2002; Project Start 10-JAN-2000; Project End 31-DEC-2003 Summary: Ischemic cardiomyopathy is the most common etiological cause of heart failure but the factors responsible for initiating decompensated LV dysfunction are unknown. Although considerable work has focused on irreversible injury following infarction, many patients have symptoms of heart failure in association with viable dysfunctional or "hibernating" myocardium. Pathological studies support the notion that the degree of dysfunction frequently exceeds the amount of structural fibrosis identified at postmortem exam. Preliminary studies by the applicant have reproduced the physiological features of hibernating myocardium in pigs with a chronic LAD stenosis. While this occurs with normal LV function and without infarction, there is increased regional myocyte apoptosis, a 30 percent loss of myocytes and compensatory myocyte hypertrophy after a period of 3 months. At the molecular level, there is a regional downregulation of SR calcium uptake proteins. These changes, arising from reversible ischemia (i.e. angina pectoris) and with normal global LV function, are identical to the abnormalities found in end-stage heart failure. Thus, the overall hypothesis of this application is that myocyte apoptosis and SR dysfunction arise in areas with chronically reduced coronary flow reserve and are early rather than late events in the pathogenesis of ischemic cardiomyopathy. Aim 1 will define the role of apoptosis mediated myocyte loss and LV remodeling from reversible ischemia in hibernating myocardium. A 2-vessel stenosis model that progresses to global LV dysfunction with LV dilatation and increased LV filling pressure will be used to determine how diastolic stretch and the size of the dysfunctional region modulates apoptosis and LV remodeling. Aim 2 will identify the temporal progression of apoptosis in ischemic and normal regions in relation to the expression of the pro- and antiapoptotic proteins Bax and Bcl-2 which will be quantified in vivo on a regional basis. Aim 3 will define the extent that apoptosis mediated myocyte loss and altered SR protein expression affects the reversibility of function in hibernating myocardium after surgical revascularization and after stimulating angiogenesis with basic fibroblast growth factor (FGF-5). Aim 4 will determine whether apoptosis and altered SR protein expression can be prevented pharmacologically with beta blockade, by stimulating angiogenesis prior to the development of myocyte loss and by overexpressing Bcl-2 in vivo. This integrative approach should provide a better understanding of the events that lead to the progression of ischemic LV dysfunction at a time when therapeutic interventions such as revascularization and in vivo gene transfer can be used to interrupt the progressive myocyte loss, contractile dysfunction and irreversible structural fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 17

•

Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Haponik, Edward F.; Professor of Internal Medicine; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The Clinical Core will serve as the coordinating center for patient recruitment, specimen procurement and data base management. It is the mission of this Core to identify and provide disease-specific candidate genes from patients with such clinical disorders as acute lung injury, COPD, cystic fibrosis, asthma, pulmonary hypertension, pulmonary fibrosis, ischemic heart failure and both lung and cardiac transplant rejection. This core will also be responsible for the establishment of a Cardiopulmonary Tissue Repository that will maintain an archive of cryopreserved tissues and maintain an accurate data base of patient demographic and clinical data for correlation with biological end points produced by cDNA microarray. Following patient consent and registration, tissue samples and peripheral blood are delivered to the Core laboratory. The freezing facility will also serve as a repository for cyropreserved human lung and cardiac specimens. The Core Investigators will meet regularly to review all diagnostic materials on each specimen procured including histochemical stains and biopsies in order to determine a precise diagnosis and relevant demographic and clinical data for entry into the Project's data base which will include critical variables for the analysis of the biological data obtained. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: AUTOIMMUNE THYROIDITIS--INDUCTION AND RESOLUTION Principal Investigator & Institution: Mullen, Helen B.; Professor; Internal Medicine; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 30-SEP-1985; Project End 31-MAR-2003 Summary: T cells from mouse thyroglobulin (MTg)-sensitized donors activated in vitro with MTg, anti-IL-2R and/or IL-12 induce severe granulomatous experimental autoimmune thyroiditis (G-EAT) in recipient mice. Thyroid lesions reach maximal severity at 19-21 days and completely resolve by 35-50 days if all thyroid follicles are not damaged. Depletion of CD8+ T cells inhibits resolution. If most thyroid follicles are damaged at day 21, there is continuing inflammation, with decreased serum T4, fibrosis and atrophy of the thyroid. The objective is to define the mechanisms involved in resolution and fibrosis of G-EAT and to determine if resolution can be promoted by preventing or reversing fibrosis. MTg- specific CD4+ T cells initiate injury to the thyroid by releasing cytokines. Cytokine-deletion mutant mice will be used to determine how particular inflammatory mediators regulate induction and resolution of G-EAT. CD4+ T cells or cytokines also recruit other cells to the thyroid; these include other inflammatory cells which induce more damage, and CD8+ T cells which become activated and terminate the inflammatory response, possibly by inducing apoptosis of CD4+ T cells. When inflammation is very severe, CD8+ T cells are unable to terminate the inflammation and lesions progress to fibrosis. Excessive production of TGFbeta by inflammatory cells is hypothesized to play a major role in excessive collagen deposition resulting in fibrosis. These studies will test the hypothesis that CD8+ T cells promote resolution of G-EAT, in part, by inducing apoptosis of inflammatory cells and that fibrosis develops when TGFbeta is overproduced. TGFbeta inhibitors and depletion of CD4+ T cells or neutrophils will be used to attempt to promote resolution and prevent or reverse fibrosis. This murine G-EAT model is a well-characterized animal model of autoimmune disease in which the host's immune system promotes healing of lesions.

18

Fibrosis

Our studies are aimed at understanding the mechanisms that enable the host to regulate and resolve this autoimmune inflammatory response and understanding how to prevent or reverse more severe destructive inflammatory responses that result in a failure of resolution, and a fibrotic end-stage disease. Granulomatous inflammation and fibrosis occur in many human diseases with presumed autoimmune mechanisms. These studies should provide directions for new clinical investigations that may lead to more rational and specific forms of therapy and provide insight into recovery mechanisms for autoimmune diseases, particularly those associated with granulomatous immunopathology, vasculitis and fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BILIARY ATRESIA CLINICAL RESEARCH CONSORTIUM Principal Investigator & Institution: Shepherd, Ross W.; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The creation of a multi-center collaborative consortium provides an unprecedented opportunity to improve the lives of children with neonatal liver disease. This Clinical Center application from four pediatric medical centers describes the collective clinical expertise, collaborative research experience, and outstanding institutional core facilities needed to be productive contributing members to this consortium. This application proposes participation in the consortium in three ways: 1. Clinical Data Collection: A uniform, concise data form and electronic collection system will be developed to manage clinical data. Relevant clinical data and tissue specimens will be contributed to the Consortium. The two research programs and four clinical programs collaborating in this proposal can contribute data from approximately 25 new patients with biliary atresia (BA)/year and 12 patients with neonatal hepatitis (NH)/yr. 2. Short-term study: Using available and accumulated specimens, we will study the pathogenesis, natural history, and clinical correlates of hepatic fibrogenesis in patients with biliary atresia and NH. A variation of the Knodell hepatic fibrosis scale will be used to determine the extent of hepatic fibrosis at the time of the Kasai procedure. Immunohistochemical and in situ hybridization techniques will be used to quantify the expression of specific molecular markers of hepatic fibrosis and inflammation. The severity of fibrosis or specific staining patterns will be correllated with patient diagnosis and response to the Kasai procedure. 3. Long-term study: To identify patterns of protein and gene expression that are unique to biliary atresia or that predict response to the Kasai procedure, gene expression profiles will be determined in wedge liver biopsies as well as in hepatocytes and biliary epithelial cells isolated by laser capture microdissection (LCM). Modern proteomic techniques will also be applied to serum samples to identify proteins synthesized and released by the injured liver. Similar to the genetic profile, the pattern of proteins will be correlated with clinical data to identify patterns of serum proteins that are disease specific or predict prognosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: BILIARY SECRETORY PATHWAYS IN CYSTIC FIBROSIS Principal Investigator & Institution: Cho, Won K.; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-MAY-1999; Project End 31-DEC-2003 Summary: Cystic fibrosis (CF) is the most common lethal inherited diseases in white population. As CF patients live longer, liver disease has become the second leading

Studies 19

cause of death. The development of CF disease is believed to result from the secretory defects in the bile ducts leading to the obstructions of bile ductules by tenacious bile secretions, thereby secreting in focal periportal biliary fibrosis/cirrhosis. This explanation in addition to the recent finding that CFTR is only expressed on bile duct cells, but not on hepatocytes, suggest that studying biliary secretion is crucial to understanding the pathophysiology and developing therapeutic strategies for CF liver. A novel polarized isolated bile duct unit (IBDU) prepared from rat liver has demonstrated to be an ideal tool to study bile ductular secretion but the lack of CF rat model limited its use in CF studies. By applying these isolation methods, recently, IBDUs have been isolated from normal and CF mice. Therefore, the aims of this research are to further characterize bile duct cells (BDC) and IBDU from normal and CF knockout mice, to characterize ion transporters in BDC, and to study the actions and mechanisms of various secretagogues including neuroendocrine peptides in biliary secretion in order to find ways to activate alternative, cAMP-independent biliary secretory pathways in CF mice. Preliminary experiments to isolate IBDU from normal mouse yielded intact polarized functional IBDU that responds to secretin, vasoactive intestinal peptide, and DBcAMP-IBMX. Similar IBDUs were also isolated from CF mice but need further characterization. Quantitative videomicroscopy will be used to screen potential secretagogues to stimulate biliary secretion in normal and CF mice and to characterize their underlying ion transporters by using ion substitutions and inhibitor studies. These ion transporters will be further studied by BCECF dual ratio methods for measuring pH, micropuncture, and patch clamping techniques. Signal transduction systems involved in their action will be studied by monitoring changes in the concentrations of secondary messengers. Understanding transport systems and their underlying mechanisms of biliary secretion in normal and CF mice will help to formulate therapeutic approaches to overcome the CFTR defect. This project, in turn, will provide the candidate with an excellent opportunity to broaden and develop research and cognitive skills to become independent researcher, as well as help to successfully compete for future research grants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOMARKERS IN SPUTUM IN COPD Principal Investigator & Institution: Broide, David H.; Associate Professor of Medicine; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The overall goal of this proposal is to identify biomarkers in the sputum of patients with emphysema that associate with emphysema but not with either healthy controls, smokers without emphysema, or lung diseases associated with airway inflammation and fibrosis such as asthma or idiopathic pulmonary fibrosis. The approach we plan to use to identify sputum biomarkers in emphysema will use both hypothesis driven experiments to explore candidate sputum biomarkers of inflammation (LTB4, IL-8, TNF), fibrosis (TGF- beta, PGDF, FGF), metalloproteases (MMP-1, MMP-9, MMP-12, TIMP), elastin degradation (desmosine in urine) as well as an alternative approach using both proteomic analysis of sputum and bronchoalveolar lavage, and genomic studies of airway epithelium and alveolar macrophages to identify potential novel biomarkers of emphysema that correlate with CT scan evidence of emphysema. Levels of biomarkers will be measured over a two year period and be correlated with CT scan extent of emphysema. If such a non-invasive biomarker were identified this could either serve as a biomarker in studying the effects

20

Fibrosis

of intervention with anti-inflammatory medications or smoking cessation in subjects with emphysema, or alternatively serve to identify smokers at risk for the development of emphysema. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD36 AND HEPATIC STELLATE CELL ACTIVATION Principal Investigator & Institution: Devilliers, Willem Js.; Medicine; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: The central hypothesis to be examined in this R21 proposal is that the class B scavenger receptor, CD36, plays an important role in hepatic stellate cell activation and hepatic fibrogenesis through the alcohol-induced generation of lipid peroxidation products and activation of the nuclear transcription factor, peroxisome proliferatoractivated receptor gamma (PPAR-G). The major difficulty in devising specific therapies for alcoholic liver disease has been our limited understanding concerning the mechanisms underlying the progressive nature of the liver injury and fibrosis in this disease process. The class B scavenger receptor CD36 binds oxidized LDL (OxLDL) and is critical in macrophage foam cell formation and lipid flux. Oxidized cholesterol esters and lipid peroxidation products have been shown to act as ligands for PPAR-G in cells. The expression of CD36, which takes up oxidized cholesterol esters from OxLDL, is positively regulated by PPAR-G, thereby establishing a positive feedback control loop through which oxidized LDL induces greater CD36 expression which in turn leads to increased OxLDL accumulation in cells. The CD36-thrombospondin complex is required on the cell surface for the formation of activated transforming growth factor-beta (TGFb). We present preliminary data that PPAR-G agonists similarly increases CD36 expression and function in hepatic stellate cells, linking alcohol-induced generation of lipid peroxidation products and hepatic fibrosis. It is well documented in experimental models of alcoholic liver disease that addition of polyunsaturated fatty acids to the diet enhances liver injury and fibrosis. It is our working hypothesis that the CD36 scavenger receptor is upregulated in alcoholic liver disease and is critical for stellate cell activation and fibrogenesis. We therefore propose basic studies in vitro and in animal models of liver fibrosis that address the specific role of CD36 class B scavenger receptors in hepatic stellate cell activation. We believe the proposed research is likely to generate data that will lead to a regular research project grant. The specific aims of this R21 Experimental/Developmental Proposal are: Aim 1: To determine the extent to which PPARG activation and CD36 expression regulate stellate cell activation. Stellate cell activation will be measured by Collagen expression and secretion of activated TGF-B. Aim 2: To document that stellate cells from spontaneously hypertensive rats deficient in CD36 are resistant to activation and fibrogenesis. Moreover, we will determine whether the over expression of CD36 in these CD36-deficient stellate using an adenoviral vector will reconstitute their ability to become activated in response to lipid peroxidation products. Aim 3: To determine the influence of hepatic stellate cell CD36 expression on the development of hepatic fibrosis in rodent models. We will determine whether spontaneously hypertensive rats and CD36-deficient mice are resistant to the development of hepatic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 21

•

Project Title: CELLULAR MECHANISMS OF MATRIX REGULATION IN LIVER REPAIR Principal Investigator & Institution: Tracy, Thomas F.; Rhode Island Hospital (Providence, Ri) Providence, Ri 02903 Timing: Fiscal Year 2002; Project Start 01-MAY-1994; Project End 31-JUL-2007 Summary: (provided by applicant)At critical points in chronic liver injury the potential for liver repair is lost. Timely surgical and medical treatment however, initiates liver repair interrupting the cycle of inflammation and hepatic fibrosis. The subsequent cellular regulation of matrix protein degradation and resolution of injury dependent fibrosis is unknown. The long-term goals of our studies are to define the molecular mechanisms required for ordered matrix resorption and liver repair without scar. Specific aims have been designed to test the hypothesis that repair, resolution of scar, and the restoration of hepatic architecture depend on coordinated regulatory mechanisms of matrix degradation through matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) gene expression, cellular localization and most importantly, biologic activity. Further, we propose that Kupffer cells (KC), the resident macrophage population, have a central role in the inflammatory and fibrogenic regulation of liver repair after chronic injury. Specific Aim 1 addresses the molecular and cellular mechanisms of reversible hepatic fibrosis and those of delayed matrix resorption. A unique rat model of reversible biliary obstruction will simulate early, intermediate, and late, near end stage cholestatic liver injury. This model allows biliary decompression to initiate liver repair. [The effect of injury duration on key matrix (collagen I and III, laminin), MMP (1,2,8,9) and TIMP (1,2) mRNA and protein expression will be measured in whole liver and in [individual] cells using new methods of laser capture microdissection. [These data will demonstrate the mechanism and physiology of matrix resorption through measurement of MMP activity by in-gel and in-situ zymography]. Specific Aim 2 tests the hypothesis that KC are in vivo regulators of matrix metabolism. Through strategies of KC depletion/ inactivation by gadolinium or Dexa-Man10-HSA targeted dexamethasone during repair, matrix resorption, regulatory cytokine profiles and MMP-TIMP activity will be localized in cells and measured. In Specific Aim 3 we will establish the effect of progressive injury on the in vitro capacity of isolated hepatic macrophages (MPh) to express specific MMP and fibrogenic/ antifibrogenic cytokine (TGFbeta, IL1, 6, 10) profiles during repair. KC inactivation and MMP stimulation/ suppression strategies will isolate the net collagenolytic activity of MPh. [In addition to the broad clinical implications for the treatment of cholestatic or other chronic liver diseases in infants, children, and adults, these studies may be the first to identify key molecular mechanisms for successful repair after progressive liver injury. They have the unique potential to yield targets for therapy to promote liver repair or rescue patients approaching end stage liver disease Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CFTR REGULATION OF ION CHANNELS Principal Investigator & Institution: Egan, Marie E.; Associate Professor; Pediatrics; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 07-APR-1998; Project End 31-DEC-2003 Summary: The gene that is defective in patients with cystic fibrosis (CF) encodes a protein termed the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a member of a superfamily of transmembrane proteins known as the ATP Binding Cassette (ABC) Transporters. It is clear that CFTR functions as a cAMP dependent

22

Fibrosis

protein kinase A stimulated chloride (CI-) channel. Although abnormal CI- channel activity, specifically cAMP- dependent protein kinase A (PKA) stimulation of CIsecretion, is a predominant feature of CF- affected epithelial cells and believed to be a direct result of the dysfunctional CFTR protein, there are a number of other ion transport abnormalities that are characteristic of CF- affected epithelial cells. There is increasing evidence that CFTR can interact with other channel proteins and act as a channel regulator as do a number of the ABC transporters. Our hypothesis is the CFTR is a bifunctional peptide that acts as a regulator of ion channels and transporters as well as a regulated CI- channel. Furthermore it is likely that the ability to act as a channel regulator depends on domains that are common to many members of the ABC transporter superfamily. The studies proposed in this application will examine how CFTR acts as a channel regulator. Voltage clamp and patch clamp techniques will be used to dissect the mechanisms that control CFTR's interactions with ion channels and identify which domains of CFTR participate in these interactions. The ultimate goal of this project is to apply insights gained from these basic science studies of CFTR function to improve the clinical management of cystic fibrosis patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLEARANCE OF APOPTOTIC CELLS IN CYSTIC FIBROSIS Principal Investigator & Institution: Vandivier, Richard W.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 17-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) that is associated with chronic, debilitating airway inflammation. In CF, airway inflammation begins almost immediately following birth and continues inexorably until death ensues from pulmonary failure in the majority of patients. Studies have observed the accumulation of inflammatory cells and mediators in the airways of CF neonates in the absence of detectable infection, suggesting that CFTRdeficiency may have the capacity to disturb normal regulatory mechanisms, and initiate airway inflammation. Resolution of inflammation normally involves the orderly removal of apoptotic inflammatory cells, thereby suppressing their ability to do damage. This process promotes the resolution of inflammation by, 1) preventing spillage of proinflammatory cell contents, and by 2) inducing the phagocyte to produce antiinflammatory mediators such as TGFI3 and PGE2, through interaction with the phosphatidylserine receptor. We have observed that apoptotic inflammatory cells accumulate in the airways of young adults with CF, and have shown that protease cleavage of the PS receptor is involved. We now provide evidence that CFTR-deficiency impairs apoptotic cell ingestion by airway epithelium, and prevents apoptotic cell suppression of inflammatory mediator release. A role for CFTR in epithelial cell clearance of apoptotic cells may be related to the fact that CFTR is a member of the ATPbinding cassette (ABC) protein superfamily, which includes members known to be involved with apoptotic cell removal (e.g. ced7 and ABC-1). These findings and the known role for epithelial cells in apoptotic cell clearance suggest that failed phagocytosis by epithelial cells may contribute to the accumulation of apoptotic cells and persistent inflammation in CF airways. Therefore, we propose to 1) test the effect of CFTR on ingestion mechanisms unique to uptake of apoptotic cells, to 2) test various mechanisms whereby apoptotic cells may enhance the inflammatory response in CFTRdeficient epithelial cells, and to 3) determine the effect of dysfunctional CFTR on apoptotic cell clearance and inflammation in vivo. These studies will help to elucidate

Studies 23

the role of CFTR in a previously unknown function, phagocytosis of apoptotic cells and regulation of inflammation, and in the future may help direct therapies toward mitigating this process and diminishing the long-term effects of chronic airway inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COLLAGEN TRANSCRIPTION AND LUNG FIBROSIS Principal Investigator & Institution: Smith, Barbara D.; Professor; Biochemistry; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: Certain lung injuries induce large increases in connective tissue content, particularly collagen, resulting in fibrosis. During injury, cells are exposed to molecules such as interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGFbeta), regulating production of matrix components. Clinical trials for interstitial pulmonary fibrosis (IPF) are ongoing. However, very little is understood concerning collagen repression by this mediator. This project focuses on establishing the mechanisms by which collagen transcription is repressed by IFN- gamma. We have recently described a regulatory factor for X-box (RFX) binding site at the collagen transcription start site. RFX1 represses collagen transcription. RFX1 interacts with and activates c-Abl, a non- receptor tyrosine kinase that can phosphorylate itself, RFX1 and the carboxyl domain of RNA polymerase II (CTD). C-Abl interacts with RFX1 at the collagen transcription start site. This proposal determines whether c-Abl participates in signal transduction pathways leading to decreased collagen synthesis. RFX5 forms a complex at the collagen transcription start site when RFX1 is removed. IFN-gamma induces class II transcription activator (CIITA) which interacts with RFX5 forming a complex with two other proteins that activate major histocompatibility class II proteins (MHC-II). Since IFN-gamma represses collagen synthesis, we hypothesize that RFX proteins mediate collagen transcription repression during IFN-gamma treatment. Our overall hypothesis is that IFN-gamma repression occurs on the collagen promoter by cooperative interactions of RFX protein family members at the start site with other proteins binding to the proximal promoter. The specific aims are to; 1) Determine the function and interactions of RFX family before and after IFN-gamma treatment. 2) Examine the functional interactions of c-Abl with RFX proteins at the collagen transcription start site. 3) Examine the localization and kinase activity of c-Abl and RFX in lung fibroblasts under different treatments and in samples of human lung tissue. 4) Use transgenic animals with collagen-promoter-CAT constructs or animals deficient in c-Abl or RFX5 complex to investigate collagen transcriptional regulation during fibrosis and treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CONNECTIVE TISSUE GROWTH FACTOR IN HEPATIC FIBROSIS Principal Investigator & Institution: Brigstock, David R.; Children's Research Institute 700 Children's Dr Columbus, Oh 43205 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-MAY-2006 Summary: The broad long-term objectives are to establish the role of connective tissue growth factor (CTGF) in causing fibrotic disease. CTGF is a highly pro-fibrogenic molecule which is over- expressed in all fibrotic lesions examined to date. It is transcriptionally activated by transforming growth factor-beta (TGF-beta) and mediates many of the matrix-inducing properties that have previously been attributed to TGF-

24

Fibrosis

beta. The studies described in this proposal focus on the role of CTGF in liver fibrosis, including that related to alcohol abuse. Preliminary data show that CTGF is overexpressed in fibrotic livers and is produced by hepatic stellate cells (HSCs), the principal fibrogenic cell type, both in response to TGF-beta and as a function of activation. HSCs show enhanced adhesion and levels of alpha smooth muscle actin in response to CTGF. In addition, ethanol and its fibrogenic metabolite, acetaldehyde, stimulate CTGF transcription in fibroblasts. Our hypothesis is that local up-regulation of CTGF in the liver drives the fibrogenic response, including that initiated by alcohol. Our Specific Aims are (1) To determine mechanisms of CTGF regulation in HSCs, including the role played by TGF-beta and acetaldehyde (which stimulate HSCs and CTGF production) as well as retinoic acid and TNF-alpha (which inhibit HSC function and CTGF production); (2) To determine the effects of CTGF on HSC function by examining HSC DNA synthesis, division, matrix metabolism, vitamin A content, and adhesion in HSCs treated with or over-expressing various mass forms (1OkDa, 16-20kDa, 38kDa) of CTGF which occur naturally in vivo and which are a product of HSCs maintained in vitro, and to determine the role of CTGF-stimulated kinases in these processes; and (3) To produce recombinant adeno-associated viruses for the delivery of the CTGF gene into the liver in vivo to directly establish the ability of 10 kDa and 38kDa CTGF to stimulate liver fibrosis. These studies will define the fibrogenic properties of CTGF in terms of its regulation, biological properties, signaling mechanisms and protein structure. In addition, these studies will help establish whether CTGF is a therapeutic target for treating fibrosis, which is a contributing factor in 45 percent of deaths in the USA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE CENTER - CYSTIC FIBROSIS Principal Investigator & Institution: Davis, Pamela B.; Professor; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-MAR-2006 Summary: The Core Center for Research in Cystic Fibrosis (CF) at Case Western Reserve University has existed since 1964, in one form or another, through its structure and core functions have evolved as the research base has changed. The current Center, which garners over $9 million in external grants and contracts in support of CF-related research, consists of 42 investigators from 9 departments with focus in three main scientific areas. The area of cell and molecular biology of CFTR, with leadership from Mitchell Drumm, M.D., co-director of the Center, and Ulrich Hopfer, M.D., a member of the Executive Committee, is supported largely through R01 and Cystic Fibrosis Foundation (CFF) grants, and studies CFTR molecular conjugates, and modifier genes. The second main area, with leadership from Melvin Berger, M.D., Ph.D., underlying basis, and how it might be modified therapeutically. This work is the topic of a SCOR grant (funded 1998) and CF, the third area of focus, which receive support from the CFF Therapeutics Development Network (funded 1998), industrial sponsors, and federal and CFF grants. The Center is directed by Pamela Davis, M.D., Ph.D., who also directs the CFF Research Development Program, the SCOR in inflammation, and the T32supported training program. The Core Center consists of five cores besides the administrative: Biostatistics (Mark Schluchter, Ph.D., Director); Epithelial Cell Culture (Calvin Cotton, Ph.D., Director); Imaging (Ulrich Hopfer, M.D., Ph.D., Director); BAL/Inflammatory Mediator (Ronald Walenga, Ph.D., Director) and Animal (Mitchell Drumm, Ph.D., Director), each of which provides services to at least ten funded projects. In addition, the Center operates a pilot and feasibility program to encourage new ideas in CF research. In addition, the Center operates a pilot and feasibility program to

Studies 25

encourage new ideas in CF research. Of past P&F projects, 74% received additional grant support (60%, federal grants) and more than 90% continue involvement in CF research. The Center emphasizes translational research, and the next five year cycle should see the testing of new therapeutic strategies developed in the Center in CF patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANIMAL MODEL AND DELIVERY Principal Investigator & Institution: Matalon, Sadis; Acting Associate Provost for Research; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: (Taken directly from the application) Five of the pilot projects in the current application, and ten investigators with funded RO1s or other grants for gene transfer, have indicated a need for assistance with 1) instillation or aerosolization of gene delivery vehicles, 2) detection of reporter transgenes, 3) ion transport measurements in CF mice, or 4) histopathology in order to test safety and biologic effect of gene transfer to mammalian airways. The purpose of this core is to provide that expertise in a central, standardized fashion. The Core will process murine lungs for reporter gene activity (including luciferase, chloramphenicol acetyltransferase (CAT), and LacZ). We will also develop and test a new, highly sensitive reporter construct ($ -lactamase) for activity in vivo. Nasal potential difference measurements will be performed before and after gene transfer to cystic fibrosis and normal mice. This assay will be designed to test for functional correction of cystic fibrosis defects after CFTR gene expression in vivo. Finally, we will provide expertise in histopathology, so that lungs treated with gene transfer vectors can be processed and sectioned for qualitative and quantitative analysis of the extent and duration of the host inflammatory responses. These core functions are designed to facilitate the transition from in vitro proof of concept trials to in vivo analyses of CF gene transfer. The protocols described here are a crucial aspect of the development of gene therapy in cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: DEAFNESS AND OSSIFICATION IN LABYRINTHITIS OSSIFICANS Principal Investigator & Institution: Brodie, Hilary A.; Otolaryngology; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-JAN-2000; Project End 31-DEC-2004 Summary: (Adapted from the Investigator's Abstract) Labyrinthitis ossificans (LO) is the growth of pathologic new bone within the lumen of the cochlea. It is multifactorial in origin and may result in deafness. Profound hearing loss and LO in children are most commonly associated with meningogenic labyrinthitis. The relationship of LO to meningogenic cochlear pathology and its mechanism of induction have not been clearly defined. Cochlear implants are a significant treatment option for improving hearing and quality of life in these patients. However, LO can reduce the efficacy of cochlear implantation. The long-term objective of this research program is to understand the mechanisms which lead to the development, progression, and destructive aspects of LO. Such an understanding may lead to new strategies to prevent the devastating effects of hearing loss associated with this disease. The specific aims of this application are: (1) to correlate hearing loss with the temporal and spatial progression of bacterial meningitis from the subarachnoid space to the cochlea; (2) to correlate hearing loss with the temporal and spatial sequence for both labyrinthine fibrosis and ossification and the

26

Fibrosis

histopathology of cochlear tissues: spiral ganglion, organ of Corti, Reissner's membrane, stria vascularis, and spiral ligament; (3) to determine the relationship of bone lining cells to osteoblast formation and recruitment during labyrinthine neo-ossification; and (4) to determine the effects of decomplementation, non-steroidal anti-inflammatory compounds, and bacteriostatic vs. bactericidal antibiotics on neo-ossification and hearing loss. There are four hypotheses/specific aims outlined and they are as follows: Bacterial invasion of the cochlear labyrinth from the subarachnoid space correlates with hearing loss and occurs principally via the cochlear aqueduct and not the internal auditory canal; The destruction of cochlear tissue occurs subsequent to the arrival of inflammatory cells and not with the appearance of bacteria within the cochlea. Hearing loss may occur prior to observable pathology and reflect central auditory damage related to meningitis; Bone lining cells of the endosteum are activated and become mature osteoblasts and are the principal source of neo-ossification in labyrinthitis ossificans; and The inflammatory response to suppurative labyrinthitis includes fibrosis and neo-ossification formation and causes cochlear tissue destruction. Inhibition of this process will result in a reduction in both hearing loss and bone deposition. Methods used: The investigators propose to use an experimental gerbilline model of LO, histomorphometry, fluorescent bone histomorphometry, transmission and scanning electron microscopy, autoradiography, and auditory brainstem evoked response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETIC CARDIOMYOPATHY: TGFBETA ACTIVATION AND FIBROSIS Principal Investigator & Institution: Murphy-Ullrich, Joanne E.; Professor; Pathology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2006 Summary: (provided by applicant): Diabetic cardiomyopathy, characterized by myocyte hypertrophy and interstitial fibrosis, is a potentially life-threatening complication resulting from lack of glycemic control. Hypertension associated with diabetes increases disease severity. TGF-beta is the primary effector of fibrosis in response to hyperglycemia. Bioactivation of latent TGF-beta is a major regulatory step in controlling TGF-beta and a logical point for therapeutic intervention. Yet, regulation of TGF-beta bioactivity in these diseases is not well understood. The platelet/matrix protein, thrombospondin l (TSP 1), is a physiologic regulator of latent TGF-beta activation. TSP 1 regulates glucose-stimulated increases in TGF-beta bioactivity and matrix protein synthesis in mesangial cells. TSP-dependent TGF-beta activation is also important for the diabetic myocardium, since high glucose stimulates TSP1 and TGF-beta bioactivity in rat cardiac fibroblasts and increases in TGF-beta bioactivity are blocked with TSP antagonist peptides. Similarly, data show that angiotensin II (Ang 11)-stimulates increased TSP 1 expression and TGF-beta bioactivity that can be blocked by addition of the antagonist peptides. Both glucose and Ang II up-regulate TSP 1 expression, potentially through modulation of PKC and nitric oxide (NO). These data support the hypothesis that glucose-mediated modulation of PKC, NO, ROS, and Ang II are involved in the regulation of TSP1 expression, leading to latent TGF-beta activation, matrix protein synthesis, and myocardial fibrosis. In this proposal, we will use a cultured cardiac fibroblast system to determine 1) the interrelationships between glucose, PKC activity, and oxidative balance in regulation of TSP 1 expression, TGF-beta bioactivity, and matrix protein synthesis and; 2) the role of Ang II in regulation of TSP 1dependent TGF-beta activation and its relation to glucose stimulation. In addition, rats with diabetes (streptozotocin) and hypertensive diabetes will be used to determine 3)

Studies 27

whether peptide antagonists of TSP-mediated TGF-beta activation ameliorate diabetic myocardial fibrosis under normo- and hypertensive conditions. These studies will further our understanding of how TGF-beta is regulated in diabetes and hypertension, and will potentially identify new strategies for therapeutically attenuating myocardial fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF SILICA AND ASBESTOS ON MACROPHAGE FUNCTION Principal Investigator & Institution: Holian, Andrij; Professor; Pharmaceutical Sciences; University of Montana University Hall 202 Missoula, Mt 598124104 Timing: Fiscal Year 2002; Project Start 01-MAY-1989; Project End 31-JAN-2005 Summary: (Adapted from the Investigator's Abstract) Inhaled asbestos and crystalline silica are recognized as occupational and ubiquitious fibrognic particles, both capable of inducing lung inflammation and fibrosis. Despite well-established recognition of fibrogenesis from these particles at an anatomic level, the molecular and cellular mechanisms of fibrosis remain poorly understood. The proposed research postulates three main hypotheses: 1) silica and asbestos mediate alveolar macrophage (AM) apoptosis through the scavenger receptor class A (SRA) and this process requires participation of one or more caspases; 2) stimulatory AM phenotype are the most resistant AM subpopulation to undergo apoptosis following exposure to fibrogenic agents; 3) apoptosis of the suppressor AM subpopulation allows stimulatory AM to activate T helper cells that ultimately progresses to lung fibrosis. The specific aims of the proposal are to: 1) characterize the involvement of the class A type I/II scavenger receptor (SRA) and the caspase family of proteases in initiating and regulating the induction of AM apoptosis and fibrosis by silica and asbestos; 2) characterize the involvement of T helper cells in silica and asbestos-induced lung fibrosis; 3) characterize AM phenotypes and epitopes corresponding to the phenotype markers and confirm that silica and asbestos induce apoptosis of the suppressor AM phenotype. Aims 1 and 2 will be accomplished using SRA knockout mice, SRA antagonists and caspase inhibitors, as well as mice that are cytokine knockouts and transgenics. These studies will focus on determining the requirements of AM apoptosis to signaling T helper cell activation leading to lung fibrosis. Aim 3 will be accomplished by isolating and characterizing the phenotypes of different subpopulations of human AM and examining their functions and responses to silica and asbestos induced apoptosis. The proteins corresponding to the epitopes will be characterized and AM from fibrotic patients will be examined. The importance of the work relates to the large numbers of asbestos and silica exposed individuals, and to the continual exposure of the public to potentially fibrogenic particles in the urban environment. By improving understanding of these mechanisms, this work may allow development of improved therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: EXTRACELLULAR MATRIX IN RENAL FIBROSIS Principal Investigator & Institution: Fogo, Agnes B.; Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-APR-1992; Project End 31-MAR-2007 Summary: Description (provided by applicant) Transforming growth factor-beta 1 (TGFbeta) has been implicated as a key molecule in fibrosis, and its expression is increased in numerous fibrotic conditions. The relationship of TGFbeta to other

28

Fibrosis

profibrotic mechanisms, such as angiotensin and plasminogen activator inhibitor-1 (PAI-1), and the differential role of infiltrating versus parenchymal cells are complex. TGFbeta can be locally activated by alphavbeta6, which is an integrin heterodimer that is expressed in epithelia in lung, skin and kidney and mediates cleavage of TGFbeta from latency associated peptide. Mice deficient in avB6 lack the ability to activate local TGFbeta through this alphavbeta6 integrin dependent mechanism and had marked protection against fibrosis in the unilateral ureteral obstruction model, with decreased PAI-1 expression, despite robust infiltration of macrophages. A full fibrotic response was restored by infusion of angiotensin or aldosterone, together with restoration of local increase of PAI-1. These projects will examine the TGFbeta1 dependent and independent mechanisms of fibrosis. We hypothesize that PAI-1 induction occurs even in the absence of local TGFbeta, and that PAI-1 by itself can effect fibrosis. We further hypothesize that both parenchymal and infiltrating cell mechanisms are necessary for full fibrotic response. We postulate that injury promotes epithelial-mesenchymal transdifferentiation, and that inadequate macrophage clearance of apoptotic cells both contribute to fibrosis. We will use the alphavbeta6 knockout mouse and bone marrow transplant, to experimentally manipulate parenchymal versus infiltrating cells combined with pharmacological manipulations, to determine mechanisms of interstitial fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FIBROBLAST ABLATION AS TREATMENT FOR PULMONARY FIBROSIS Principal Investigator & Institution: Henke, Craig A.; Associate Professor of Medicine; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Pulmonary fibrosis is characterized by the progressive accumulation of fibroblasts within the alveolar wall and airspace with subsequent deposition of collagen in the distal airspace. This is manifested clinically by severe shunt physiology and often leads to respiratory failure and death. Unfortunately, therapeutic modalities for fibroproliferative lung diseases, which suppress inflammation, have had limited clinical benefit in terms of halting progressive fibrosis. This suggests therapy targeting fibroblasts is essential. It is well documented that some patients with extensive alveolar fibrosis are capable of full recovery. Experimental evidence indicates that removal of unwanted fibroblasts occurs by apoptosis at a critical timepoint during tissue repair allowing restoration of normal anatomic patterns. Therefore, we hypothesize that selective removal of fibroblasts actively participating in the fibrotic process at a critical time period after lung injury will be beneficial in attenuating pulmonary fibrosis and promoting lung repair. In a proof of principle study we plan to utilize transgenic mice we have developed expressing HSV-TK from the mouse alpha 2 type I [alpha2(I)] collagen promoter to test our hypothesis. To selectively target fibroblasts, an alpha2(I) collagen promoter that has selective expression by fibroblasts will be used. To achieve fibroblast ablation, we will employ the thymidine kinase gene of the herpes simplex virus (HSV-TK). Those fibroblasts actively participating in the fibrotic process (e.g., those actively synthesizing large amounts of type I collagen) will express transgene derived HSV-TK and metabolize the antiviral agent ganciclovir (GCV) to toxic nucleotide analogs which disturb nucleic acid synthesis and induce cell death. To create pulmonary fibrosis, the murine model of bleomycin-induced pulmonary fibrosis will be utilized. In this model of pulmonary fibrosis alpha2(I) collagen gene expression by fibroblasts is markedly increased. Therefore fibroblast ablation will be regulated both

Studies 29

regionally by the use of the alpha2(I) collagen promoter to target lung fibroblasts actively synthesizing type I collagen and temporally by when GCV is administered. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FIBRONECTIN DEPOSITION AND PULMONARY FIBROSIS Principal Investigator & Institution: Hocking, Denise C.; Assistant Professor; Pharmacology-Physiology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2004 Summary: (Applicant's abstract): Pulmonary fibrosis is a potentially lethal lung disorder characterized by fibroblast proliferation and excessive accumulation of extracellular matrix proteins, including fibronectin and types I and III collagen. As a consequence of matrix deposition, thickening of the alveolar septum and loss of functional alveolar capillaries can lead to impaired pulmonary function. The development of pulmonary fibrosis is a common response to acute injury and inflammation in the lung. Current therapies, however, have little effect on the progression of the disease. Fibronectin expression and deposition are markedly increased in tissues following injury, where it functions as a chemoattractant and adhesive molecule for migrating cells. Excess or inappropriate deposition of fibronectin into the extracellula matrix during the reparative phase of injury has been associated with fibrotic changes. Evidence suggests that polymerized fibronectin may serve as a templat for subsequent collagen deposition. However, the precise relationship between fibronectin polymerization and collagen synthesis and deposition during pulmonary fibrosis is not known. The goal of these studies is to elucidate the role of multimeric fibronectin in regulating cell migration, collagen synthesi and collagen deposition. Recombinant fibronectin fragments, which inhibit fibronectin polymerization in vitro, will be used to determine the relationshi between fibronectin polymerization and collagen deposition, in vitro and in vivo, using an animal model of fibrosis. These studies will provide informatio crucial to understanding the role of extracellular matrix fibronectin in regulating cell activities which contribute to the development of fibrosis. Elucidating the effect of fibronectin matrix assembly on cell behavior is central to designing methods of intervention during abnormal or altered fibronectin deposition, as occurs during fibrosis. As such, the overall aim of this proposal is to identify mechanisms which control and modulate fibronectin deposition in order to define strategies aimed at limiting the excess deposition of extracellular matrix during pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: FIBROSIS: MOLECULAR BASIS OF FIBROBLAST ACTIVATION Principal Investigator & Institution: Trojanowska, Maria; Professor; Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 10-AUG-1994; Project End 31-MAR-2008 Summary: (provided by applicant): The long-term objectives of our research focus on elucidation of the mechanisms that mediate controlled regulation of the extracellular matrix (ECM) turnover in healthy tissues and uncontrolled ECM turnover under pathological conditions. Excessive deposition of the ECM occurs in fibrotic diseases and is the main pathological manifestation of scleroderma (SSc), while accelerated ECM degradation occurs in the rheumatoid arthritis and during cancer progression and metastasis. During the previous funding period we proposed to test the hypothesis that

30

Fibrosis

constitutive upregulation of collagen and other ECM genes in SSc is caused by different expression levels and modification patterns of transcription factors involved in collagen gene expression by SSc fibroblasts. Our recent findings significantly strengthen this hypothesis. We demonstrated that Ets family transcription factors, particularly Fli-1, are important regulators of collagen homeostasis in healthy skin fibroblasts and among the key contributors to the excessive collagen production by SSc fibroblasts. We demonstrated that Fli-1 is a specific repressor of collagen gene transcription in cultured fibroblasts and in healthy skin in vivo. In addition, we made a novel observation that Fli-1 and Ets-1 are targeted by the TGF-beta signaling pathway, which induces rapid hyperacetylation of these proteins in healthy fibroblasts. In contrast, Fli-1 is constitutively hyperacetylated in SSc fibroblasts. Fli-l is also underexpressed in SSc fibroblasts in vitro. Significantly, during active stage of disease, Fli-1 protein is undetectable in fibroblasts in SSc lesions, correlated with increased collagen production. Based on these observations we hypothesize that in human dermal fibroblasts, Ets factors are the critical mediators of the fibrogenic TGF-beta signaling pathway and that alterations of the levels and acetylation status of Fli-1 contribute to dysregulation of ECM deposition in SSc. To test this hypothesis and to establish a direct linkage between Fli-1 and the development of fibrosis in SSc we propose five Specific Aims. In Specific Aim 1 we will further delineate the role of Fli-1 in the formation of the multiprotein complex that regulates transcription of the COL 1A2 gene, focusing on the TGF-beta induced post-translational modifications of Fli-1, including acetylation and phosphorylation. In Specific Aim 2 we will employ several approaches, including yeast two-hybrid screens to identify fibroblast-specific proteins that physically interact with Fli-1. In Specific Aim 3 we will determine whether Fli-1 contributes to phenotypic alterations of SSc fibroblasts. In Specific Aim 4 we will analyze in vivo expression of Fli1 protein and its partners, as well as Fli-1 target genes in SSc and healthy skin biopsies. In Specific Aim 5 we will use established animal models of SSc to determine the contribution of Fli-1 expression to fibrosis development in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR CYSTIC FIBROSIS Principal Investigator & Institution: Boucher, Richard C.; Director; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 30-SEP-1993; Project End 31-MAR-2004 Summary: The goal of the PPG (Gene Therapy for Cystic Fibrosis) is to create gene transfer vectors that will efficiently transduce cells of the lung. Major but not exclusive therapeutic targets are the epithelia of the large and small airways, which are sites of cystic fibrosis lung disease. The major hypotheses tested in the PPG are: (1) new vectors are needed, including higher capacity, better expressing AAV vectors; high titer, safe lentiviral vectors; and adenoviral vectors specifically targeted to airway epithelial receptors; and (2) that a rate-limiting variable for gene transfer efficiency in the lung is at the site of initial vector-cell interaction, including both binding and entry across the plasma membrane. Three Projects and four Cores are proposed. Project I (Parvovirus) Vectors for Airway Delivery, R.J. Samulski, P.I.) proposes to design and produces new AAV vectors that increase the vector packaging size, augment the efficiency of vector entry, and increase the efficiency of expression (conversion from single strand to double strand DNA templates) using chimeric virion capsids, targeting ligands and modified viral terminal repeats. (Equine Lentiviral Vectors for Gene Delivery, J.C. Olsen, P.I.) proposes to develop high titer, efficiently expressing, and are equine lentiviral vectors. The important targets for the lentiviral vectors will be airway epithelial cells, which

Studies 31

throughout the airways exhibit low rates of proliferation. Project III (Cell Biology of Airway Epithelial Gene Transfer, R.C. Boucher, P.I.) proposes to define the barriers and targets in the apical domain of airway epithelia, modify the barriers using either oxidant injury or more specific modulators of the tight junctions, and finally, modify vectors to target a class of receptors on the apical membrane that exhibit cellular internalization in response to agonist addition. The Projects are supported by the Administrative Core; the Cell Culture Core that will supply human airway cultures to all Projects, small airway cultures, and smooth muscle cells, the Vector Core that will generate AAV, lentiviral and adenoviral vectors (radio-labeled/fluorescently labeled); and the Morphology Core that will provide histology, electron microscopy, and confocal microscopy. The PPG is a highly interactive program designed to modify vectors and test their interactions with target cells in vitro and in murine models in vivo. Achievement of the PPG goal will be to bring to the next clinical trials vectors that are safer and more efficient for the treatment of lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC AND ANATOMIC BASIS OF THE FIBROSIS SYNDROMES Principal Investigator & Institution: Engle, Elizabeth C.; Associate Professor of Neurology; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 20-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The congenital fibrosis syndromes are oculomotility disorders characterized by restrictive ophthalmoplegia with or without ptosis, and each disorder varies in the fixed position of the globes and in the specifically affected cranial nerve(s) and extraocular muscles (EOMs). The neuropathologic bases of two fibrosis syndromes have been described; Duane syndrome results from absence of the abducens nerve and nucleus, while CFEOM1 results from an absence of the superior division of the oculomotor nerve and corresponding oculomotor subnuclei. The laboratory's longterm goals are to uncover the molecular basis of the fibrosis syndromes and to study the development of the oculomotor lower motor neuron system. Toward these goals, we have genetically defined four congenital fibrosis loci and one congenital ptosis locus, and are in the process of positionally cloning these genes. In this grant, we seek funding to address the following specific aims: (1) Identify families with the congenital fibrosis syndromes for our clinical and genetic studies and analyze their DNA for linkage to the known CFEOM loci. (2) Define the anatomic and functional basis of CFEOM by highresolution orbital MRI studies in affected members of genetically defined families. (3) Clone the CFEOM1 disease gene (which is mutated in the most common inherited form of the congenital fibrosis syndromes) and analyze CFEOM1 families for disease-causing mutations. (4) Initiate structural and functional characterization of the CFEOM1 RNA and protein product. Significance: The molecular bases of strabismic disorders remain poorly understood. Though rare, several of the fibrosis syndromes are inherited, and thus provide a unique opportunity to investigate the etiology of this subset of strabismic disorders. Our large collection of CFEOM1 families, coupled with a detailed physical map and access to genomic sequence within the CFEOM1 critical region, places us in a unique position to identify this disease gene. In addition, the correlation of this genetic data with the proposed clinical, anatomic, and functional characterization of genetically defined patients provides a unique and strong foundation for phenotype-genotype correlations and functional studies. By defining the genetic and anatomic bases of CFEOM1, we will develop a tool with which to study its molecular basis and to search for related fibrosis genes, and with which we should gain important new insights into brainstem cranial nerve development. These data will be invaluable to our

32

Fibrosis

understanding of the developmental roles of these genes, and should also contribute to improved therapy of the fibrosis syndromes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLUCOSE SENSOR/TISSUE INTERACTIONS ENGINEERING Principal Investigator & Institution: Moussy, Francis; Associate Professor; Mechanical Engineering; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): A major obstacle to the widespread application of implantable glucose sensors is that they progressively lose function after a relatively short period of time in vivo. This loss of function is in part a consequence of inflammation and fibrosis resulting from the tissue trauma caused by the sensor implantation and by reactions within the tissue. For an implantable glucose sensor, mere tissue toleration of the device is not sufficient; the sensor must also remain functional. It must be emphasize that although it is known that tissue reactions plays an important role in loss of sensor's function, the specific contribution of each tissue reactions (i.e. inflammation, fibrosis and loss of vasculature) has not yet been determined nor quantified. Furthermore, little work has been done so far on controlling these reactions to implanted biosensors. Based on the preceding information, we have developed the following hypotheses. Grant Hypotheses: We hypothesize that inflammation, fibrosis and loss of vasculature affect both the transport properties and the local concentration of glucose around the implanted sensor. As a result, implanted glucose sensors progressively lose function and become unreliable after implantation. We further hypothesize that our experiments and mathematical models will show that all threetissue reactions play a significant role in the loss of sensor function. However, we also hypothesize that use of an anti-inflammatory drug delivery system, with an anti-fibrotic decorated surface hydrogel, and VEGF gene transfer can enhance the function and lifespan of the implanted sensors by decreasing inflammation and fibrosis, as well as by enhancing neovascularization. To test these hypotheses, we propose to use the current electrochemical Nation-based glucose sensor developed in our laboratory and all in vivo experiments will be conducted in the rat model. Therefore, the goals of this proposal will be: 1) to determine the specific contributions of inflammation, fibrosis and blood vessel density on the sensor's loss of function, using in vitro and in vivo studies as well as mathematical models, and 2) to control these reactions using a combination of approaches (decorated hydrogels, drug delivery and gene transfer) to enhance the glucose sensor's function and lifetime in vivo. Our overall goal for this proposal is to have a glucose sensor that can be implanted and provide reliable and continuous monitoring for at least 4 weeks. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: GROWTH FACTORS AND INFLAMMATORY BOWEL DISEASE Principal Investigator & Institution: Lund, Pauline K.; Professor in Physiology, Pediatrics And; Cellular/Molecular Physiology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-SEP-1995; Project End 31-MAY-2007 Summary: (provided by applicant): Major objectives of this research are to gain a better understanding of positive and negative mediators of inflammation induced intestinal fibrosis, an incurable complication of Crohn's disease (CD). Findings in animal models of acute colitis and in patients with CD indicate benefits of growth hormone (GH)

Studies 33

therapy in CD but the documented fibrogenic effects of GH and insulin-like growth factor-I (IGF-I) which is induced by GH, support a hypothesis that GH therapy may exacerbate fibrosis in CD. Locally expressed IGF-I is up-regulated in myofibroblasts at sites fibrosis in CD and animal models of chronic intestinal inflammation implicating IGF-I as an endogenous mediator of fibrosis. Preliminary data support a hypothesis that suppressors of cytokine signaling (SOCS), may limit the fibrogenic actions of therapeutic or endogenous cytokines and growth factors in the inflamed intestine. Other data support a hypothesis that IGF-I interacts with another key cytokine, TNF-alpha to mediate collagen synthesis or proliferation in intestinal myofibroblasts, key cellular mediators of fibrosis in CD. Specific aims are as follows:Aim 1 will define if systemic GH increases fibrosis, circulating or locally expressed IGF-I during PG-PS induced enterocolitis. Cellular sites and levels of SOCS expression will be assessed to verify that SOCS2 or SOCS3 are expressed at in vivo sites that would permit them to limit fibrosis.Aim 2 will define if IGF-I mediates GH action on collagen synthesis or proliferation in intestinal myofibroblasts and test whether SOCS limit GH or IGF-I action.Aim 3 will define if mice with absolute or mesenchyme-specific SOCS2 deficiency show altered fibrosis, JGF-I induction or GH action during TNBS-colitis.Aim 4 will define mechanisms if TNF-alpha has additive or synergistic effects with IGF-I, to induce collagen synthesis in intestinal myofibroblasts and if SOCS limit these effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATOCYTE GROWTH FACTOR MIMETIC FOR LIVER FIBROSIS Principal Investigator & Institution: Mento, Peter F.; Angion Biomedica Corporation 350 Community Dr, Room 145 Manhasset, Ny 11030 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): Hepatic fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response that occurs in response to chronic injury from viral hepatitis B or C, excessive alcohol use, and iron overload, and often leads to liver failure and death. Despite the availability of antiviral and other therapies, most are ineffective in treating the underlying fibrosis and are associated with many side effects. Death from complications of liver fibrosis is expected to triple over the next decade as a result of the hepatitis C (HCV) epidemic and growing incidence of liver disease associated with obesity, so-called "non-alcoholic steatohepatitis" (NASH). Increasing numbers of patients are presenting to tertiary care centers in need of liver transplantation. Unfortunately, the number of cadaveric organs available for transplantation has plateaued and living related donor transplants have not shortened waiting lists. Hence, there is a critical need for potent antifibrotic therapies. Several recently published studies have demonstrated the therapeutic potential of exogenously administered HGF in the treatment of animal models of liver fibrosis. Endogenous HGF plays a key role in inhibiting fibrogenesis at least in part by downregulating TGFb1, the most potent factor for fibrogenesis. It may also act by its proliferative and anti-apoptotic actions. While administration of HGF holds promise as a therapeutic avenue for the treatment of liver fibrosis, protein-based therapies are notoriously difficult to administer because of potential immune responses, instability in solution, and costprohibitive production schemes. To overcome these shortfalls, low molecular weight compounds that mimic the activity of HGF would provide substantially improved therapeutic potential. Angion Biomedica Corp. has identified C6, a small molecular weight compound that mimics the effects of HGF both in vitro and in vivo. C6 inhibits renal cell apoptosis, promotes angiogenesis, prevents increased creatinine by renal ischemia and decreases the incidence of tubular necrosis in the mercuric chloride model

34

Fibrosis

of kidney failure. It is likely that C6 will have an antifibrotic effect in an animal model of liver fibrosis. These studies will provide the basis for more extensive Phase II studies to bring this potential therapy into clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HGF GENE THERAPY FOR CHRONIC RENAL FIBROSIS Principal Investigator & Institution: Liu, Youhua; Associate Professor; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (Provided by applicant): End-stage renal disease (ESRD) is one of the most devastating diseases with great morbidity and mortality, and the number of patients is on the rise worldwide. Despite diverse primary etiologies, the pathogenesis of chronic renal diseases progressing to ESRD is a remarkably monotonous process characterized by relentless accumulation of extracellular matrix (ECM) leading to widespread tissue fibrosis. Thus, developing a scheme to inhibit fibrosis appears to be a key strategy for the treatment of chronic renal disease. Preliminary studies in our laboratory suggest that hepatocyte growth factor (HGF) is an important regulator of extracellular matrix turnover leading to inhibition of tissue fibrosis in animal model of renal diseases. Because exogenous HGF is very unstable in blood circulation due to the rapid clearance by liver, we recently develop a gene transfer strategy using naked plasmid vector resulting in efficient expression of HGF protein in vivo. Based on these results, we hypothesize that delivery of HGF gene is an effective therapeutic strategy for the treatment of chronic renal disease. In this application, we propose to administrate HGF gene into animal model of progressive renal disease to evaluate its therapeutic efficacy. We will investigate the mechanism underlying HGF ameliorating renal fibrosis by examining the regulation of myofibroblast activation and TGF-Beta1 signaling. These will be accomplished in the following three specific aims: 1) to evaluate the efficacy of HGF gene therapy for chronic renal fibrosis; 2) to investigate the role of HGF in renal myofibroblast activation; 3) to elucidate the molecular mechanism underlying HGF blocking pro-fibrogenic cytokine TGF-Beta1 signaling. These studies will provide fundamental information such as the feasibility and efficacy of HGF gene therapy for chronic renal diseases, and will eventually lead to new therapeutic strategies to human chronic renal fibrosis, which is otherwise incurable. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: IL-6 REGULATION OF MATRIX DEGRADATION IN LIVER FIBROSIS Principal Investigator & Institution: Bansal, Meena B.; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant) Understanding mechanisms that favor regenerative rather than fibrotic responses is essential to developing strategies for treating and reversing chronic liver disease. This application addresses the central role played by interleukin-6 (IL-6) in determining this outcome through its effects on the activity of matrix degrading proteases in liver. IL-6-/-mouse livers exhibit increased injury, delayed wound healing, and fibrosis in models of acute and chronic toxin-induced injury, which correlates with increased matrix-metalloproteinase-2 (MMP-2) expression. Our data suggest that MMP-2 is profibrogenic, not only by hastening the replacement of the low density subendothelial matrix with a scar-like interstitial matrix rich in type I

Studies 35

collagen, but also by its ability to degrade membrane type-1 matrix metalloproteinase (MT1-MMP), a potent type I collagenase. In addition, our results indicate that inappropriate downregulation of alpha2-macroglobulin, an IL-6 regulated gene, plays a critical role in increasing the net activity of MMP-2 in vivo and contributes to the increased injury and fibrosis in IL-6-/-livers. We hypothesize that IL-6 is a critical cytokine in the hepatic wound healing response by downregulating MMP-2 activity at the level of gene expression, activation of latent enzyme, and/or inhibition of active enzyme. The Specific Aims of this application are: (1) To characterize the level(s) at which IL-6 regulates MMP-2 expression and/or activation; (2) To determine whether increased activation of MMP-2 leads to decreased collagen type I degradation due to reduced levels/activity of MT1-MMP; (3) To assess the role of alpha2-macroglobulin in inhibiting MMP-2 in vivo; (4) To test the importance of MMP-2 in liver injury in vivo by administering MMP-2 inhibitors to IL6 +/+ and-/-mice with acute and chronic liver injury. These interrelated Specific Aims will be explored primarily using CC14 induced models of acute and chronic liver injury and primary stellate cell culture from IL-6+/+ and IL-6-/-livers. Immunoblot analysis, northern blot analysis, nuclear run-on assays, promoter analysis, gelatin zymography, and co-immunoprecipitation will be utilized to study specific aspects of these aims. In summary, the overall goal of this application is to elucidate the role of interleukin-6 in regulating liver injury and fibrosis via its effects on matrix degradation. Understanding these mechanisms will provide the basis for the development of novel anti-fibrotic therapies to treat a widely prevalent disease for which there is no effective treatment to date. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOBIOLOGY OF LUNG FIBROSIS Principal Investigator & Institution: Mora, Ana L.; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 04-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal form of interstitial lung disease. The pathogenesis of IPF is not well understood but a common paradigm postulates an initial alveolar injury, which triggers an inflammatory response and fibrosis. Certain subsets of T lymphocytes have been implicated in promoting lung fibrogenesis. Specifically, a predominantly T helper type 2 lymphocyte (Th2) response with the characteristic cytokine profile consisting of IL-4, IL5, IL-10 and IL-13 production (as opposed to a Th1 response) predisposes towards a fibrotic response rather than repair. In addition, Th2 cytokines stimulate the production of TGF-beta, a critical fibrogenic factor. In this project, we propose to clarify the roles of T cell isotypes and their characteristic cytokines on lung fibrosis in animals. We will conduct parallel studies in the rodent bleomycin model and in a new murine gamma herpesvirus model that we believe relevant to the human disease. Therefore, we propose the following hypotheses: 1. Murine gamma herpesvirus (MHV68) infection of the lungs of susceptible mice will cause a predominantly Th2 lymphocyte response and will cause persistent and progressive pulmonary fibrosis. 2. Defective Th1 effector function and/or a predominance of Th2 responses predisposes to the development of lung fibrosis caused by either bleomycin or gamma herpesvirus infection. 3. The IL-4 receptor (IL-4Ralpha) signaling pathway in lung cells mediates increased TGF-beta production and lung fibrosis. To test these hypotheses, we propose the following specific aims: 1. In B cell deficient mice, to determine effects of bleomycin or infection of the lungs with MHV68 on lung function, histopathotogy, lung collagen content, Th1 and Th2 lymphocyte responses and cytokine ILL-4, IL-5, IL-13, IFNgamma, TGFbeta)

36

Fibrosis

production by whole lung and lung-derived T lymphocytes. 2. To determine effects of specific depletion of CD4+ and CD8+ T cell subsets on pulmonary responses to bleomycin or MHV68 infection. 3. Using adoptive transfer of in vitro polarized Th1 and Th2 cells and genetically engineered mice biased toward Th1 or Th2 responses, to clarify relationships between the T-lymphocyte responses and responses of the lungs to bleomycin or MHV68 infection. 4. Using IL-4 receptor deficient mice with and without adoptive transfer of normal Th2 cells, to determine whether IL-4 signaling in cells other than T lymphocytes is important to the lung fibrogenic response to MHV68 or bleomycin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPACT OF HIV ON HEPATITIS C INFECTION IN HEMOPHILIA Principal Investigator & Institution: Ragni, Margaret V.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 11-APR-2001; Project End 31-MAR-2005 Summary: (provided by applicant) The purpose of this study is to determine the impact of HIV infection on hepatitis C virus (HCV) liver disease outcome, and the prevalence, risk factors, and viral and immunologic characteristics of liver disease in HCV-infected hemophiliacs, both HIV(+) and HIV(-). Approximately 826 HCV-infected hemophiliacs from 10 U.S. hemophilia treatment centers will be available for study. This group is unique in that patients are well characterized, closely followed, the time of HCV infection is known, HCV infection duration is greater than 20 years, and the incidence of liver disease progression is increasing. The specific objectives of this study include: (1) a cross-sectional cohort study in which hemophiliacs with HCV infection, both HIV(+) and HIV(-), are enrolled and undergo transjugular liver biopsy to determine the prevalence of cirrhosis and fibrosis progression rate. (2) a cross-sectional study comparing HCV-infected patients, both HIV- and HIV+, to determine clinical, life-style, and laboratory, e.g. biochemical, serologic, molecular biologic, and immunologic characteristics associated with development of cirrhosis and stage of fibrosis progression. (3) a cytokine study, comparing cytokine mRNA levels, interleukin-6 (IL-6), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta 1 and TGF-beta 2) in liver tissue, cytokine immunoassay levels in plasma, and cytokine expression genotypes with liver histopathologic score and with fibrosis progression rate in prospectively-biopsied hemophiliacs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: IMPROVING MUSCLE HEALING THROUGH PREVENTION OF FIBROSIS Principal Investigator & Institution: Huard, Johnny; Henry J. Mankin Associate Professor of o; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213 Timing: Fiscal Year 2002; Project Start 10-AUG-2001; Project End 31-JUL-2005 Summary: Muscle injuries, especially pulls and strains, present a challenging problem in traumatology and are among the most common and most often disabling injuries in athletes. The injured muscles are capable of healing, although very slowly and often with incomplete functional recovery. The injured muscle can promptly initiate regeneration for the healing process, but that process in inefficient and is hindered by fibrosis ie, scar tissue formation. More importantly, the scar tissue that replaces the damaged myofibers is a potential contributing factor in the tendency of strains to recur.

Studies 37

We have identified various growth factors capable of enhancing myoblast proliferation and differentiation, and their delivery within injured muscle improves muscle regeneration, but the development of fibrosis still limits recovery. On the other hand, it has been reported that the over expression of transforming growth factor (TGF-) in various injured tissues is the major cause of fibrosis in animals and humans. Indeed, we have observed that TGF- plays a central role in skeletal muscle fibrosis and, more importantly, that the use of antifibrosis agents, such as decorin, that inactivate the effect of this molecule can reduce muscle fibrosis and consequently improve muscle healing to a near complete recovery after injuries. Our recent observation that decor in can also enhance muscle regeneration makes this molecule more than ideal to improve muscle healing after injury. We therefore propose to investigate the kinetics of TGF- expression, muscle regeneration, and fibrosis after strain and to delineate the mechanism by which this molecule initiates the fibrosis cascade in skeletal muscle. We will consequently develop biological approaches based on decor in to efficiently prevent the scarring process by blocking the action of TGF- and activate muscle regeneration at the adequate time period post-injury. We finally propose to characterize efficient way to deliver therapeutic and lasting levels of decor in into the injured muscle through the following strategies: (1) direct intramuscularly injection of the recombinant proteins and (2) in vivo gene delivery by gene vectors. These studies should further our understanding of the muscle healing process, expedite the methodology to promote efficient muscle healing, and contribute to the development of innovative therapies for other muscle diseases, such as dystrophies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IN VIVO FUNCTION OF PULMONARY INTERGRINS Principal Investigator & Institution: Sheppard, Dean C.; Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-MAR-2004 Summary: (Adapted from the Applicant's): This is a competitive renewal application to study the mechanisms whereby the epithelial integrin avb6 regulates pulmonary inflammation and fibrosis as well as airway remodeling. The investigators have shown that a homozygous null mutation of the b6 subunit gene leads to an accumulation of activated macrophages and lymphocytes in the lungs and airways of affected mice and to induction of the macrophage metalloelastase (MME) gene, yet the mice are protected from bleomycin-induced pulmonary fibrosis. Having shown that avb6 binds to a specific sequence within the latency-associated protein (LAP) of TGFb1, the investigators propose to use the b6 subunit knockout mouse (b6-/-) model to study the in vivo role of avb6 in lung inflammation and fibrosis. There are 3 specific aims. The first aim is to determine the role of TGFb1 activation in the induction of lung inflammation and protection from pulmonary fibrosis in beta6-/- mice. For this, transgenic mice expressing full-length and mutant forms of the b6 subunit will be used to determine whether TGFb1 activation or other effects of avb6 can prevent lung inflammation or induce pulmonary fibrosis. Also, they will evaluate whether avb6 acts upstream or downstream of TGFb1 activation, by infecting wild type and b6-/- mice with adenoviruses expressing either active or latent TGFb1 or transgenes that are considered to induce pulmonary fibrosis by acting upstream of TGFb. The second aim is to determine the significance of MME induction in the beta-/- phenotype. For this purpose, they will examine macrophage phenotypic features of double knockout (MME/- b6-/-) mice generated by cross breeding of MME-/- and b-/- mice. The third aim is to determine the role of avb6 induction in airway remodeling. This will be accomplished

38

Fibrosis

by cross breeding b6-/- mice with transgenic mice that develop sub-epithelial fibrosis due to overexpression of IL-6, IL-11 or IL-13. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERFERON-G REGULATION OF BLEOMYCIN PULMONARY TOXICITY Principal Investigator & Institution: Chen, Edward S.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 04-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The genetic and immunologic basis of pulmonary fibrosis is poorly understood. In rodents, intratracheal bleomycin induces rapidly progressive inflammation similar to human organizing diffuse alveolar damage (DAD), with sub-acute lung injury characterized by exudative events involving cellular infiltration, increased lung permeability, and fibrin deposition. In bleomycin-susceptible mouse strains, pro-inflammatory cytokines play a key role in initiating inflammation and lung injury, and likely mediate subsequent granulation tissue formation and associated acute collagen synthesis. By addressing mechanisms that mediate exudative events that follow inflammation and lung injury, we may develop a critical understanding of factors that promote the transition from granulation tissue to chronic fibrosis that may bear relevance to the progression of human interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF). Our published data demonstrate that interferon-gamma (IFN-gamma) plays an important role in the inflammatory and fibrotic processes in the murine bleomycin model. We found that IFN-gamma protein in bronchoalveolar lavage (BAL) fluid was significantly higher 12 to 24 h following bleomycin administration in bleomycin-sensitive but not in resistant mouse strains, and that the inflammatory and fibrotic response to bleomycin in IFN-gamma knockout mice was significantly reduced compared to sensitive wild-type controls, strongly supporting a role for IFN-gamma in mediating Neomycin-induced pulmonary toxicity. Since these studies stand in contrast to well-known direct anti-fibrotic effects of IFN-gamma, we suggest that differential effects of IFN-gamma on inflammation and fibrosis in response to bleomycin may be dependent on the timing and regulation of endogenous IFNgamma expression, or on the dosing schedule and route of administration of exogenous IFN-gamma. Furthermore, we hypothesize that IFN-gamma-mediated bleomycin pulmonary toxicity is enhanced by up-regulation of IL-12 and IL-18, inducers of IFNgamma, and is effected, in part, through the induction of iNOS with enhanced lung injury. The specific aims of this proposal are: (1) to determine the role of post-exposure IFN-gamma administration on the inflammatory and fibrotic response to Neomycin, (2) to determine if IFN-gamma regulatory cytokines IL-12 and IL-18 mediate bleomycininduced pulmonary toxicity through enhanced IFN-gamma production, and (3) to determine if IFN-gamma potentiates bleomycin-induced pulmonary toxicity through direct up-regulation of iNOS expression. Understanding the mechanisms involved in IFN-gamma mediated pulmonary inflammation and fibrosis in the murine model of bleomycin pulmonary toxicity may provide insight into mechanisms involved in pulmonary fibrosis associated with human DAD, Th1 mediated interstitial lung diseases such as sarcoidosis, hypersensitivity pneumonitis, silicosis, and possibly, IPF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 39

•

Project Title: FIBROSIS

INTERFERON-GAMMA

IN

EXPERIMENTAL

PULMONARY

Principal Investigator & Institution: Enelow, Richard I.; Associate Professor and Chief; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-JUL-2003 Summary: (provided by applicant): Chronic fibrotic lung disease occurs in a variety of clinical settings, including the idiopathic interstitial pneumonias, as well as in many of the rheumatic diseases. We previously developed a model of acute T cell-mediated pulmonary injury, which results in severe alveolar injury, leading to significant respiratory impairment and death within a few days. This model involves the adoptive transfer of activated CD8+ T cells into recipient animals expressing the specific antigen on alveolar epithelial cells. In contrast with the acute lung injury occurring after transfer of wild-type CD8+ T cells, we have recently found that chronic inflammation and fibrosis may result from the CD8+ T cell recognition of alveolar antigen in the absence of IFN-gamma exclusively in the antigen-specific cell population, and have found that these T cells induce a totally different pattern of lung injury, including a more chronic pattern of inflammation and, importantly, interstitial and intraluminal fibrosis. This was accomplished by using IFN-gamma-deficient CD8+ T cell clones for adoptive transfer, which results in inflammation and fibrosis that evolves over a period of 2-4 weeks after administration. This very exciting result represents the first animal model of pulmonary fibrosis that does not involve an exogenous toxin, and which evolves entirely from a single, well-defined molecular interaction, the T cell receptor recognition of antigen on alveolar epithelial cells. In order to understand the mechanisms which underly the resolution of acute pulmonary inflammation which results directly from expression of IFN-gamma by the antigen-specific CD8+ T cell, and the factors which may lead to chronic inflammation and fibrosis in its absence, we propose the following Specific Aims:1. To characterize the impact of IFN-gamma expressed by CD8+ T cells on input and host T lymphocyte activities in vivo.2. To characterize the specific effects of IFN-gamma expressed by CD8+ T cells on host macrophages and the impact on progression to chronic pulmonary inflammation.3. To characterize the specific effects of CD8+ T cell recognition in the absence of IFN-gamma on antigen-presenting epithelial cells and the impact on progression to chronic pulmonary inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LUNG RADIATION PROTECTION BY MNSOD TRANSGENE THERAPY Principal Investigator & Institution: Greenberger, Joel S.; Professor and Chairman; Radiation Oncology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-DEC-1998; Project End 31-JAN-2006 Summary: (provided by applicant): Thoracic radiotherapy (RT) is often limited by lung toxicity (pulmonary fibrosis). Pulmonary fibrosis ensues after an unexplained latent period which follows the acute reaction and is characterized by reduction in pulmonary vital capacity and exertional dyspnea. Elevation of fibrogenic cytokines, most notably, TGF-B1 and B2 (TGF-B1-B2), and fibroblast proliferation that extends from irradiated to adjacent lung, are features at the molecular and cellular levels. The principal investigator recently demonstrated that intratracheal (IT) injection of manganese superoxide dismutase-plasmid/liposomes (MnSOD-PL) protects the murine lung from

40

Fibrosis

irradiation-induced organizing alveolitis/fibrosis induced by single dose or fractionated irradiation. The proposed research will use validated, genetically modified animal models along with quantitative molecular methods to elucidate the cellular mechanism of irradiation lung fibrosis and the level(s) at which epitope-hemagglutinin (HA)tagged MnSOD transgene therapy protects. The first specific aim tests the hypothesis that organizing alveolitis/fibrosis is initiated by accumulation of macrophage attractant, VCAM-1 in endothelial cells at 80-100 days after irradiation. The second specific aim tests the hypothesis that TGF-B1-B2 production by bone marrow-derived bronchoalveolar macrophages (BAMs) mediates fibroblast recruitment and proliferation. The third specific aim tests the hypothesis that circulating fibroblast progenitor cells, also of bone marrow origin, home to, and proliferate in irradiated lung to produce organizing alveolitis/fibrosis. Methods include BrdU in situ labelling, histopathology, green fluorescent protein-positive (GFP+) male hematopoietic stem cell (macrophage progenitor) engraftment to GFP- female mice and transplantation of GFP+ purified bone marrow stromal cells (BMSCs), continuous anti-TGF-B antibody or soluble TGF-B receptor (TGF-B-R) delivery, injection of HA-MnSOD-PL, fractionated irradiation, and in situ assays of DNA damage. These experiments will provide substantial, new insight into the basic pathogenesis of the pulmonary irradiation response. A comprehensive understanding of the underlying mechanisms is critical for identifying novel targets for intervention. This project may facilitate development of specific strategies to minimize pulmonary irradiation toxicity, thereby making RT safer and more effective. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF AGE RELATED FIBROSIS Principal Investigator & Institution: Agnes, Fogo; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (Taken directly from the application) Aging is a complex physiological condition in which the function of many organ systems becomes altered. The changes in kidney function along with progressive renal fibrosis are among the most dramatic. We have recently shown that high dose angiotensin (Ang) type 1 receptor antagonist (AT1RA) in the aged rat not only prevents ongoing age-related changes but reverses existing glomerulosclerosis, an effect linked to normalization of dysregulated extracellular matrix (ECM) metabolism and decreased plasminogen activator inhibitor-1 (PAI-1). This regression was also linked to altered cortical cell turnover, with abolishment of apoptosis. AT1 and AT2 receptors are postulated to be key in modulation of the balance of proliferation and apoptosis. In addition, cyclooxygenase-2 (COX-2) has been implicated in cell turnover in addition to arachidonic acid metabolism. COX-2 abrogates RAS responsiveness, implicating COX-2 in RAS actions. We further hypothesize that the immune system could also contribute to age-related changes. With aging, there is a decrease in antigen-stimulated immunity, and an increase in innate, i.e., macrophage-driven immunity. We hypothesize that aging changes of parenchymal cells, involving altered cell cycle proteins, lead to apoptosis, and that aging macrophages are defective in clearing these apoptotic cells. We will explore the following mechanisms of age-related renal fibrosis in studies of knockout mice with selective manipulation of macrophage vs. parenchymal cell genotype by bone marrow transplant: dysregulated ECM metabolism in aging, and the potential and mechanisms of regression of this injury; cell cycle events in aging related to the renin

Studies 41

angiotensin system and COX-2, and their impact on injury; and the potential role of macrophages and defective clearance of apoptosis in age-related organ fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF MYOFIBROBLAST SURVIVAL IN FIBROSIS Principal Investigator & Institution: Riches, David W.; Professor and Division Head; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) is a fatal parenchymal lung disease characterized by interstitial and alveolar fibroproliferation and the appearance of myofibroblasts. Little is known about the mechanisms of myofibroblast accumulation in IPF/UIP or why they fail to be eliminated as occurs during normal wound repair. Previous studies from this and other laboratories have shown that survival factors, especially IGF-I, are abundantly expressed by macrophages and alveolar epithelial cells in IPF/UIP. In this proposal, we will test the hypothesis that the presence of survival factors, including IGF-I, in the parenchyma and airspaces of patients with IPF/UIP protect myofibroblasts from apoptosis. Under these conditions, myofibroblasts are proposed to accumulate in numbers and can thus contribute to parenchymal fibrosis for extended periods of time. The major goals of this proposal are three-fold: (i) to investigate the conditions and mechanisms that mediate myofibroblast apoptosis under conditions of growth factor and stretch withdrawal; (ii) to determine how IGF-I serves to protect myofibroblasts from undergoing apoptosis; and (iii) to investigate the mechanism of dysregulation of myofibroblast apoptosis in IPF/UIP. These goals will be addressed by four specific aims. Specific aim one will address the role of growth factors, physical forces and IGF-I in myofibroblast differentiation, reversion to a fibroblast phenotype and apoptosis. These studies will form a basis for determining the mechanisms that promote myofibroblast apoptosis with a focus on the mechanisms of caspase activation (specific aim two). The objective of specific aim three is to uncover the mechanisms through which IGF-I prevents the initiation of the death program. The focus of these studies will include the mechanism of inactivation of the effector capsases (3, 6 and 7) and the potential role of anti-apoptotic proteins. Lastly, in specific aim four, we propose to apply what has been learned from this studies conducted in this proposal to address the mechanisms that promote protection from apoptosis in the lungs of patients with IPF/UIP. The findings from this work are expected to provide new insights into the mechanism of myofibroblast apoptosis and how this process becomes dysregulated in IPF/UIP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MECHANISMS OF PAI1 REGULATION BY LUNG MATRIX MOLECULES Principal Investigator & Institution: Olman, Mitchell A.; Associate Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Pulmonary fibrosis is a frequent and devastating complication of acute or indolent lung injury for which current therapy is effective in only 1/3 of cases. The fibroproliferative response after lung injury is characterized by matrix fibrin deposition and collagen accumulation. Several recent in vivo studies indicate that the serine protease inhibitor, plasminogen activator inhibitor (PAI-1) contributes to the fibrotic

42

Fibrosis

response. For example, in bleomycin-injured mice, PAI-1 is up- regulated in fibroproliferative lesional fibroblasts, and genetic deletion of PAI-1 confers protection from lung injury-induced fibrin and collagen deposition. These in vivo data provide strong evidence of a fibrogenic role for PAI-1, however, the regulatory pathways involved in fibroblast PAI-1 expression have yet to be elucidated. Furthermore, the proposed mechanism of PAI-1's in vivo effect through inhibition of alveolar fibrin clearance remains unproven. Our goal is to understand the mechanism of regulation of PAI-1 expression, and its role in the molecular events that result in pulmonary fibrosis. We have recently shown that fibroblasts up-regulate their expression of PAI-1 in response to fibrin D dimer, a plasmin-generated proteolytic fragment of fibrin that is abundant in fibroproliferative lesions. The work proposed herein will advance the field by defining the mechanism(s) by which D dimer increases PAI-1 expression in fibroblasts, and by determining the effect of in vivo manipulation of alveolar fibrinolysis on PAI-1 expression and on the fibrotic process. In the first two specific aims, we will determine the relative importance of changes in PAI-1 transcription rates and mRNA half-fife, and identify the critical cis and trans acting factors in basal and D dimerstimulated PAI-1 transcription in fibroblasts. In specific aim 3, we will study effect of experimentally-induced alveolar fibrinolysis, with its attendant generation of D dimer, on lung PAI-1 expression and on the fibrotic response to bleomycin lung injury. We hope the knowledge of the molecular events in pulmonary fibrosis will lead to novel identifiable targets for therapeutic modalities aimed at reducing the fibroproliferative response to lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEDIATORS OF FIBROSIS IN SCLERODERMA SKIN AND LUNG Principal Investigator & Institution: Feghali, Carol A.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology that affects mostly women and is associated with significant morbidity and mortality. No effective therapies or cures for SSc are yet available. One of the hallmarks of SSc is overproduction of extracellular matrix components such as collagen and fibronectin by fibroblasts in the skin and internal organs. We have made the novel observation of a 20-fold increase in the expression of insulin-like growth factor binding protein 5 (IGFBP-5) in fibroblasts from the clinically affected skin of SSc patients. IGFBP-5, as well as IGFBP-3, are produced by fibroblasts and modulate the actions of IGF-I, including fibroblast activation and overproduction of collagen. We hypothesize that the IGFBP/IGF-I axis contributes to the development and perpetuation of skin and lung fibrosis in SSc. Our studies will use two unique sample sets available to us--fibroblasts and tissues from monozygotic (MZ) and dizygotic (DZ) twins discordant for SSc and from lungs of SSc patients undergoing lung transplant surgery and unused donor lungs-and target two organs affected by SSc--skin and lung. These samples constitute a unique and valuable resource. Our aims are l) to determine the regulation of IGFBP-3 and IGFBP-5 in vitro and in vivo in skin an lung tissues of SSc patients and twin and non-twin controls; 2) to determine the function of IGFBPs on skin and lung fibroblasts and identify key molecules downstream of IGFBPs; 3) to determine the mechanism of IGFBP-mediated effects on fibroblasts, including whether the effect of IGFBPs is IGF-I-dependent or - independent, the identification of IGFBP binding partners, and the effect of suppressing IGFBP expression on the fibrotic phenotype. Our combined approach using lung and skin fibroblasts and tissues will allow us to identify

Studies 43

the systemic mechanisms that underlie the skin and lung phenotype in SSc, while the use of samples from twins discordant for SSc will allow us to determine the importance of the inherited genetic background in the development of the 'scleroderma' phenotype. Our results will provide important insights into mechanisms of overproduction of extracellular matrix components by fibroblasts and thus the pathogenesis of fibrosis. Identifying key steps in the cascade of events culminating in fibrosis will facilitate the development of novel targeted therapies for scleroderma and for other fibrotic conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR AND FUNCTIONAL IMPACT OF CARDIAC FIBROSIS Principal Investigator & Institution: Vikstrom, Karen L.; Pharmacology; Upstate Medical University Research Administration Syracuse, Ny 13210 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: Changes in cardiac function reflect underlying changes in the content and organization of the muscle substrate. In the failing heart, these changes reflect interactions between myocyte and non-myocyte components of the heart. "Cross-talk between the myocardium, the vasculature and the non-myocyte cellular populations of the heart all may play a role in influencing cardiac pathogenesis. The development of fibrosis, or abnormal accumulations of extracellular matrix, is one ramification of this process. The presence of fibrosis in the failing heart has adverse effects on the structure and function of the myocardium. Increased levels of myocardial extracellular matrix alter ventricular stiffness, contribute to the risk of life threatening arrhythmias and may promote the progressive deterioration of contractile function. We propose to determine if fibrosis plays a significant role in the development of progressive cardiac dysfunction in a transgenic mouse model of hypertrophy and early failure. We have developed a transgenic mouse model for hypertrophic cardiomyopathy (HCM) through cardiac specific expression of a mutant myosin heavy chain (Vikstrom et al., 1996). These animals exhibit the histopathologic features of human HCM, including myocellular disarray, fibrosis and the presence of abnormal small coronary vessels. In this model, females continue to hypertrophy while males progress from a hypertrophied to a dilated phenotype concomitant with increased fibrosis. The HCM mice should prove to be useful for identifying changes in cardiac gene expression during chronic cardiac hypertrophy and the development of early heart failure, including those changes that provoke fibrosis. Our analysis will consist of three branches. i) We will evaluate the role of TGFbeta1 and angiotensin-converting enzyme (ACE) gene expression in the HCM mouse heart and determine the spatial and temporal patterns of their expression with respect to the development of fibrosis. ii) We will determine the ramifications of myocardial fibrosis on contractile function and electrical conduction in the isolated mouse heart. iii) We will determine the requirement for ACE expression in the development of fibrosis through genetic cross-breeding experiments. Our goal is twofold. 1) use the HCM mice as a tool for assessing the molecular and functional implications of fibrosis in the heart and 2) develop new analytical approaches for studying gene expression and electrical conduction in the mouse heart. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MOLECULAR STUDIES OF ABC TRANSPORTERS Principal Investigator & Institution: Li, Min; Associate Professor; Physiology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218

44

Fibrosis

Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 31-MAY-2005 Summary: (provided by applicant): The ATP-binding cassette (ABC) superfamily proteins are important functional transporters in both prokaryotes and eukaryotes, playing the primary roles in mediating the entry and exit of a variety of molecules, which is essential for growth and regulation. Increasing evidence has shown that the native forms of these membrane-bound proteins are highly organized macromolecular complexes where the molecular composition and functional stoichiometry confer the native biology of these proteins and are dynamically regulated.The long-term objective of the proposed research is aimed at investigating the molecular organization and function of ABC transporting by focusing on cystic fibrosis transmembrane conductance regulator (CFTR). In particular, we will focus on biochemical and functional interactions between the CFTR and its associated proteins. The proposed experiments in this application focus on a group of four previously unknown CFTRAssociated proteins (CAPs) that have been purified on the basis of high affinity association with the CFTR protein. The genes encoding these four CAPs have been isolated in our laboratory. The proposed experiments are designed to address their potential molecular and functional roles in the CFTR activities. Through a combination of proposed biochemical, cellular, molecular, and electrophysiological experiments, we wish to obtain important information about the mechanism by which CAPs interact with CFTR as well as the potential functional roles of CAPs in modulation of the CFTR activity. Cystic Fibrosis (CF) is an autosomal recessive disorder caused primarily by mutations of a membrane channel protein known as cystic fibrosis transmembrane conductance regulator (CFTR). The mutations found in CF patients cause changes of both channel activity and subcellular location of the CFTR protein. Interactions between CFTR and other structural and regulatory proteins are essential for its proper function in human. Thus, the knowledge about these various interactions is essential for the full understanding of human diseases caused by the mutated CFTR Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR STUDIES ON THE ROLE OF IL-4 & IL-13 IN FIBROSI Principal Investigator & Institution: Bona, Constantin A.; Professor; Microbiology; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2004 Summary: (provided by applicant): The thrust of our application is based on our reported data demonstrating in vivo the role of profibrogenic cytokines in the occurrence of skin fibrosis in TSK mice developing a scleroderma-like syndrome due to a mutation of Fibrillin-1 gene. These mice did not develop fibrosis subsequent to disruption of IL-4, IL-4R and TGF-a genes. The lack of compensatory effect on collagen synthesis by TGF-beta in mice with disrupted IL-4 gene suggested that 1L-4 may influence the expression of TGF-beta gene in fibroblasts. Little is known about the molecular mechanisms of upregulation of collagen genes in fibroblasts by 1L-4 and IL13, on molecular basis of epistatic interaction between IL-4 and TGF-beta genes and on the link between mutated Fbn-1 gene and over synthesis of collagen in TSK/mice. The overall goal of this application is to address these specific questions. The specific aims are: 1. Characterize the IL-4 and 1L-13 signaling pathways leading to upregulation of collagen genes in fibroblasts. This will be studied by investigating the involvement of Stat6 and three major mammalian MAPK families in IL-4/IL-13 stimulated fibroblasts by measuring collagen promoter activity, the levels of the transcription of collagen genes and the level of synthesis of collagen by fibroblasts 2. To delinate the molecular mechanisms of IL-4 and TGF-beta interactions regulating the expression of collagen

Studies 45

genes. We propose to clone TGF-beta promoter I and 2 and to study the effect of profibrogenic cytokines on TGF-a promoter activity using TGF-beta /CAT as well as deletion mutants of TGF-beta promoter/CAT fusion genes. In addition we will study the DNA binding activity to TGF-a promoter of transcription factors such as SP-, AP-1 GATA3, Stat6, c-Maf and NF-1 in fibroblasts transfected with deletion mutants of promoter and stimulated with 1L-4and IL-13. 3. To identify the link between mutated Fbn-1 and cutaneous hyperplasia in TSK/+ mice. Since we did not find an increased synthesis of collagen in fibroblasts transfected with TSK-Fbn-1 gene, we hypothesized that the link between mutated Fbn-1 gene and fibrosis is mediated by Fbn-1 specific T cells producing profibrogenic cytokines. This hypotheses will be tested by generating Fbn-1 specific T cell clones. The pathogenic clones will be selected in adoptive transfer experiments and then used in vitro to measure the synthesis of collagen by fibroblasts cocultured with T cell clones producing profibrogenic cytokines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW PATHWAYS IN IL7 MEDIATED ANTIFIBROTIC RESPONSES Principal Investigator & Institution: Dubinett, Steven M.; Professor of Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Idiopathic pulmonary fibrosis (IPF) is a devastating disease with less than a 50% five-year survival. Thus novel therapeutic strategies are cleariv needed. A developing paradigm views pulmonary fibrosis as an "IFNgamma deficiency disorder" the therapeutic replacement of IFNgamma has shown promise in preliminary clinical trials. In the current study we will investigate the capacity of the potent type 1 cytokine interleukin 7 (IL-7) to limit pulmonary fibrosis by both IFNgamma-dependent and independent pathways. In marked contrast to the current forms of therapy for IPF, IL-7 potently enhances cell-mediated immunity. In addition to its capacity to induce IFNgamma, IL-7 downregulates both TGF-beta production and TGF-P signaling in pulmonary fibroblasts. In this 1 proposal we hypothesize that IL-7 can augment antifibrotic responses by: 1) stimulating IFNgamma production, 2) downregulating fibroblast TGF-beta synthesis and TGF-beta signaling and. 3) promoting epithelial survival by induction of cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production. Our preliminarv studies indicate that IL-7 potently upregulates IFNgamma, downregulates both TGF-beta production and signaling and significantly inhibits bleomycin-induced pulmonary fibrosis in vivo. The specific alms are: 1) To assess the determinants of the IL-7-mediated anti-fibrotic response in in vivo models of pulmonary fibrosis. 2) To assess the efficacy and mechanisms of IL-7mediated inhibition of human fibroblast TGF-beta production and signaling. 3) The longitudinal variation of expression of COX-2 and PGE2 in IPF patients will be correlated with clinical parameters of therapeutic response during IFNgamma therapy. Although IL7 shares several biological effects with IFNgamma, its capacity to induce endogenous IFNgamma production in vivo contrasts with the effect of administration of recombinant IFNgamma. These activities, together with the capacity to promote epithelial cell survival, make IL-7 a compelling cytokine for investigation in IPF. The development of pathogenesis-based. biological therapy for IPF offers an entirely new avenue for translational investigation that will lead to new therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

46

•

Fibrosis

Project Title: NITRIC OXIDE AND CARDIAC REMODELING FOLLOWING INFARCTION Principal Investigator & Institution: Sun, Yao; Medicine; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2002; Project Start 10-JUL-2001; Project End 31-MAY-2004 Summary: (provided by applicant): The overall objective of this proposal is to explore the mechanisms for antifibrotic role of nitric oxide on myocardial remodeling following infarction. The hypothesis to be tested is that nitric oxide regulates myofibroblasts (myoFb) apoptosis/growth, collagen turnover, and transforming growth factor (TGF)beta1 expression in the infarcted heart, thus protecting the heart from ongoing collagen accumulation. Extensive myocardial fibrosis is a characteristic feature in the failing heart with previous myocardial infarction (MI). Locally generated factors serve as chemical mediators by either promoting or suppressing cardiac fibrosis. A discordant balance in reciprocal regulation accounts for progressive structural remodeling of the myocardium. An emerging body of evidence implicates nitric oxide as an inhibitory regulator of cardiac fibrosis. The pathway by which nitric oxide regulates such cardiac remodeling remains uncertain, MyoFb, phenotypically transformed fibroblast-like cells, are central for cardiac extracellular matrix remodeling and create a dynamic microenvironment for collagen turnover in the infarcted heart. By using a mouse model of MI and inducible nitric oxide synthase gene knockout mice together with cultured myoFb obtained from infarcted heart, the following specific aims will be fulfilled. Aim 1: to determine whether nitric oxide regulates myoFb growth/survival and activity in the infarcted heart by characterizing its influence on myoFb apoptosis and regulatory genes, myoFb replication and phenotype change. Aim 2: to detect whether nitric oxide is involved in collagen turnover by detecting its potential role in metalloproteinase-1 (MMP-1) synthesis, MMP-1 activation, tissue-derived MMP inhibitors expression, and cardiac collagen synthesis. Aim 3: to determine whether nitric oxide modulated TGFbeta1 expression and activity at sites of cardiac fibrosis by investigating its effect on TGF-beta1 synthesis, activation and receptor expression. Findings derived from the proposed studies should advance our understanding on pathogenesis and management cardiac remodeling by fibrous tissue, which will provide the opportunity for pharmacologic interventions that limit collagen deposition in the heart with MI and improve cardiac function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NON-INVASIVE NMR IMAGING OF CARDIAC REMODELING IN AGING Principal Investigator & Institution: Forder, John R.; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2003 Summary: This project is directed toward the effects of aging on the cardiovascular system and age-related changes in extracellular matrix. Normal aging results in myocyte loss, increased fibrosis and myocardial stiffness, and depressed contractility. Aging is also associated with a significant increase in the incidence of cardiac hypertrophy, often accompanied by changes in the extracellular matrix such as increased collagen deposition and fibrosis. Thus, myocardial remodeling plays an important role in the development of cardiac dysfunction seen with increased age. However, the distinct between normal aging and the effects of underlying disease processes is difficult to assess. Currently the only quantitative methods available to assess the extent of

Studies 47

remodeling are histological or biochemical, and require fixation or extraction of tissue samples. Clearly such methods are not optimal for the investigation of relationships between aging, left ventricular (LV) remodeling, and contractile function in humans. Magnetic resonance imaging (MRI) has great clinical potential for the non-invasive detection and monitoring of cardiac disease and its response to therapy. In addition to high quality anatomic information, it can also be used to obtain quantitative information of both global and regional LV function. Recently, we demonstrated that MRI could detect changes in the diffusion of water during myocardial ischemia. In exciting new studies, we demonstrated that diffusion MRI could be used to determine myocardial fiber angle orientation with a high degree of precision, and the use of high diffusion gradients uncovers multiple diffusion components that correlate to different compartments in the tissue (extracellular, intracellular, etc.) The main hypotheses of this proposal are: 1) that decreased diffusion of water will be correlated with a increase in collagen accumulation and fibrosis, and 2) that measurements of myocardial fiber angle orientation combined with diffusion measurements will be used to distinguish between the effects of normal aging and the development of cardiac hypertrophy. In order to test these hypotheses diffusion tensor MRI experiments will be carried out on perfused hearts isolated from 6 and 18 month old spontaneously hypertensive rats (SHR) and age-matched non- hypertensively Wister-Kyoto rats. Hydroxyproline content of the myocardium will be used as a measure of the total tissue collagen content. This proposal will provide the foundation for the application of diffusion MRI in the quantitative evaluation of both normal and pathophysiological remodeling that occurs in the myocardium. The ability to non-invasively determine changes in the extracellular matrix of the myocardium coupled with measurements of fiber orientation will constitute a major advance in understanding the effects of aging on cardiac structure and function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDANTS DIFFERENTIATION

AND

TGF-BETA

IN

MYOFIBROBLAST

Principal Investigator & Institution: Thannickal, Victor J.; Assistant Professor; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: The pathology of fibrotic lung diseases is characterized by fibroblastic foci in areas of active fibrosis. These fibroblastic foci contain fibroblasts with an activated, "myofibroblast" phenotype. Myofibroblasts are key effector cells in the pathogenesis of pulmonary fibrosis due to their high protein synthetic capacity [extracellular matrix (ECM) proteins, integrins, growth factors, growth factor receptors], resistance to apoptosis, enhanced proliferative responses to mitogens and ability to generate extracellular oxidants. The pro-fibrotic cytokine, TGF- beta1, is a potent induces of myofibroblast both in-vivo and in-vitro. However, this differentiation signal induced by TGF-beta1 is dependent on cell adhesive events that have yet to be fully characterized. Myofibroblast differentiation is associated with the assembly/activation of a submembranous, adhesive, cytoskeletal complex that results in the generation of extracellular H2O2. We hypothesize that myofibroblast-derived H2O2mediates oxidative cross-linking of ECM proteins that alters the substratum for fibroblasts, promoting further myofibroblast differentiation and, thereby, resulting in a selfperpetuating, positive feedback loop, leading to an unrelenting fibrotic process. Our specific aims are to: (1) Define signaling pathways that regulate myofibroblast differentiation: requirement for combinatorial signal integration of TGF-beta1 and cell

48

Fibrosis

adhesive signaling, (2) Characterize the H2O2-generating oxidase in myofibroblasts: association with focal adhesion and actin cytoskeleton, and (3) Examine physiologic/pathophysiologic effects of the myofibroblast- derived oxidants: role in oxidative cross-linking of ECM proteins. It is anticipated that completion of these studies will provide a better understanding of myofibroblast biology that will aid in the development of novel, targeted therapies for fibrotic diseases in which myofibroblasts play an active role including idiopathic pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENEISIS OF CYSTIC FIBROSIS IN THE GI SYSTEM Principal Investigator & Institution: Delisle, Robert C.; Associate Professor; Anatomy and Cell Biology; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2002; Project Start 01-MAR-2000; Project End 31-JAN-2004 Summary: The long-term objective is to understand how loss of functional CFTR (the cystic fibrosis transmembrane regulator) affects expression and post- translational processing of sulfated glycoconjugates and the role of these altered glycoproteins in the development of cystic fibrosis (CF). High levels of sulfated glycoconjugates with abnormal post-translational processing are believed to contribute to obstruction in the pancreas and intestines, and digestion and absorption of nutrients is abnormal in CF. The model mucin-like sulfated glycoprotein Muclin will be used to explore these issues. Muclin is over-expressed in the pancreas and small intestine of CFTR (-/-) mice, and immunolocalization of Muclin in these tissues shows that it is associated with protein plugs in the acinar lumen and mucin plugs in the intestinal crypt lumen. The hypothesis is that in the absence of functional CFTR, mucin-like glycoconjugates, such as Muclin, are over-expressed and have altered post-translational processing. They then contribute to the deleterious accumulation of protein aggregates in the lumina of the pancreatic acini and small intestinal crypts. The following specific aims will be addressed. 1. To test the hypothesis that post-translational processing of Muclin is altered in the absence of CFTR in epithelial cells which normally express CFTR, i.e., the intestinal crypt cell, and to determine the mechanism of this change. The carbohydrate structure and protein core size of Muclin in normal and CF intestine will be determined. 2. To test the hypothesis that excess Muclin alters the protein secretory pathway in gastrointestinal tissues of CF mice. Pancreatic secretions will be studied in vivo and in vitro in normal and CF mice, and the effect of pH on the interaction of Muclin with zymogens will be assessed. Also, the luminal pH of secretory compartments in CF and normal cells will be measured to test whether CFTR has a functional role in pH gradients in the cell. 3. To test the hypothesis that abnormal acidity in the intestine mediates CF pathogenesis and the over-expression of Muclin. Pathology and Muclin expression will be compared in CF mice, and CF mice crossed with gastrin deficient mice (lack gastric acid secretion) to normalize intestinal Ph. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PATHOGENESIS HYPERTENSION

OF

HEPATIC

FIBROSIS

AND

PORTAL

Principal Investigator & Institution: Rockey, Don C.; Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-APR-1996; Project End 31-MAR-2005 Summary: The response to injury, in liver and in other systems is fibrosis. Chronic or recurrent liver injury leads to hepatic fibrosis and ultimately cirrhosis, with both intra

Studies 49

and extra hepatic complications which include impaired hepatocellular function and portal hypertension. The key pathogenic event in this process is transition of resident perisinusoidal cells termed hepatic stellate cells (Ito or stellate cells) from a quiescent to an "activated" state. This process is characterized by production of increased amounts of extracellular matrix and de novo expression of smooth muscle alpha actin, the latter characteristic consistent with their transformation to myofibroblasts. We have recently demonstrated that contractility is a further prominent feature of the activated phenotype, elicited in particular by the endothelins, a group of 21 ammo acid peptides known primarily for their vasoactive properties. Moreover, we have shown that in injured liver preproendothelin-1 mRNA levels are elevated. During the last granting period, we demonstrated that the cellular source of endothelin-1 (ET-1) during liver injury is (in contrast to predicted) the hepatic stellate cell rather than the hepatic endothelial cell. Moreover, we showed that the mechanism of this shift is largely due to upregulation of the enzyme that converts precursor ET-1 to the mature peptide, endothelin converting enzyme-1 (ECE-1). This identifies ECE-1 as central component in the regulation of ET during liver injury. Finally, we demonstrated that inhibition of ET action in the liver with a mixed ET receptor antagonist, partially inhibited the stellate cell fibrogenic response to injury. Collectively, the data indicate that increased production of ET in liver plays a central role in liver injury, contributing to both stellate cell activation and fibrogenesis. This model, in which ET is a key element has substantial relevance to other forms of wound healing. The overall focus of this program is to understand pathobiology of endothelins in disease; the specific aims of the current proposal are to explore the regulation of endothelins in liver fibrosis in vivo. Toward this goal we will (1) examine regulation of ECE-1 by elements important in the wound healing response such as TGF-beta1 and extracellular matrix (2) characterize ET receptor modulation (3) investigate ECE-1 transcriptional and translational control (4) and in experimental liver injury, determine whether inhibition of ECE-1 inhibits stellate cell activation, hepatic fibrosis or intrahepatic resistance typical of portal hypertension. These studies have direct relevance to human liver disease and will lead to new approaches for the treatment of hepatic fibrosis and portal hypertension as well as other forms of fibrosing injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF VIRAL PROLIFERATIVE BRONCHIOLITIS Principal Investigator & Institution: London, Lucille; Associate Professor; Microbiology and Immunology; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-MAR-2004 Summary: (Adapted from the applicant's abstract): Bronchiolitis obliterans with organizing pneumonia (BOOP) is a term for a long observed, but unclassified pattern of acute lung injury. In humans, BOOP is characterized by fibrosis of small airways with fibrous extension into the alveolar spaces with preservation of alveolar ducts and walls. It is frequently associated with a peribronchiolar organizing pneumonia. The lesions may also be accompanied by lipid-laden foamy alveolar macrophages trapped in the air spaces by the fibrosis and by a T cell rich lymphocytic interstitial infiltrate in the regions of the lung directly affected by the lesion. Also, necrosis and sloughing of epithelial cells has been observed and is thought to result in the partial alveolar collapse seen in human BOOP. While BOOP can be associated with documented viral and bacterial infections, many cases are not associated with known causes and are thus classified as idiopathic. Little is known concerning the pathogenesis and treatment of BOOP since no animal

50

Fibrosis

models were available for this disorder. The investigators are the first to establish an experimental animal model for this disease. In this model, CBA/J mice infected with reovirus serotype 1/strain Lang develop BOOP lesions which closely resemble the histopathological picture of human BOOP. In addition, the development of BOOP lesions in CBA/J mice is virus strain specific. The central hypothesis of this proposal is that "Disruption of the epithelial basement membrane determines the susceptibility to fibrosis". The investigators propose to characterize the host and/or viral factors (both immune and non-immune cellular populations) that result in initiation of damage to the basement membrane and relate these finding to the development of fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOLOGY OF RENAL MATRIX METABOLISM Principal Investigator & Institution: Lovett, David H.; Professor; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 30-SEP-1987; Project End 31-MAR-2005 Summary: The progressive decline in renal function characteristic of most forms of renal disease is intimately associated with the development of glomerular and interstitial fibrosis. The extent of interstitial fibrosis closely predicts the ultimate clinical outcome in terms of development of end stage renal disease. Progressive interstitial fibrosis may be initiated by multiple factors, including immune injury, hypoxia, reduction in renal mass and diabetes mellitus; however, these insults converge to a final common pathway associated with tubular epithelial cell transdifferentiation to pro- sclerotic myofibroblasts and fibroblasts, This laboratory has focused on the role of specific matrix metalloproteinases in the initiation and perpetuation of the pro-fibrotic transdifferentiation of tubular epithelial cells. Specifically, coordinate expression of two matrix metalloproteinases, gelatinase A and MT1-MMP, appears to drive the transdifferentiation process in vitro and in vivo. The Specific Aims of this proposal are to define at the transcriptional level, with an emphasis on TGFbeta, common signaling pathways and transcription factors which link gelatinase A and MT1-MMP transcription. Secondly, a transgenic approach will be taken to examine the relationship between gelatinase A and MT1-MMP gene expression in a TGF-beta-driven model of progressive renal fibrosis. Finally, the ability of gelatinase A to directly induce interstitial fibrosis in vivo will be assessed using targeted conditional expression in the transgenic mouse. Taken together, these complementary approaches may provide important new insights into the mechanisms of progressive renal fibrosis and point out specific molecular targets suitable for new forms of therapies of these disabling disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PLASMIN, FIBRIN, AND METALLOPROTEINASES IN LUNG FIBROSIS Principal Investigator & Institution: Sisson, Thomas H.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 20-AUG-2000; Project End 31-JUL-2005 Summary: The outlined proposal is designed as a training program that builds on prior experiences and ultimately leads to a career of independent research. Included in this program for the applicant is the introduction of new experimental techniques, investigation of a new area of basic science, and interaction with a new mentor. The research project will investigate an important aspect of the development of pulmonary

Studies 51

fibrosis. Pulmonary fibrosis has been shown to occur in conjunction with depressed alveolar plasminogen activator activity. This impaired activity occurs from an imbalance between urokinase-type plasminogen activator (uPA) and its major inhibitor, plasminogen activator inhibitor-1 (PAI-1). Enhancing alveolar plasminogen activator activity through various means including targeted deletion of the PAI-1 gene or adenoviral-mediated gene transfer of the uPA cDNA results in decreased collagen accumulation following a fibrogenic insult. The mechanism by which enhanced alveolar plaminogen activator activity mitigates fibrosis is unknown. Insights into this mechanism may lead to new treatments. Of several possibilities, two mechanisms are most likely. The hypothesis of this proposal is that enhanced alveolar plasminogen activator activity may reduce fibrosis by removing the provisional fibrin matrix or by increased levels of matrix metalloproteinases (MMPs). To test this hypothesis, 3 models of enhanced alveolar plasminogen activator activity will be employed. These models include a PAI-1 deficient transgenic mouse, adenoviral-mediated gene transfer of the uPA cDNA to the alveolar space, and an inducible lung-specific uPA expressing transgenic mouse. In addition, to investigate the importance of fibrin in lung scarring, a fibrinogen deficient transgenic mouse will be employed. With these models, differences in fibrin accumulation and MMP activation in mice protected from fibrosis will be compared to susceptible controls. The opportunities provided by the training program will provide the foundation for career advancement and hopefully lead to new therapies for fibrotic lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PPAR-GAMMA REGULATION ALPHA 1 TYPE I COLLAGEN PROMOTER Principal Investigator & Institution: Yavrom, Sharom; Pathology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): Induced collagen expression by hepatic stellate cells (HSC) is the hallmark of alcoholic liver fibrosis. Our laboratory recently demonstrated the potential link between depletion of PPARgamma in HSC and liver fibrogenesis and the reversal of HSC activation with PPARgamma ligands. The trainee will test the hypothesis that PPARgamma inhibits alpha1(I) collagen promoter in HSC line and liver fibrosis. Specific aims include determination of the specificity of PPARgammamediated inhibition of the promoter and elucidation of the mechanisms underlying the effect. The former will be achieved by transient transfection assays with the promoterreporter gene and expression vectors for the members of nuclear receptors including PPARgamma. The latter will address PPARgamma-mediated negative cross-coupling with DNA-binding proteins for the promoter via DNase foot printing and gel shift assays and inhibition of co-activator recruitment by this nuclear protein which will be assessed by GST-fusion protein pull down assays and coimmununoprecipitation. PPARgamma-mediated suppression of the promoter will further be tested in vivo using the transgenic mice expressing GFP driven by the collagen promoter and adenoviralmediated PPARgamma overexpression targeted to HSC by alpha-smooth muscle actin promoter. A similar approach will be taken to finally test the efficacy of PPARgamma overexpression for CCI[4] liver fibrosis in mice. These experiments will define the molecular basis for inhibition of collagen gene expression by PPARgamma and will test the potential of this mode if intervention as a novel therapy for alcoholic liver fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

52

•

Fibrosis

Project Title: QUANTATIVE PATHOGENESIS

IMAGE

ANALYSIS

MODELS

OF

IPF

Principal Investigator & Institution: Goldin, Jonathan G.; Acting Section Chief; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Recently, imbalance in angiogenesis, dysregulation of the extra cellular matrix and fibroproliferation rather than inflammation has been postulated to perpetuate lung fibrosis in IPF. Detection of alveolitis may therefore have little prognostic or pathogenic relevance in the assessment of these cases. The heterogeneous pathology of UIP results in BAL and trans-bronchial biopsy (TBBx) to be subject to sampling errors compounding attempts to elucidate pathogenic pathways. A noninvasive mechanism to provide a "morphometric" assessment of the whole lung on a global and regional basis would be ideal. Quantitative Image Analysis (QIA) of HRCT data has shown a correlation with inflammation, angiogenesis and fibrosis and can identify these independent manifestations of IPF on a global and regional basis not possible with bronchoscopy or visual inspection of HRCT. The hypothesis is: CT-QIA can better detect the presence, extent and progression of inflammation, angiogenesis and fibrosis in patients with ILD and so can be used to distinguish patients with UIP, DIP, NSIP or NSIP with fibrosis not possible with conventional clinical, radiographic and physiologic assessment or with sampling limited BAL and TBBx. The specific aims are to 1) develop a CT-QIA model of pulmonary fibrosis in a murine model capable of assessing the development and progression of pulmonary fibrosis 2) develop a CT-QIA model of IPF capable of distinguishing inflammation, angiogenesis and fibrosis to better characterize patients with clinically diagnosed ILD with respect to pathologically defined UIP, DIP, NSIP and NSIP with fibrosis and 3) to determine the relative progression of inflammation, angiogenesis and fibrosis in patients with clinically assessed IPF treated with Prednisone alone, or IFN-gamma and low-dose prednisone or azathioprine plus prednisone. The main objective of this project is to distinguish between angiogenesis, inflammation and fibrosis in the pathogenesis of IPF in order to better characterize their relationship to the pathogenesis of IPF and to distinguish patients with UIP, DIP, NSIP or NSIP with fibrosis not possible with conventional techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RAPID CYSTIC FIBROSIS DNA MUTATION SCREENING TEST Principal Investigator & Institution: Mandecki, Wlodek; Pharmaseq, Inc. 1 Dear Park Dr, Ste F Monmouth Junction, Nj 08852 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JAN-2004 Summary: (provided by applicant): Cystic fibrosis (CF) is a highly morbid, autosomal recessive disease caused by one or more mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR protein is important in transporting sodium and chloride ions through the membranes of epithelial cells lining the lungs and other organs. In Caucasians, CF is the most lethal inherited disease of childhood (frequency of 1:3,300). In the U.S., about 25,000 people have CF and about 850 individuals are diagnosed with CF each year. CF affects all races and ethnic groups and it is underdiagnosed, especially in minorities. Present genetic screening assays are best suited for detecting CF in Caucasians and Ashkenazi Jews but, the mutations currently assayed for in the CF screening does not detect mutations

Studies 53

specific for Black Americans and Hispanics. Electronic microtransponders will be used in a novel DNA detection system to quickly and accurately detect large numbers of CF DNA mutations in a single high-speed flow assay. Each microtransponder is an integrated circuit composed of photocells, memory and antenna. It stores information identifying the sequence of an attached oligonucleotide probe in its electronic memory. Complementary, dye-tagged target DNA sequences bind to probes on microtransponders and the results are read in a high-speed flow reader. The Specific Aims of Phase I are to prove feasibility of a novel, rapid and inexpensive microtransponder-based CFTR screening assay: 1) Select ten important cystic fibrosis (CF) mutations in Caucasians, Black Americans and Hispanics and prepare synthetic DNA probes to these mutations; 2) Prepare primers for all CFTR mutations tested for use in multiplex PCR reaction; 3) Covalently attach optimized DNA probes to microtransponders, perform a microtransponder-based DNA probe assay using cell lines containing CFTR gene mutations and match results to purchased cell line descriptions; 4) Perform the microtransponder CF assay on a small number of patient and control samples and compare results to standard methods used in a genetics laboratory in a major medical center in New Jersey. The microtransponder-based, multiplex assay proposed with extended mutation detection for domestic ethnic groups will significantly increase the utility of this important assay for more U.S. patients by adding important CFTR mutations observed in Blacks and Hispanics into a single, affordable, accurate, high-speed assay. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF COLLAGEN FORMATION IN PULMONARY FIBROSIS Principal Investigator & Institution: Goldstein, Ronald H.; Professor; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: The activation of myofibroblast is a central feature of interstitial pulmonary fibrosis. The objective of this proposal is to examine the regulation of the lung myofibroblast phenotype with an emphasis on the signal transduction pathways utilized by these cells to increase matrix deposition. Following lung injury in vivo, fibroblasts in the interstitial wall display a myofibroblast phenotype with increased expression of alpha-smooth muscle actin and alpha1(I) collagen mRNA. We have shown that prostaglandin E2 (PGE2) down-regulated steady state levels for alpha1(I) collagen, connective tissue growth factor and alpha- smooth muscle actin mRNA. PGE2 also stimulated Ca2+ activated K+ channels that decrease cell volume, and sensitized the cells to death receptor mediated apoptosis. These results indicate that PGE2 inhibits expression of the myofibroblast phenotype and has significant anti-fibrogenic properties. Preliminary data indicate that treatment of fibroblasts with PGE2 causes decreases in phosphatidylinositiol 3-kinase (PI-3K) as assessed by levels of phosphorylated protein kinase B/Akt. Employing inhibitors to PI-3K and mutant Akt constructs, we find that the activity of the PI-3K system regulates the stability of the alpha1(I) collagen mRNA. We hypothesize that fibroblast activation and the development of the myofibroblast phenotype involves an up- regulation in the activity of the PI-3K signal transduction pathways which in turn up-regulates alpha1(I) collagen and alpha- smooth muscle actin mRNA expression. PGE2 down-regulates these processes by affecting PI-3K activity and decreasing cell hydration. We plan to use cellular and molecular approaches to test our hypothesis in vitro and in vivo. Our

54

Fibrosis

studies will provide new insights into the regulation of the myofibroblast and suggest new therapeutic options for the treatment of pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF HEPATIC STELLATE CELL RESPONSES TO INJURY Principal Investigator & Institution: Yee, Hal F.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Hepatic stellate cells mediate the liver's response to injury. Consequently, these perisinusoidally-located non-parenchymal cells control normal wound healing and the development of fibrosis. The broad, long-term objective of this project is to elucidate the signal transduction pathways that direct stellate cell responses in order to facilitate development of novel strategies for the prevention and treatment of cirrhosis from diverse causes, including alcoholism and viral hepatitis. We have developed new assays and reagents for quantitatively measuring myosindependent contractility in stellate cells. Employing these new methods, and other more standard procedures, we have started to demonstrate the role of myosin and focal adhesion kinase (FAK) in the regulation of essential cell functions. These results have led to this proposal's main hypothesis that the coordinated regulation of myosin and FAK, by injury induced factors, play a central role in the signal transduction pathways that mediate the stellate cell behaviors responsible for fibrosis. This hypothesis will be tested by the following specific aims: 1) Characterize the mechanisms by which injuryinduced factors regulate myosin-dependent contractility. To address this aim we will determine the relative roles of myosin light chain kinase and rho-associated kinase signal transduction pathways in myosin-dependent contractility. 2) Elucidate the mechanisms by which injury-induced factors regulate activation of FAK. This will be achieved by testing our proposal that ET-1, LPA, and PDGF-BB stimulate FAK activation through distinct signaling pathways involving myosin-dependent contractility and membrane ruffling. 3) Test the hypothesis that myosin-dependent contractility and FAK activation control stellate cell behaviors responsible for fibrosis. We will demonstrate the roles of myosin and FAK in the regulation of stellate cell morphology, contraction, migration, proliferation, and collagen synthesis. In summary, the signal transduction mechanisms through which the injury-induced mediators, ET-1, LPA, and PDGF-BB, regulate critical stellate cell responses will be systematically defined using established pharmacological and genetic interventions in primary cultures of hepatic stellate cells isolated from normal rats and rats that have undergone chronic hepatic injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CHROMIUM

REGULATION

OF

TRANSCRIPTIONAL

COMPETENCE

BY

Principal Investigator & Institution: Barchowsky, Aaron; Associate Professor; Pharmacology and Toxicology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2003 Summary: Hexavalent chromium (Cr(VI)) is in the top 20 compounds of the ATSDR/EPA priority list since it promotes interstitial lung fibrosis, induces asthma, and is recognized as a probable human lung carcinogen. Despite the epidemiological

Studies 55

evidence for both occupationally and environmentally-derived pulmonary disease following inhalation of Cr(VI), there are few studies that define the cellular and molecular basis for pathologic changes in the Cr(VI)-exposed lung. Overall Objective: The overall objective of the proposed studies is to define the molecular signaling mechanisms through which non-cytotoxic concentrations of Cr(VI) alter inducible cytokine and profibrotic gene expression in airway and alveolar epithelial cells. We have recently defined a novel pathway through which Cr(VI) inhibits the transcriptional competence of the transcription factor NF-kappaB by promoting recruitment of the essential co-activator CREB-binding protein (CBP) to c-Jun. We hypothesize that Cr(VI)induced alteration of co-activator recruitment changes the profile of inducible gene expression and potentiates Fas-induced apoptosis. These effects of Cr(VI) favor development of pulmonary fibrosis. Specific Objectives: Aim 1 of the grant will use human lung cells in culture to define cellular signaling pathways that regulate Cr(VI)induced recruitment of CBP to specific transcription factors (e.g. c-Jun). Aim 2 will use these models to demonstrate that competition for CBP is the rate limiting step in Cr(VI)induced loss of NF-kappaB transactivation. The consequence of a switch in CBPdependent transcription factor competence on FAS- induced apoptosis and gene expression will be examined. The final Aim will use normal and unique transgenic mouse models to examine Cr(VI)-induced regulation of transcription factor activity and of inducible pro-apoptotic and pro-fibrotic phenotypic changes in vivo. Significance: The studies will define fundamental epigenetic mechanisms for altered inducible gene expression and increased susceptibility of airway and alveolar epithelial cells to apoptosis following exposure to Cr(VI). Apoptosis of the airway is now recognized as an underlying non-inflammatory mechanism for lung fibrosis. Thus, these studies will translate observations in cell culture into in vivo models of exposure to greatly improve the basic understanding of how Cr(VI) promotes pulmonary diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REPAIR AND REGENERATION IN THE CORNEA Principal Investigator & Institution: Fini, M. Elizabeth; Professor & Research Director; Ophthalmology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 01-DEC-1993; Project End 31-MAR-2005 Summary: ( applicant's abstract): The fibrotic response is essential for normal wound repair, but it is also the basis for numerous pathologies, many of which occur in the eye. For example, fibrosis is a major complication following trabeculectomy for glaucoma, reversing the improvement in aqueous outflow resulting from surgery. Subcapsular fibrosis in the lens can result in cataracts. Inappropriate fibrosis is central to the proliferative retinopathies, which are devastating diseases. In the cornea, fibrosis creates opacity, and the contraction of fibrotic tissue alters corneal shape. These effects impinge undesirably on the capacity to refract light on the retina, and impact on the outcome of refractive surgery. The long term goal of the proposed project is to improve our understanding of the fibrotic response in the cornea, and to investigate how this response can undertake a more stromal cell expression of collagenase, and enzyme which participates in regenerative remodeling of fibrotic repair tissue once it is deposited. The most significant finding relates to a mechanism for reciprocal interaction between the cell and its extra cellular matrix. It was discovered that such interactions are mediated through an interleukin-1alpha autocrine feedback loop - expression of IL1alpha is induced, and this collagenase in response to these stimulatory conditions because they are incompetent to activate or sustain the IL-1alpha loop. Based on this observation, the PI has developed a working model in which fibrotic differentiation is

56

Fibrosis

under hierarchical regulation and involves progressive acquisition of competencies to respond to environmental signals. The hypothesis driving this proposal is that control of fibrotic program progression determines the regenerative nature of corneal repair. In the next grant period, experiments are proposed to define molecular deficiencies in signaling pathways required for IL-1alpha autocrine loop activity in stromal cells from uninjured cornea. It is further proposed to identify extrinsic/intrinsic factors required for competence to activate the IL-1alpha autocrine loop and for progression of the fibrotic differentiation program. Finally, gene profiles of corneas repairing by fibrosis and corneas repairing via a more regenerative response - cell replacement - will be compared. The results of our proposed studies should elucidate mechanisms controlling fibrotic program progression and provide some of the essential rationale for developing new therapeutic approaches applicable to improving outcomes of corneal surgeries. These results may also be generally applicable to strategies for managing fibrotic pathologies in other parts of the eye. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOID METABOLISM IN HEPATITIC STELLATE CELLS Principal Investigator & Institution: Bosron, William F.; Professor; Biochem and Molecular Biology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The overall goal of this proposal is to understand the role of specific rat retinoid metabolizing enzymes (especially retinyl ester hydrolases) in the regulation of retinoid metabolism in hepatic stellate cells. Hepatic stellate cells are the main reservoir of Vitamin A in the liver where it is stored mainly as retinyl palmitate in highly visible intracellular lipid droplets. When animals are exposed to hepatotoxins or humans chronically abuse alcohol, the stellate cells become activated and transform into myofibroblast-like cells. These transformed cells are the sites of collagen and extracellular matrix protein formation in alcohol-induced hepatic fibrosis. One of the earliest events in stellate cell activation is the hydrolysis of retinyl esters and the depletion of the intracellular lipid droplets. The most likely retinyl ester hydrolase candidates are the members of the families of broad substrate specificity lipases and carboxylesterases. The specific retinyl ester hydrolases expressed in hepatic stellate cells and the mechanisms for regulation of their activity during stellate cell activation is not known. In preliminary data, we show that the five most common rat liver carboxylesterases with retinyl palmitate activity are not highly expressed in stellate cells. However, the hormone-sensitive lipase gene is expressed in rat hepatic stellate cells and it has retinyl palmitate hydrolase activity in vitro. The goals of the grant are to identify the specific retinyl ester hydrolases (lipases and carboxylesterases) that are expressed in isolated rat liver cells (stellate cells, Kupffer cells, hepatocytes) by real-time, quantitative PCR of RNA and immunofluorescence microscopy of stellate cells with enzyme-specific antibodies. The expression of retinyl ester hydrolases and retinol dehydrogenases will be correlated with retinoid autofluorescence in lipid droplets and expression of cellspecific markers in cultured rat stellate cells as they undergo activation to myofibroblast-like cells. When feasible, we will measure retinyl palmitate hydrolase activity and perform protein gel electrophoresis of cellular extracts with esterase activity staining. We will examine the kinetics of purified rat stellate cell retinyl ester hydrolases and examine the effects of enzyme activators and inhibitors. Inhibitors of retinyl ester hydrolysis in stellate cells may be an effective therapeutic strategy for arresting stellate cell activation early in hepatic fibrosis.

Studies 57

Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF CELL AND DEBRIS REMOVAL IN FIBROSIS Principal Investigator & Institution: Henson, Peter M.; Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Tissue damage and inflammation have long been associated with fibrotic changes during wound healing and in pulmonary fibrosis. Resolution of inflammatory lesions involves removal of apoptopic inflammatory cells by uptake into macrophages and surrounding tissue cells, such as epithelial cells and fibroblasts. We suggest that the engulfment of apoptotic cells is driven by a variety of adhesion ligands acting in conjunction with a critical receptor for phosphatidylserine (the PS receptor or PSR) that actually mediates the signaling for phagocytosis. Ingestion via this receptor also initiates the production of active TGF. This mediator then has important effects in limiting further generation of inflammatory mediators, as well as the potential to initiate fibroblast to myofibroblast phenotypic conversion and the process of fibrosis. It is further suggested that cell debris and membrane fragments are removed by similar mechanisms with similar consequences. To explore these suggestions, the PSR will be examined 1) for its potential ability to initiate myofibroblast conversion via a reciprocal feedback induction of TGF; 2) for its upregulation in cells adjacent to an area of damage with resultant ingestion of the damaged cells and fragments as well as local generation of TGF; and 3) for its potential role in mediating resolution of inflammation and progression to fibrosis. Because of the ability of PSR ligation to initiate TGF synthesis and secretion from a variety of cell types in vitro and in vivo, this proposal will also examine the mechanisms of this induction by determining the points in TGF synthesis, secretion and activation that are affected and to begin to examine the signaling pathways involved. Experiments will be performed in epithelial cells, fibroblasts and macrophages since each of these express the PSR, ingest apoptotic cells and respond by induction of TGF, although with different consequences. The in vivo studies will be carried out in murine models of inflammation and fibrosis and will make use of a number of valuable knockout strains. The overall objective is to examine in detail one potentially important mechanism for inducing the generation of myofibroblasts in the lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ROLE OF SMAD SIGNALING IN RENAL INFLAMMATION Principal Investigator & Institution: Lan, Hui Y.; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: Glomerulonephritis is a major cause of end stage renal disease (ESRD). While the pathogenic rote of proinflammatory cytokines, chemokines, and adhesion molecules in giomerulonephritis has been extensively studied, the renal protective role of antiinflammatory cytokines such as TGF-beta has received little attention. In this proposed research, we will explore the role of TGF-beta in the resolution of renal inflammation and explore three novel mechanisms. First, we will examine the hypothesis that TGFbeta may signal through its inhibitory signaling protein, Smad7, to counter-regulate the activation of NF.kappaB by inhibition of IkappaBalpha degradation (phosphorylation). This is important since NF.kappaB has been shown to play a key role in glomerulonephritis. Second, we will further investigate the mechanisms of TGF-

58

Fibrosis

beta/Smad7 in the renal inflammation by overexpression of Smad7 in vitro and in vivo. We expect that inhibition of NF.kappaB-driven immune and inflammatory responses including expression of MHC class II, cytokines (IL-1, TNFalpha), chemokine (MCP-1), adhesion molecules (ICAM-1), iNOS, macrophage/T cell infiltration, and cell proliferation is the mechanisms by which Smad7 plays a role in anti-renal inflammation. Finally, we will determine the functional role of Smad7 in the resolution of renal inflammation and develop a novel therapeutic strategy by gene transfer of inducible Smad7 in a rat model of crescentic glomerulonephritis. These studies will therefore explore the underlying mechanisms of TGF-beta/Smad7 in negative regulation of renal fibrosis and renal inflammation. Outcomes from these studies will allow the identification of a unique negative regulating rote for Smad7 in the pathogenesis of renal fibrosis and inflammation. Importantly, inhibition of both renal inflammation and fibrosis by overexpression of Smad7 will provide new information for the development of novel therapeutic strategies to combat kidney diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCOR: PATHOBIOLOGY OF FIBROTIC LUNG DISEASE Principal Investigator & Institution: Mason, Robert J.; Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 05-SEP-2001; Project End 31-JUL-2006 Summary: (Applicant's Abstract) The overall purpose of this SCOR proposal is to investigate the role of the myofibroblast in idiopathic pulmonary fibrosis (IPF). We are particularly interested in defining the source and regulation of TGF-beta production, especially the contribution of the ingestion of apoptotic cells and cell debris, the relationship of paracrine factors and mechanical factors on myofibroblast gene regulation, the role of survival factors for myofibroblasts such as IGF- I and myofibroblast apoptosis, interactions of myofibroblasts with alveolar epithelial cells, and finally regulation by interferon gamma (INF). In the clinical portion of this SCOR proposal, Dr. Schwarz will evaluate INF in the treatment of idiopathic pulmonary fibrosis. A major aspect of this proposal will be to use DNA microarrays to define gene expression of specific cell types as well as alterations in fibrotic lung and microdissected fibroblastic foci in IPF and Masson bodies in BOOP. In project 1, Dr. Henson will study the regulation of TGF-beta production by the ingestion of apoptotic cells. This is a new biologic process for the production of TGF-beta. In project 2, Dr. Worthen will study the regulation of the myofibroblast phenotype especially the interaction between paracrine factors such as TGF-beta and mechanical stress. In project 3, Dr. Riches will determine the role of IGF-1 as a survival factor which prevents the apoptosis of myofibroblasts. In project 4, Dr. Mason will study the interactions between myofibroblasts and alveolar type II cells. A significant portion of this project is to define the interactions between KGF, TGF-beta, and INF on the alveolar epithelium. In project 5, Dr. Schwarz will determine the clinical efficacy of INF as therapy for idiopathic pulmonary fibrosis, myofibroblast proliferation and apoptosis in IPF, and gene expression in fibroblastic foci in IPF and Masson bodies of BOOP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: SELECTINS AND FETAL WOUND HEALING Principal Investigator & Institution: Olutoye, Oluyinka O.; Surgery; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2008

Studies 59

Summary: (provided by applicant): The overall objective of this project is to gain an in depth understanding into the role of selectins in the modulation of the inflammatory response following wounding in the adult and fetus. Fetal dermal wound healing is characterized by a scant inflammatory response and minimal fibrosis. Although fetal inflammatory cells are generally considered immature, an acute inflammatory response (with fibrosis) can be evoked at the site of fetal wounds by the application of diverse stimuli. Selectins are cell surface lectin molecules expressed on both leukocytes and endothelial cells that interact with their respective carbohydrate ligands to facilitate the early events of leukocyte recruitment, and thereby, contribute significantly to the inflammatory process. The contributions of these adhesion molecules to wound closure, repair and scar formation are poorly understood. This study is therefore proposed to evaluate the role of selectins in wound healing. The application will be centered on the hypothesis that the minimal inflammation noted in fetal dermal wounds is a consequence of alterations in expression of P- and E-selectin on fetal platelets and endothelial cells. To test this hypothesis, the relative expression of selectins on adult and fetal platelets and endothelial cells will be determined. Mice with targeted deletions of individual or combinations of selectins will be studied to determine the consequences of selectin absence on wound healing. Using the murine syngeneic fetal skin transplantation model and creating mice chimeric for selectins, the specific contributions of platelet or endothelial selectins in the inflammatory response will be elucidated. Understanding the mechanism of scarless fetal wound healing will provide alternative avenues to modulate the postnatal wound healing response. This will have implications not only in the management of complications of dermal wound healing (bum contractures, keloids, hypertrophic scars, non-healing ulcers, etc.) but also in all conditions where fibrosis is an undesired consequence, such as pulmonary fibrosis, strictures, peritoneal adhesions, hepatic fibrosis, etc. Furthermore, understanding how selectins modulate the inflammatory response in the fetus will reveal valuable information that may explain the predisposition of neonates and premature infants to infections. These may then provide opportunities to assist with the inflammatory responses in these children when they are most vulnerable. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: S-NITROSOTHIOL BREAKDOWN BY AIRWAY EPITHELIAL CELLS Principal Investigator & Institution: Gaston, Benjamin M.; Associate Professor of Pediatrics; Pediatrics; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2003; Project Start 01-JAN-1999; Project End 31-DEC-2006 Summary: (provided by applicant): S-Nitrosothiols are endogenous adducts of nitric oxide and cysteine thiols. Increasingly, it is appreciated that S-nitrosylation reactions may result in post-translational protein modifications. These modifications have been associated with cyclic GMP-independent bioactivities that may be regulated to physiological advantage. For example, proteins may be modified by transnitrosation reactions with S-nitrosylated peptides such as S-nitrosoglutathione, concentrations of which appear to be enzymatically regulated. Indeed, several enzymes are now appreciated to regulate the catabolism of S-nitrosoglutathione, including glutathionedependent formaldehyde dehydrogenase and gamma-glutamyl transpeptidase. Snitrosothiol biochemistry may be involved in the regulation of a broad spectrum of bioactivities in the airway, including ion channel conductivity, inflammatory cell apoptosis, and airway smooth muscle relaxation. Of note, we have recently observed that S-nitrosoglutathione increases the expression and maturation of the most common

60

Fibrosis

mutant form of cystic fibrosis transmembrane regulatory protein (CFTR), deltaF508. Levels of S-nitrosothiols appear to be low in the airways of patients with both cystic fibrosis and with asthma, in part because of increased activity of S-nitrosoglutathione catabolic enzymes. Indeed, if it was not for accelerated S-nitrosoglutathione catabolism, S-nitrosoglutathione replacement therapy could be envisioned as a novel therapy for both cystic fibrosis and asthma. In this project, we plan to 1) characterize the regulation of S-nitrosothiol catabolism in the cystic fibrosis and asthmatic airway epithelium; 2) define the mechanism by which S-nitrosoglutathione and other S-nitrosothiols may increase the maturation of kF508 CFTR; and 3) evaluate mechanisms by which Snitrosoglutathione catabolism might be circumvented to achieve salutary bioactivities in the airways, including increased CFTR maturation. We anticipate that this project will provide new tools for understanding the cell biology of cystic fibrosis and asthma, and that it may lead to the development of new therapies for both diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL STUDIES OF BACTERIAL QUORUM SENSING REGULATOR Principal Investigator & Institution: Churchill, Mair E.; Associate Professor; Pharmacology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: (provided by applicant): Persistent bacterial infections are a major cause of death in cystic fibrosis patients and immune-compromised individuals. A number of gram-negative bacteria including Pseudomonas aeruginosa, a major pathogen in cystic fibrosis, cause infections that are difficult to treat because the bacteria form a "biofilm community" that renders them less sensitive to traditional antibiotics. Quorum sensing, mediated by acylhomoserine lactone (AHL) signaling molecules, regulates pathogenesis and biofilm formation in P. aeruginosa. Therefore, understanding the molecular basis of quorum sensing is a high priority in the development of novel anti-bacterial agents. The long term goal of this project is to extend the understanding of the quorum-sensing system to the atomic level to develop a detailed description of the mechanisms that control bacterial pathogenesis. The main focus of this proposal is the class of enzymes that produce the AHL signal, AHL-synthases, because bacteria lacking the AHL signal fail to become pathogenic or form stable biofilms. Although there are models of the mechanism of action of the AHL-synthases, there are currently no structures of any AHL synthase. High resolution structural information is absolutely essential for fully understanding the mechanism of AHL synthesis and will provide the basis for future structure-based inhibitor design for development of novel therapeutics. The specific aims for this project are: (I) determine the high resolution crystal structure of the Pantoea stewartii subsp. Stewartii AHL-synthase (EsaI) to understand its function, mechanism, and relationship to other enzymes that utilize similar substrates. Perform mutagenesis, binding and kinetics experiments with EsaI to better understand the catalytic mechanism and substrate specificity. (II) Study the P. aeruginosa AHLsynthase, LasI, using structural and biochemical techniques to understand how specificity of AHL production is determined. (III) Establish whether the AHL-synthase homologues in divergent organisms produce a homoserine lactone signal using mass spectrometry and activity assays. Study the structures and mechanisms to determine similarities to other AHL synthases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 61

•

Project Title: SUBSYNOVIAL CONNECTIVE TISSUE AND CARPAL TUNNEL SYNDROME Principal Investigator & Institution: Amadio, Peter C.; Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Carpal tunnel syndrome (CTS) is one of the most common causes of work-related disability in the US. The most common pathological finding is non-inflammatory synovial fibrosis and thickening, but whether this fibrosis is a cause of, or merely an associated finding with the compression neuropathy of the median nerve that is characteristic of CTS is unknown. This study will attempt to address this important issue by investigating the motion behavior, mechanical properties, and biological response of the synovium, and specifically the subsynovial connective tissue (SSCT), the gliding interface which links the tendons and synovium in the carpal tunnel. We hypothesize that activity-related damage may occur to the SSCT, resulting in fibrosis, diminished elasticity and increased gliding resistance in the carpal tunnel, setting up a vicious cycle of progressive injury that ultimately impairs permeability of the synovium, increases carpal tunnel pressure, and thereby causes the median neuropathy of CTS. To test this hypothesis, we propose three Specific Aims. Aim 1 is to describe the motion characteristics of the SSCT, by video, fluoroscopic, and ultrasound imaging, in normal human cadavers, patients with CTS, and in candidate animal models of CTS (dog and rabbit); in Aim 2, the mechanical properties and permeability of the SSCT in these same groups will be studied and compared. Aim 3 will characterize the histology and immunohistochemistry of the SSCT in these tissues; if this hypothesis regarding the etiology of CTS is correct, a biological basis for cumulative trauma as an etiology will be established for the first time for CTS. In addition, suitable animal models will be characterized for further experimental investigations of CTS. Finally, a new perspective would be provided, which could serve as a foundation for new therapies and prevention strategies for CTS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: T CELL AND EOSINOPHIL RECRUITMENT IN LUNG FIBROSIS Principal Investigator & Institution: Tager, Andrew M.; Assistant in Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 04-AUG-1999; Project End 31-JUL-2004 Summary: With the proposed Mentored Clinical Scientist Development Award, the applicant will build upon his prior experiences investigating the biology of inflammation in the lung. Based on very positive experiences in the laboratory to date, the applicant is firmly committed to a career in academic pulmonary and critical care medicine. The laboratory of Dr. Andrew D. Luster at the Massachusetts General Hospital will provide a rich intellectual environment to foster the candidate's scientific development toward his goal of independent investigation. The present proposal provides the applicant the opportunity to master a broad range of current laboratory techniques in molecular and cellular biology, supplemented by a program of didactic study of immunology. The research project proposed focuses on pathogenic mechanisms of pulmonary fibrosis. Pulmonary fibrotic disorders appear to be initiated by inflammation of the lower respiratory tract, which causes activation and proliferation of mesenchymal cells, and results in increased extracellular matrix deposition. Data both from patients and animal models indicate T cells and eosinophils participate in the inflammation of the lower respiratory tract, which causes activation and proliferation of

62

Fibrosis

mesenchymal cells, and results in increased extracellular matrix deposition. Data both from patients and animal models indicate T cells and eosinophils participate in the inflammation initiating at least some of these disorders. The research proposed is based on the hypotheses that the recruitment of T cells, their polarization toward the Th2 phenotype, and the consequent recruitment of eosinophils contribute to the pathogenesis of pulmonary fibrotic disorders The applicant specifically proposes to: (1) Investigate the role of the T cell chemoattractant IP-10 (interferon-induced protein of 10 kd) in T cell recruitment in BLM-induced fibrosis; (2) investigate the balance of Th1 versus Th2 responses in BLM-induced fibrosis, and the role of cytokines and costimulatory molecules in determining this balance; and (3) investigate the role of Th2 cytokines, and the eosinophil chemoattractants eotaxin and LTB4 (leukotriene B4), in eosinophil recruitment in BLM- induced fibrosis. The last area of the research proposed will include the generation of mice genetically deficient for the recently described murine LTB4 receptor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TGFB AND GENE THERAPY IN SILICA INDUCED LUNG FIBROSIS Principal Investigator & Institution: Sime, Patricia J.; Assistant Professor of Medicine; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: Inhalation of silica in mining, sandblasting and quarrying occupations results in serious, potentially life threatening, pulmonary inflammatory and fibrotic pathologies including acute and chronic (nodular pulmonary fibrosis) silicosis. Thus the first objective of this proposal is to determine the mechanisms underlying silica-induced pulmonary inflammation and fibrosis, particularly the role of the cytokine transforming growth factor beta 1(TGfb1). TGFb is strongly implicated in pulmonary fibrosis induced by silica and other agents. The second objective is to develop novel gene-based therapeutic strategies for treatment of these fibrotic pathologies. The hypothesis will be tested that activated TGFb is a key mediator of crystalline silica-mediated fibrosis, and if inhibited a fibrotic outcome can be prevented. Two different anti-TGFb strategies will be utilized. The first will involve adenoviral vector mediated overexpression of the core protein of the proteoglycan decorin in mouse lung. Decorin is a physiological inhibitor of active TGFb. The second strategy will exploit the inhibitory nature of the preproportion of the TGFb molecule itself, termed the LAP. Transgenic mice overexpressing LAP under control of the lung specific SP- C promoter will be used, and should produce prolonged inhibition of active TGFb. Unlike crystalline silica, amorphous silica induces inflammation, but not fibrogenesis. It is hypothesized that this is related to failure of amorphous silica to upregulate active TGFb. The concept will be tested that over-expression of low levels of active TGFb, in the context of ongoing amorphous silica-induced injury and inflammation, will drive silica-mediated inflammation to fibrogenesis. Assessment will also be made of the ability this inflammatory milieu itself to activate latent TGFb. Finally, to further address the mechanisms of inflammation and fibrogenesis induced by different silicas, their potential to activate fibroblasts in vitro will be examined. The PI of this project has just been recruited as faculty to the Depts. of Medicine and Environmental Medicine. She is committed to an academic career, and will spend 80% of her time in research studies. She has had previous training in inflammation, fibrogenesis and gene transfer, and now plans to expand her studies to investigate environmental and occupational lung disease. To achieve this she wishes to obtain additional training in environmental toxicology, and the role of the immune system in fibroblast activation. The environment in

Studies 63

Rochester has a critical mass of international experts in these areas, whose interests are aligned with those of the PI. They will collaborate with the PI, and form her advisory committee. In conjunction with a formal education program me this should allow her to successfully develop as an independent investigator, while yielding new insights into the pathogenesis and treatment of fibrotic pathologies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TH2 CYTOKINES AND CC CHEMOKINES IN PULMONARY FIBROSIS Principal Investigator & Institution: Keane, Michael P.; Assistant Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) The pathogenesis of idiopathic pulmonary fibrosis is charactenized by an intense inflammatory response with accompanying fibroproliferation and deposition of extracellular matrix. The initial stimulus for inflammatory cell recruitment and the mechanisms responsible for the perpetuation and evolution of chronic inflammation, granulation tissue formation, and fibrosis have not been fully elucidated. While IL-13, a Th2 cytokine, has been shown to have direct effects on fibroblasts that supports fibroproliferation it is also a potent inducer of a novel CC chemokine, CIO, which is chemotactic for mononuclear phagocytes. The macrophage/mononuclear phagocyte has been shown to have a pivotal role in the pathogenesis of pulmonary fibrosis, serving as an important source of growth factors that regulate extracellular matrix synthesis. We hypothesize that the cytokine pathway of IL-13 to C1O promotes pulmonary fibrosis via a mechanism that is independent of the direct effect of IL-13 on fibroblasts. The expression of IL-13 and its receptor leads to the induction of C10, which promotes recruitment of a specific population of pro-fibrotic macrophages. The specific aims are as follows: 1)A. To characterize the expression and regulation of C1O during the pathogenesis of bleomycin-induced pulmonary fibrosis. B. To determine the relative and specific contributions of IL-13 and CIO to the development of pulmonary fibrosis. 2) To compare and contrast the disparity between ligand/receptor expression of IL-4/IL4R and IL-13/IL-13R as they relate to the induction of CIO, and the subsequent development of pulmonary fibrosis. 3) To assess IL-13/IL-13R signal transduction pathways that lead to the induction of CIO, and the subsequent development of pulmonary fibrosis. 4) To establish that CIO recruits a distinct population of macrophages that induce pulmonary fibrosis. 5) To study the effect of administration of exogenous interferon-gamma to patients with IPF on the balance of Th1/Th2 cytokines and the expression of MIP-18 (human homologue of C1O), and to correlate these findings with clinical, radiological and physiological parameters of disease activity. In this project both the bleomycin and FITC models of pulmonary fibrosis will be used. Techniques to be employed include a variety of molecular, immunological and cellular bioassays. Successful completion of these specific aims will provide insight into a novel pathway for macrophage recruitment that may lead to new therapeutic interventions in IPF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: THE ROLE OF GELATINASE A IN INTERSTITIAL FIBROSIS Principal Investigator & Institution: Cheng, Sunfa; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-JUL-2006

64

Fibrosis

Summary: (adapted from the application) The paucity of therapeutic options for the treatment of chronic renal diseases results in the inexorable progression to end stage renal disease, characterized by interstitial fibrosis and glomerulosiderosis. In both processes, the myofibroblast has a central role as an effector cell elaborating excessive inflammatory mediators and extracellular matrix. In interstitial fibrosis, the degree of fibrosis and progression of renal disease directly correlates with the presence of myofibroblasts. Interstitial myofibroblasts arise mainly from tubular epithelial cells and fibroblasts. Factors implicated in the transformation include transforming growth factor (TGF)- beta1, endothelin- 1, and angiotensin ll- profibrogenic growth factors shown to stimulate gelatinase A production. In the glomerulus, gelatinase A transforms the mesangial cell into myofibroblasts. Similarly, gelatinase A is a key mediator of tubular epithelial cell- myofibroblast transdifferentiation in vitro. To locate the key regulatory elements for constitutive and growth factor- inducible gelatinase A transcription in the renal interstitium, a series of 5' flanking region deletion constructs of the rat gelatinase A gene will be transfected into normal rat kidney epithelial (NRK- 52e) and fibroblast (NRK- 49f) cells. The constructs extend to - 1686 bp of the immediate 5' flanking region and contain a laciferase reporter. Once the specific constitutive and growth factordependent enhancer sequences have been mapped, the specific interacting transcription factors will be characterized by the yeast one- hybrid system. A transgenic mouse model constitutively expressing activated gelatinase A will be constructed to directly test the relevance of gelatinase A on epithelial cell transdifferentiation to myofibroblasts and generation of interstitial fibrosis. To avoid a lethal phenotype, a tissue- specific, tetracycline- inducible transgenic system will be utilized. Using the mouse gammaglutamyl transpeptidase II promoter, the tetracycline transactivator protein (tTA) will be restricted to the proximal tubules. The tTA mouse will be crossed with a mouse harboring the gelatinase A gene under the control of a synthetic tetracycline operator (tet0). Only those cells with tTA (i.e. the proximal tubules) will be able to express activated gelatinase A. tTA, and consequently gelatinase A expression, is inhibited by doxycycline, so temporal control over activated gelatinase A expression will be maintained by doxycycline administration. To further evaluate gelatinase A's role in interstitial fibrosis, a gelatinase A knockout strain will be crossed with a TGF- beta1 transgenic strain. Since the TGF- beta1 transgenic mouse develops fibrosis, this crossing will evaluate gelatinase A as distal effector for TGF- beta1- induced fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF LEPTIN IN LIVER FIBROGENESIS Principal Investigator & Institution: Anania, Frank A.; Assistant Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Non-alcoholic steatohepatitis or non-alcoholic fatty liver (NAFL) is a growing clinical problem that may account for a newly recognized etiology for cryptogenic cirrhosis. Leptin, a 16-kilodalton protein resulting from the transcription of the obese gene, is a hormone associated with weight and satiety control. NAFL, along with obesity, type II diabetes mellitus, and hyperlipidemia, are conditions characterized by high circulating concentrations of the hormone leptin. The overall goal of this proposal is to demonstrate the biological consequences of leptin as a novel mediator of liver fibrosis, the precursor to cirrhosis. Preliminary data indicate leptin has profibrogenic activity in the principal collagen producing cells of the liver, hepatic stellate cells (HSCs). In vivo data indicate that leptin is also required for liver fibrosis induced by carbon tetrachloride (CCl4) in lean, but not obese, mice. The preliminary

Studies 65

data and the current proposal meet the long-term objectives of this laboratory: to understand basic mechanisms underlying chronic liver fibrosis. In this proposal, it is hypothesized that leptin is a profibrogenic cytokine in activated hepatic stellate cells and increases (2(I) collagen expression by phosphorylated signal transduction and activator of transcription (pSTAT) enhancing AP-1 binding to the alpha2(I) collagen promoter. Three aims are outlined to test this hypothesis. First to (a) further characterize leptin as a novel profibrogenic cytokine by examining genes responsible for increased extracellular matrix (ECM) production in fibrotic liver; and (b) to elucidate the specific signal transduction pathway(s) responsible for the effect of leptin on (2(I) collagen expression in HSCs. Second to (a) characterize leptin-associated alpha2(I) collagen mRNA stabilization; to (b) identify specific cis-acting elements along the human alpha2(I) collagen promoter affected by leptin signaling that are responsible for increased collagen gene expression by employing deletion mutant and site-directed mutagenesis; and (c) to identify, by DNase I protection analysis and electrophoretic mobility shift assay, specific transcription factors associated with leptin altered collagen gene expression. Third, to exploit rodent animal models of obesity, and their lean littermates, to determine the mechanisms by which leptin may be required for liver fibrosis in wildtype mice exposed to CC14 but not in identically treated db/db or ob/ob mice; and whether leptin is required in a common bile duct ligation (CBDL) injury model using fa/fa, or Zucker Diabetic Fatty (ZDF) rats and their lean littermates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPEUTIC TARGETING OF RANTES/CCL5 IN FUNGAL ASTHMA. Principal Investigator & Institution: Hogaboam, Cory M.; Associate Professor; Pathology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Profound airway inflammation and airway remodeling accompanies responses to the fungus Aspergillus fumigatus, complicating asthma and cystic fibrosis. The introduction of A. fumigatus conidia into the airways of mice previously sensitized to A. fumigatus leads a fungal asthma-like disease characterized by elevated IgE and IgG1, and pulmonary expression of chemokines and Th2 cytokines. These events are also associated with a marked peribronchial accumulation of CD4+ T cells and eosinophils concomitant with marked airway hyperresponsiveness, goblet cell hyperplasia and peribronchial fibrosis. Previously, we have shown that the immunoneutralization of monocyte chemo-attractant protein-1 (MCP-1/CCL2) in A. fumigatus-sensitized mice challenged with conidia leads to aggressive fungal colonization due to a major compromise in the innate immune response. In contrast, we have observed that the immunoneutralization of regulated on T-cell activation, normal T cell expressed and secreted (RANTES/CCL5) does not impair the elimination of A. fumigatus and inhibits the development of chronic fungal asthma. Using this model, we will address the hypothesis that the selective targeting of RANTES/CCL5-responsive cells in the lung abolishes allergic effector and remodeling features of this model without compromising the necessary innate immune responses. This hypothesis will be addressed through the following three Specific Aims: 1) To determine the roles of RANTES/CCL5 in the pulmonary innate immune response against live A. fumigatus conidia. 2) To determine the mechanism through which iRANTES/CCL5 modulates the allergic effector responses mediated by T cells and eosinophils. 3) To determine the mechanism through which RANTES/CCL5 contributes

66

Fibrosis

to the persistent airway remodeling features such as goblet cell hyperplasia and peribronchial fibrosis that characterize chronic fungal asthma. These detailed studies are now possible because of the availability of novel chimeric protein that selectively targets RANTES/CCL5-responsive cells in the lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPEUTIC TARGETS FOR CHRONIC ALLOGRAFT REJECTION Principal Investigator & Institution: Bishop, D. Keith.; Associate Professor; Surgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Chronic rejection (CR) is the leading cause of late allograft failure. Manifestations of chronic rejection (CR) include fibrosis of the graft and vascular neointimal development, referred to as transplant associated vasculopathy (TAV). Despite continued investigation, the underlying mechanisms responsible for these disease manifestations remain poorly defined. TGFB has been implicated in fibrosis of the graft, and smooth muscle (SM) cell migration and proliferation are thought to be critical in TAV. This proposal will employ gene transfer strategies and mAb as targeted therapies of allograft fibrosis and TAV in the mouse vascularized cardiac allograft model, where transient depletion of recipient CDA4+ T cells results in prolonged graft survival and the development of CS. Results will be compared to recipients treated with multiple doses of anti-CD40L mAb, which do not develop CR. In Specific Aim 1, cellular and cytokine mediators of CR will be identified by adoptive transfer of selected cell populations into SCID allograft recipients, and modulating responses with neutralizing mAb. The role of regulatory T cells in CR will be explored to test the hypothesis that Treg function to prevent Th1 and Th2 responses associated with acute rejection, but allow CR inducing factors to be expressed. In Specific Aim 2, the direct participation of TGFB in graft fibrosis will be assessed by inhibiting local TGFB activity by transfection with decorin, an inhibitor of TGFB. TGFB transfected grafts will be placed in recipients treated with multiple doses of anti-CD40L that do not develop CR. Since connective tissue growth factor (CTGF) is the down stream mediator of TGFB induced fibrosis, targeting CTGF will be explored to test the hypothesis that TGFB induced fibrosis may be segregated from the beneficial anti-inflammatory activities of this cytokine. In Specific Aim 3, gene transfer of the cyclin dependent kinase (cdk) inhibitors p21 and p27, will be employed to test the hypothesis that limiting vascular SM cell proliferation will inhibit the progression of TAV. Heme oxygenase-1 (HO-1) gene transfer into p21 deficient allografts will be performed to test the hypothesis that the reported protective effects of HO-1 over expression in TAV are mediated in part by regulation of upregulation of p21. Hence, the proposed studies will identify underlying mechanisms responsible for fibrosis and TAV. Further, these studies will shed light on the interactions between TGFB, decorin, CTGF, p21/p27, and HO-1 as they relate to CR. Studies of this nature have not performed previously, and will rigorously explore the use of these novel therapeutic targets in preventing the progression of CR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 67

•

Project Title: TNF-ALPHA REGULATION OF AT1 RECEPTOR & POST-MI FIBROSIS Principal Investigator & Institution: Greenberg, Barry H.; Professor of Medicine; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2004 Summary: The deposition of fibrous tissue during post-MI remodeling is a critical determinant of cardiac function. Fibrosis is seen initially at the site of myocardial necrosis where development of a replacement scar is an essential component of the wound healing process. Extensive interstitial fibrosis can also develop in non-infarcted segments of the heart. Despite the importance of fibrous tissue deposition in both the scar and in non-infarcted segments of myocardium in determining cardiac function, the mechanisms responsible for post-MI cardiac fibrosis are still poorly understood. Angiotensin (Ang) II appears to play an important role in post-MI fibrosis. Ang II binding with the type I receptor, AT1 activates cardiac fibroblasts and stimulates them to produce proteins and growth factors associated with fibrous tissue deposition. Moreover, AT1 receptor density is increased on cardiac fibroblasts post-MI. Tumor necrosis factor-alpha (TNFalpha) appears in the heart post-MI and there is evidence to suggest that it also is involved in post-MI remodeling. Recent evidence from the investigator's laboratory showing that TNFalpha increases AT1 receptor density on cultured cardiac fibroblasts suggests that an interaction between these systems may be involved in post-MI remodeling. The studies outlined in this proposal will test the significance of this interaction and the mechanisms involved. The specific aims are to determine: 1. the spatial and temporal association between the appearance of TNFalpha, increased AT1 receptor density on cardiac fibroblasts and development of fibrosis throughout post-MI remodeling; 2. if TNFalpha induced AT1 receptor upregulation enhances cardiac fibroblast functions related to post-MI extra cellular matrix remodeling; 3. increased transcription of the AT1A gene by TNFalpha is mediated by activation of NF-kappaB and AP-1, and; 4. if the absence of TNFalpha prevents AT1 receptor upregulation and causes deficient scar formation post-MI. The results are expected to show that TNFalpha upregulation of the AT1 receptor plays an important role in post-MI fibrosis and to identify signal transduction pathways and molecular mechanisms involved in the increase in AT1 receptor density in cardiac fibroblasts. This information will provide important insights into the pathogenesis of post-MI fibrosis. 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, 3 4

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.

68

Fibrosis

and type “fibrosis” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for fibrosis in the PubMed Central database: •

"Bronchial Artery Delivery of Viral Vectors for Gene delivery in Cystic Fibrosis; Superior to Airway Delivery?". by Bakhai A Dr, MRCP, Sheridan DJ Professor, FRCP, Coutelle CC Professor, Drscmed.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107842

•

[gamma][delta] T lymphocytes from cystic fibrosis patients and healthy donors are high TNF-[alpha] and IFN-[gamma]-producers in response to Pseudomonas aeruginosa. by Raga S, Julia MR, Crespi C, Figuerola J, Martinez N, Mila J, Matamoros N.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=203157

•

A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. by Anders HJ, Vielhauer V, Frink M, Linde Y, Cohen CD, Blattner SM, Kretzler M, Strutz F, Mack M, Grone HJ, Onuffer J, Horuk R, Nelson PJ, Schlondorff D.; 2002 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150841

•

A conditional probability analysis of cystic fibrosis transmembrane conductance regulator gating indicates that ATP has multiple effects during the gating cycle. by Hennager DJ, Ikuma M, Hoshi T, Welsh MJ.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30698

•

A C-terminal motif found in the [beta]2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na + /H + exchanger regulatory factor family of PDZ proteins. by Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ.; 1998 Jul 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21104

•

A cystic fibrosis pancreatic adenocarcinoma cell line. by Schoumacher RA, Ram J, Iannuzzi MC, Bradbury NA, Wallace RW, Hon CT, Kelly DR, Schmid SM, Gelder FB, Rado TA, et al.; 1990 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=54034

•

A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution. by Ostedgaard LS, Baldursson O, Vermeer DW, Welsh MJ, Robertson AD.; 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25884

•

A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr [minus sign] /[minus sign] mice. by Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG.; 1999 Nov 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24179

•

A molecular mechanism for aberrantCFTR-dependent HCO3 -- transport in cystic fibrosis. by Ko SB, Shcheynikov N, Choi JY, Luo X, Ishibashi K, Thomas PJ, Kim JY, Kim KH, Lee MG, Naruse S, Muallem S.; 2002 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=131077

•

A new direction in the pathogenesis of idiopathic pulmonary fibrosis? by Gauldie J, Kolb M, Sime PJ.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64807

Studies 69

•

A prospective assessment of the inter-laboratory variability of biochemical markers of fibrosis (FibroTest) and activity (ActiTest) in patients with chronic liver disease. by Halfon P, Imbert-Bismut F, Messous D, Antoniotti G, Benchetrit D, Cart-Lamy P, Delaporte G, Doutheau D, Klump T, Sala M, Thibaud D, Trepo E, Thabut D, Myers RP, Poynard T.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149429

•

A simple alfalfa seedling infection model for Pseudomonas aeruginosa strains associated with cystic fibrosis shows AlgT (sigma-22) and RhlR contribute to pathogenesis. by Silo-Suh L, Suh SJ, Sokol PA, Ohman DE.; 2002 Nov 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137779

•

A1 Adenosine-Receptor Antagonists Activate Chloride Efflux from Cystic Fibrosis Cells. by Eidelman O, Guay-Broder C, van Galen PJ, Jacobson KA, Fox C, Turner RJ, Cabantchik ZI, Pollard HB.; 1992 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49332

•

Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect. by Russo MA, Hogenauer C, Coates SW Jr, Santa Ana CA, Porter JL, Rosenblatt RL, Emmett M, Fordtran JS.; 2003 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=162286

•

Abnormal Secretagogue-Induced Intracellular Free Ca2+ Regulation in Cystic Fibrosis Nasal Epithelial Cells. by Reinlib L, Jefferson DJ, Marini FC, Donowitz M.; 1992 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48782

•

Absence of angiotensin II type 1 receptor in bone marrow --derived cells is detrimental in the evolution of renal fibrosis. by Nishida M, Fujinaka H, Matsusaka T, Price J, Kon V, Fogo AB, Davidson JM, Linton MF, Fazio S, Homma T, Yoshida H, Ichikawa I.; 2002 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151648

•

Activities of Tobramycin and Six Other Antibiotics against Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis. by Shawar RM, MacLeod DL, Garber RL, Burns JL, Stapp JR, Clausen CR, Tanaka SK.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89580

•

Adenoviral expression of a transforming growth factor-[beta]1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats. by Arias M, SauerLehnen S, Treptau J, Janoschek N, Theuerkauf I, Buettner R, Gressner AM, Weiskirchen R.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270053

•

Adenovirus-Mediated Persistent Cystic Fibrosis Transmembrane Conductance Regulator Expression in Mouse Airway Epithelium. by Scaria A, St. George JA, Jiang C, Kaplan JM, Wadsworth SC, Gregory RJ.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109954

•

Altered chloride metabolism in cultured cystic fibrosis skin fibroblasts. by Mattes PM, Maloney PC, Littlefield JW.; 1987 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304790

70

Fibrosis

•

Altered cytokine production by cystic fibrosis tracheal gland serous cells. by Kammouni W, Figarella C, Marchand S, Merten M.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175746

•

Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis. by Cruz-Gervis R, Stecenko AA, Dworski R, Lane KB, Loyd JE, Pierson R, King G, Brigham KL.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107846

•

An Approach for Treating the Hepatobiliary Disease of Cystic Fibrosis by Somatic Gene Transfer. by Yang Y, Raper SE, Cohn JA, Engelhardt JF, Wilson JM.; 1993 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46560

•

Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells. by Schwiebert EM, Cid-Soto LP, Stafford D, Carter M, Blaisdell CJ, Zeitlin PL, Guggino WB, Cutting GR.; 1998 Mar 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19931

•

Analysis of IL-12 p40 subunit gene and IFN-[gamma] G5644A polymorphisms in Idiopathic Pulmonary Fibrosis. by Latsi P, Pantelidis P, Vassilakis D, Sato H, Welsh KI, du Bois RM.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=185252

•

Antibody responses to lipid A, core, and O sugars of the Pseudomonas aeruginosa lipopolysaccharide in chronically infected cystic fibrosis patients. by Kronborg G, Fomsgaard A, Galanos C, Freudenberg MA, Hoiby N.; 1992 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265392

•

Antimicrobial Susceptibility of Haemophilus influenzae in the Respiratory Tracts of Patients with Cystic Fibrosis. by Moller LV, Regelink AG, Grasselier H, van Alphen L, Dankert J.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105407

•

Antisense Oligodeoxynucleotide to the Cystic Fibrosis Gene Inhibits Anion Transport in Normal Cultured Sweat Duct Cells. by Sorscher EJ, Kirk KL, Weaver ML, Jilling T, Blalock JE, LeBoeuf RD.; 1991 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52382

•

Antisense Oligodeoxynucleotides to the Cystic Fibrosis Transmembrane Conductance Regulator Inhibit cAMP-Activated but not Calcium-Activated Chloride Currents. by Wagner JA, McDonald TV, Nghiem PT, Lowe AW, Schulman H, Gruenert DC, Stryer L, Gardner P.; 1992 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49588

•

Approaches to localizing disease genes as applied to cystic fibrosis. by Dean M, Drumm ML, Stewart C, Gerrard B, Perry A, Hidaka N, Cole JL, Collins FS, Iannuzzi MC.; 1990 Jan 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=330273

•

Arbitrarily primed polymerase chain reaction as a rapid method to differentiate crossed from independent Pseudomonas cepacia infections in cystic fibrosis patients.

Studies 71

by Bingen EH, Weber M, Derelle J, Brahimi N, Lambert-Zechovsky NY, Vidailhet M, Navarro J, Elion J.; 1993 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265941 •

Association between transcript levels of the Pseudomonas aeruginosa regA, regB, and toxA genes in sputa of cystic fibrosis patients. by Raivio TL, Ujack EE, Rabin HR, Storey DG.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302984

•

Association with phagocytic inhibition of anti-Pseudomonas aeruginosa immunoglobulin G antibody subclass levels in serum from patients with cystic fibrosis. by Shryock TR, Molle JS, Klinger JD, Thomassen MJ.; 1986 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268685

•

Azlocillin pharmacokinetics in patients with cystic fibrosis. by Bosso JA, Saxon BA, Herbst JJ, Matsen JM.; 1984 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185602

•

Bacterial Diversity in Cases of Lung Infection in Cystic Fibrosis Patients: 16S Ribosomal DNA (rDNA) Length Heterogeneity PCR and 16S rDNA Terminal Restriction Fragment Length Polymorphism Profiling. by Rogers GB, Hart CA, Mason JR, Hughes M, Walshaw MJ, Bruce KD.; 2003 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=179861

•

Basal Expression of the Cystic Fibrosis Transmembrane Conductance Regulator Gene is Dependent on Protein Kinase A Activity. by McDonald RA, Matthews RP, Idzerda RL, McKnight GS.; 1995 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41379

•

beta-Lactam-resistant Pseudomonas aeruginosa with modified penicillin-binding proteins emerging during cystic fibrosis treatment. by Godfrey AJ, Bryan LE, Rabin HR.; 1981 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=181510

•

Bicarbonate Conductance and pH Regulatory Capability of Cystic Fibrosis Transmembrane Conductance Regulator. by Poulsen JH, Fischer H, Illek B, Machen TE.; 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43990

•

Bioactive tumor necrosis factor in the sputa of cystic fibrosis patients. by Kelly N, Clee S, Nakielna B.; 1995 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170189

•

Blockade of type [beta] transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. by Qi Z, Atsuchi N, Ooshima A, Takeshita A, Ueno H.; 1999 Mar 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26786

72

Fibrosis

•

Bone marrow --derived progenitor cells in pulmonary fibrosis. by Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH.; 2004 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=310750

•

Bronchoalveolar Fluid Is Not a Major Hindrance to Virus-Mediated Gene Therapy in Cystic Fibrosis. by Rooney CP, Denning GM, Davis BP, Flaherty DM, Chiorini JA, Zabner J.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136549

•

Burkholderia cepacia Complex Infection in Italian Patients with Cystic Fibrosis: Prevalence, Epidemiology, and Genomovar Status. by Agodi A, Mahenthiralingam E, Barchitta M, Giannino V, Sciacca A, Stefani S.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88256

•

Cable (cbl) type II pili of cystic fibrosis-associated Burkholderia (Pseudomonas) cepacia: nucleotide sequence of the cblA major subunit pilin gene and novel morphology of the assembled appendage fibers. by Sajjan US, Sun L, Goldstein R, Forstner JF.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=176699

•

cAMP-Inducible Chloride Conductance in Mouse Fibroblast Lines Stably Expressing the Human Cystic Fibrosis Transmembrane Conductance Regulator. by Rommens JM, Dho S, Bear CE, Kartner N, Kennedy D, Riordan JR, Tsui L, Foskett JK.; 1991 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52328

•

Capillary Electrophoresis --Single-Strand Conformation Polymorphism Analysis for Rapid Identification of Pseudomonas aeruginosa and Other Gram-Negative Nonfermenting Bacilli Recovered from Patients with Cystic Fibrosis. by Ghozzi R, Morand P, Ferroni A, Beretti JL, Bingen E, Segonds C, Husson MO, Izard D, Berche P, Gaillard JL.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85573

•

Cardiac fibrosis in mice lacking brain natriuretic peptide. by Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, Kasahara M, Hashimoto R, Katsuura G, Mukoyama M, Itoh H, Saito Y, Tanaka I, Otani H, Katsuki M, Nakao K.; 2000 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18212

•

Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis. by Saiman L, Tabibi S, Starner TD, San Gabriel P, Winokur PL, Jia HP, McCray PB Jr, Tack BF.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90740

•

Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. by Canbay A, Guicciardi ME, Higuchi H, Feldstein A, Bronk SF, Rydzewski R, Taniai M, Gores GJ.; 2003 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164289

•

CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. by Saito E, Fujimoto M, Hasegawa M, Komura K, Hamaguchi Y, Kaburagi Y, Nagaoka T, Takehara K, Tedder TF, Sato S.; 2002 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150999

Studies 73

•

Cell Death of Human Polymorphonuclear Neutrophils Induced by a Pseudomonas aeruginosa Cystic Fibrosis Isolate Requires a Functional Type III Secretion System. by Dacheux D, Attree I, Schneider C, Toussaint B.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97008

•

CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX. by Engle EC, McIntosh N, Yamada K, Lee BA, Johnson R, O'Keefe M, Letson R, London A, Ballard E, Ruttum M, Matsumoto N, Saito N, Collins ML, Morris L, Monte MD, Magli A, de Berardinis T.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=100320

•

CFTR with a partially deleted R domain corrects the cystic fibrosis chloride transport defect in human airway epithelia in vitro and in mouse nasal mucosa in vivo. by Ostedgaard LS, Zabner J, Vermeer DW, Rokhlina T, Karp PH, Stecenko AA, Randak C, Welsh MJ.; 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122478

•

'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations. by Noone PG, Knowles MR.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64805

•

Characterization of Immortal Cystic Fibrosis Tracheobronchial Gland Epithelial Cells. by Cozens AL, Yezzi MJ, Chin L, Simon EM, Finkbeiner WE, Wagner JA, Gruenert DC.; 1992 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49251

•

Characterization of Pseudomonas cepacia isolates from patients with cystic fibrosis. by McKevitt AI, Woods DE.; 1984 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=271041

•

Characterization of the Cystic Fibrosis Transmembrane Conductance Regulator in a Colonocyte Cell Line. by Cohn JA, Nairn AC, Marino CR, Melhus O, Kole J.; 1992 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48653

•

Characterization of Unusual Bacteria Isolated from Respiratory Secretions of Cystic Fibrosis Patients and Description of Inquilinus limosus gen. nov., sp. nov. by Coenye T, Goris J, Spilker T, Vandamme P, LiPuma JJ.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130740

•

Chloride channel and chloride conductance regulator domains of CFTR, the cystic fibrosis transmembrane conductance regulator. by Schwiebert EM, Morales MM, Devidas S, Egan ME, Guggino WB.; 1998 Mar 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19458

•

Clinical outcome in relation to care in centres specialising in cystic fibrosis: cross sectional study. by Mahadeva R, Webb K, Westerbeek RC, Carroll NR, Dodd ME, Bilton D, Lomas DA.; 1998 Jun 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28574

74

Fibrosis

•

Comparative activity of cefepime, alone and in combination, against clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from cystic fibrosis patients. by Bosso JA, Saxon BA, Matsen JM.; 1991 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245101

•

Comparative analysis of serum antibody responses to Pseudomonas aeruginosa exotoxin A by cystic fibrosis and intensive care unit patients. by Cukor G, Blacklow NR, Nowak NA, Rich CM, Braverman LE, Fischer RA.; 1983 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=270833

•

Comparative genomic sequence analysis of the human and mouse cystic fibrosis transmembrane conductance regulator genes. by Ellsworth RE, Jamison DC, Touchman JW, Chissoe SL, Braden Maduro VV, Bouffard GG, Dietrich NL, Beckstrom-Sternberg SM, Iyer LM, Weintraub LA, Cotton M, Courtney L, Edwards J, Maupin R, Ozersky P, Rohlfing T, Wohldmann P, Miner T, Kemp K, Kramer J, Korf I, Pepin K, AntonacciFulton L, Fulton RS, Minx P, Hillier LW, Wilson RK, Waterston RH, Miller W, Green ED.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15558

•

Comparative immunochemistry of lipopolysaccharides from typable and polyagglutinable Pseudomonas aeruginosa strains isolated from patients with cystic fibrosis. by Fomsgaard A, Conrad RS, Galanos C, Shand GH, Hoiby N.; 1988 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=266467

•

Comparative In Vitro Activities of Meropenem, Imipenem, Temocillin, Piperacillin, and Ceftazidime in Combination with Tobramycin, Rifampin, or Ciprofloxacin against Burkholderia cepacia Isolates from Patients with Cystic Fibrosis. by Bonacorsi S, Fitoussi F, Lhopital S, Bingen E.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89053

•

Comparative in vitro activity of a new quinolone, fleroxacin, against respiratory pathogens from patients with cystic fibrosis. by Akaniro JC, Vidaurre CE, Stutman HR, Marks MI.; 1990 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=171958

•

Comparative Stability Studies of Antipseudomonal [beta]-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units). by Viaene E, Chanteux H, Servais H, Mingeot-Leclercq MP, Tulkens PM.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127357

•

Comparison of adherence of Pseudomonas aeruginosa to respiratory epithelial cells from cystic fibrosis patients and healthy subjects. by Saiman L, Cacalano G, Gruenert D, Prince A.; 1992 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=257238

•

Comparison of Agar Diffusion Methodologies for Antimicrobial Susceptibility Testing of Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients. by Burns JL, Saiman L, Whittier S, Larone D, Krzewinski J, Liu Z, Marshall SA, Jones RN.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86597

Studies 75

•

Comparison of Culture and PCR for Detection of Burkholderia cepacia in Sputum Samples of Patients with Cystic Fibrosis. by Whitby PW, Dick HL, Campbell PW III, Tullis DE, Matlow A, Stull TL.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104893

•

Comparison of Immunogenicity and Safety of a Virosome Influenza Vaccine with Those of a Subunit Influenza Vaccine in Pediatric Patients with Cystic Fibrosis. by Schaad UB, Buhlmann U, Burger R, Ruedeberg A, Wilder-Smith A, Rutishauser M, Sennhauser F, Herzog C, Zellmeyer M, Gluck R.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89839

•

Comparison of Isolation Media for Recovery of Burkholderia cepacia Complex from Respiratory Secretions of Patients with Cystic Fibrosis. by Henry D, Campbell M, McGimpsey C, Clarke A, Louden L, Burns JL, Roe MH, Vandamme P, Speert D.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88640

•

Compartmentalized autocrine signaling to cystic fibrosis transmembrane conductance regulator at the apical membrane of airway epithelial cells. by Huang P, Lazarowski ER, Tarran R, Milgram SL, Boucher RC, Stutts MJ.; 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61178

•

Conversion of Pseudomonas aeruginosa to mucoidy in cystic fibrosis: environmental stress and regulation of bacterial virulence by alternative sigma factors. by Deretic V, Schurr MJ, Boucher JC, Martin DW.; 1994 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=205429

•

Conversion of Pseudomonas aeruginosa to the phenotype characteristic of strains from patients with cystic fibrosis. by Speert DP, Farmer SW, Campbell ME, Musser JM, Selander RK, Kuo S.; 1990 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269573

•

Cumulative and acute toxicity of repeated high-dose tobramycin treatment in cystic fibrosis. by Pedersen SS, Jensen T, Osterhammel D, Osterhammel P.; 1987 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=174783

•

Cystic Fibrosis Gene Encodes a cAMP-Dependent Chloride Channel in Heart. by Hart P, Warth JD, Levesque PC, Collier ML, Geary Y, Horowitz B, Hume JR.; 1996 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39024

•

Cystic Fibrosis Gene Expression is not Correlated with Rectifying Cl- Channels. by Ward CL, Krouse ME, Gruenert DC, Kopito RR, Wine JJ.; 1991 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51855

•

Cystic Fibrosis Transmembrane Conductance Regulator Activation Stimulates Endosome Fusion in vivo. by Biwersi J, Emans N, Verkman AS.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38018

76

Fibrosis

•

Cystic fibrosis transmembrane conductance regulator is an epithelial cell receptor for clearance of Pseudomonas aeruginosa from the lung. by Pier GB, Grout M, Zaidi TS.; 1997 Oct 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23711

•

Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Corneal Epithelial Cell Ingestion of Pseudomonas aeruginosa Is a Key Component in the Pathogenesis of Experimental Murine Keratitis. by Zaidi TS, Lyczak J, Preston M, Pier GB.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96484

•

Cytokines and Inflammatory Mediators Do Not Indicate Acute Infection in Cystic Fibrosis. by Wolter JM, Rodwell RL, Bowler SD, McCormack JG.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95697

•

Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca2 +-dependent potassium channels. by Vazquez E, Nobles M, Valverde MA.; 2001 Apr 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33209

•

Detection by enzyme-linked immunosorbent assays of antibody specific for Pseudomonas proteases and exotoxin A in sera from cystic fibrosis patients. by Jagger KS, Robinson DL, Franz MN, Warren RL.; 1982 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=272252

•

Detection of antibodies to Pseudomonas aeruginosa alginate extracellular polysaccharide in animals and cystic fibrosis patients by enzyme-linked immunosorbent assay. by Bryan LE, Kureishi A, Rabin HR.; 1983 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=270790

•

Development of rRNA-Based PCR Assays for Identification of Burkholderia cepacia Complex Isolates Recovered from Cystic Fibrosis Patients. by LiPuma JJ, Dulaney BJ, McMenamin JD, Whitby PW, Stull TL, Coenye T, Vandamme P.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85518

•

Differences in adhesion of Pseudomonas aeruginosa to mucin glycopeptides from sputa of patients with cystic fibrosis and chronic bronchitis. by Ramphal R, Houdret N, Koo L, Lamblin G, Roussel P.; 1989 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=260771

•

Differences in the Concentrations of Small, Anionic, Antimicrobial Peptides in Bronchoalveolar Lavage Fluid and in Respiratory Epithelia of Patients with and without Cystic Fibrosis. by Brogden KA, Ackermann MR, McCray PB Jr, Huttner KM.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96733

•

Differentiation of Burkholderia Species by PCR-Restriction Fragment Length Polymorphism Analysis of the 16S rRNA Gene and Application to Cystic Fibrosis Isolates. by Segonds C, Heulin T, Marty N, Chabanon G.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85118

•

Discrimination of Burkholderia gladioli from Other Burkholderia Species Detectable in Cystic Fibrosis Patients by PCR. by Bauernfeind A, Schneider I, Jungwirth R, Roller C.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105199

Studies 77

•

Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. by Yang J, Shultz RW, Mars WM, Wegner RE, Li Y, Dai C, Nejak K, Liu Y.; 2002 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151817

•

Distribution of Genes Encoding Putative Transmissibility Factors among Epidemic and Nonepidemic Strains of Burkholderia cepacia from Cystic Fibrosis Patients in the United Kingdom. by Clode FE, Kaufmann ME, Malnick H, Pitt TL.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86581

•

Effects of C-terminal deletions on cystic fibrosis transmembrane conductance regulator function in cystic fibrosis airway epithelia. by Ostedgaard LS, Randak C, Rokhlina T, Karp P, Vermeer D, Ashbourne Excoffon KJ, Welsh MJ.; 2003 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149937

•

Effects of Nitric Oxide on Pseudomonas aeruginosa Infection of Epithelial Cells from a Human Respiratory Cell Line Derived from a Patient with Cystic Fibrosis. by Darling KE, Evans TJ.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153226

•

Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. by Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, Birrer P, Bellon G, Berger J, Weiss T, Botzenhart K, Yankaskas JR, Randell S, Boucher RC, Doring G.; 2002 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150856

•

Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. by Vandivier RW, Fadok VA, Hoffmann PR, Bratton DL, Penvari C, Brown KK, Brain JD, Accurso FJ, Henson PM.; 2002 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150889

•

Epidemic of Pseudomonas cepacia in an adult cystic fibrosis unit: evidence of personto-person transmission. by Smith DL, Gumery LB, Smith EG, Stableforth DE, Kaufmann ME, Pitt TL.; 1993 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=266193

•

Epidemiological Analysis of Sequential Pseudomonas aeruginosa Isolates from Chronic Bronchiectasis Patients without Cystic Fibrosis. by Pujana I, Gallego L, Martin G, Lopez F, Canduela J, Cisterna R.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85036

•

Epithelial-mesenchymal transition and its implications for fibrosis. by Kalluri R, Neilson EG.; 2003 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=297008

•

Evaluation of E-Test for determination of antimicrobial MICs for Pseudomonas aeruginosa isolates from cystic fibrosis patients. by Marley EF, Mohla C, Campos JM.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228671

•

Evaluation of Reference Dilution Test Methods for Antimicrobial Susceptibility Testing of Pseudomonas aeruginosa Strains Isolated from Patients with Cystic Fibrosis. by Saiman L, Burns JL, Whittier S, Krzewinski J, Marshall SA, Jones RN.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85429

78

Fibrosis

•

Evidence that fibroblasts derive from epithelium during tissue fibrosis. by Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151091

•

Expression of ExsA in trans Confers Type III Secretion System-Dependent Cytotoxicity on Noncytotoxic Pseudomonas aeruginosa Cystic Fibrosis Isolates. by Dacheux D, Attree I, Toussaint B.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97914

•

Expression of Monocyte Chemoattractant Protein 1 mRNA in Human Idiopathic Pulmonary Fibrosis. by Antoniades HN, Neville-Golden J, Galanopoulos T, Kradin RL, Valente AJ, Graves DT.; 1992 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49293

•

Expression of the cystic fibrosis transmembrane conductance regulator gene in cells of non-epithelial origin. by Yoshimura K, Nakamura H, Trapnell BC, Chu CS, Dalemans W, Pavirani A, Lecocq JP, Crystal RG.; 1991 Oct 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=328907

•

Expression of the Cystic Fibrosis Transmembrane Conductance Regulator Gene in the Respiratory Tract of Normal Individuals and Individuals with Cystic Fibrosis. by Trapnell BC, Chu C, Paakko PK, Banks TC, Yoshimura K, Ferrans VJ, Chernick MS, Crystal RG.; 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52127

•

Expression of the human cystic fibrosis transmembrane conductance regulator gene in the mouse lung after in vivo intratracheal plasmid-mediated gene transfer. by Yoshimura K, Rosenfeld MA, Nakamura H, Scherer EM, Pavirani A, Lecocq JP, Crystal RG.; 1992 Jun 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=312463

•

Expression of the Na + /Ca2 + exchanger emerges in hepatic stellate cells after activation in association with liver fibrosis. by Nakamura T, Arii S, Monden K, Furutani M, Takeda Y, Imamura M, Tominaga M, Okada Y.; 1998 Apr 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20271

•

Factors Influencing Adeno-Associated Virus-Mediated Gene Transfer to Human Cystic Fibrosis Airway Epithelial Cells: Comparison with Adenovirus Vectors. by Teramoto S, Bartlett JS, McCarty D, Xiao X, Samulski RJ, Boucher RC.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110307

•

Fatal Pulmonary Infection Due to Multidrug-Resistant Mycobacterium abscessus in a Patient with Cystic Fibrosis. by Sanguinetti M, Ardito F, Fiscarelli E, La Sorda M, D'Argenio P, Ricciotti G, Fadda G.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87830

•

Flagella and motility alterations in Pseudomonas aeruginosa strains from patients with cystic fibrosis: relationship to patient clinical condition. by Luzar MA, Thomassen MJ, Montie TC.; 1985 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=261995

Studies 79

•

Functional Roles of the Nucleotide-Binding Folds in the Activation of the Cystic Fibrosis Transmembrane Conductance Regulator. by Smit LS, Wilkinson DJ, Mansoura MK, Collins FS, Dawson DC.; 1993 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47693

•

Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. by Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y, DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122942

•

Genetic Analysis of Pseudomonas aeruginosa Isolates from the Sputa of Australian Adult Cystic Fibrosis Patients. by Anthony M, Rose B, Pegler MB, Elkins M, Service H, Thamotharampillai K, Watson J, Robinson M, Bye P, Merlino J, Harbour C.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120616

•

Genome fingerprinting of Pseudomonas aeruginosa indicates colonization of cystic fibrosis siblings with closely related strains. by Grothues D, Koopmann U, von der Hardt H, Tummler B.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=266800

•

Genome macrorestriction analysis of diversity and variability of Pseudomonas aeruginosa strains infecting cystic fibrosis patients. by Struelens MJ, Schwam V, Deplano A, Baran D.; 1993 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265754

•

Genotypic analysis of Burkholderia cepacia isolates from 13 French cystic fibrosis centers. by Segonds C, Bingen E, Couetdic G, Mathy S, Brahimi N, Marty N, Plesiat P, Michel-Briand Y, Chabanon G.; 1997 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229902

•

Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. by Kaminski N, Allard JD, Pittet JF, Zuo F, Griffiths MJ, Morris D, Huang X, Sheppard D, Heller RA.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26512

•

Glycosylation and the cystic fibrosis transmembrane conductance regulator. by Scanlin TF, Glick MC.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59516

•

Growth factors in idiopathic pulmonary fibrosis: relative roles. by Allen JT, Spiteri MA.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64811

•

GTP-Binding Proteins Inhibit cAMP Activation of Chloride Channels in Cystic Fibrosis Airway Epithelial Cells. by Schwiebert EM, Kizer N, Gruenert DC, Stanton BA.; 1992 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50393

80

Fibrosis

•

Haemophilus influenzae is frequently detected with monoclonal antibody 8BD9 in sputum samples from patients with cystic fibrosis. by Moller LV, Ruijs GJ, Heijerman HG, Dankert J, van Alphen L.; 1992 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265533

•

Herpesvirus DNA Is Consistently Detected in Lungs of Patients with Idiopathic Pulmonary Fibrosis. by Tang YW, Johnson JE, Browning PJ, Cruz-Gervis RA, Davis A, Graham BS, Brigham KL, Oates Jr. JA, Loyd JE, Stecenko AA.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156536

•

Heterogeneity of Pseudomonas aeruginosa in Brazilian Cystic Fibrosis Patients. by Silbert S, Barth AL, Sader HS.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88474

•

Heterogeneity, persistence, and distribution of Pseudomonas aeruginosa genotypes in cystic fibrosis patients. by Fegan M, Francis P, Hayward AC, Fuerst JA.; 1991 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=270289

•

High-level beta-lactamase activity in sputum samples from cystic fibrosis patients during antipseudomonal treatment. by Giwercman B, Meyer C, Lambert PA, Reinert C, Hoiby N.; 1992 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=189229

•

Hsp70 Molecular Chaperone Facilitates Endoplasmic Reticulum-associated Protein Degradation of Cystic Fibrosis Transmembrane Conductance Regulator in Yeast. by Zhang Y, Nijbroek G, Sullivan ML, McCracken AA, Watkins SC, Michaelis S, Brodsky JL.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34585

•

Hypersusceptibility of cystic fibrosis mice to chronic Pseudomonas aeruginosa oropharyngeal colonization and lung infection. by Coleman FT, Mueschenborn S, Meluleni G, Ray C, Carey VJ, Vargas SO, Cannon CL, Ausubel FM, Pier GB.; 2003 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149939

•

Identification and Antimicrobial Susceptibility of Alcaligenes xylosoxidans Isolated from Patients with Cystic Fibrosis. by Saiman L, Chen Y, Tabibi S, San Gabriel P, Zhou J, Liu Z, Lai L, Whittier S.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88468

•

Identification of a Protein that Confers Calcitonin Gene-Related Peptide Responsiveness to Oocytes by Using a Cystic Fibrosis Transmembrane Conductance Regulator Assay. by Luebke AE, Dahl GP, Roos BA, Dickerson IM.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39630

•

Identification of an Ion Channel-Forming Motif in the Primary Structure of CFTR, the Cystic Fibrosis Chloride Channel. by Oblatt-Montal M, Reddy GL, Iwamoto T, Tomich JM, Montal M.; 1994 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43186

Studies 81

•

Identification of IS1356, a new insertion sequence, and its association with IS402 in epidemic strains of Burkholderia cepacia infecting cystic fibrosis patients. by Tyler SD, Rozee KR, Johnson WM.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229080

•

Identification of the mucin-binding adhesin of Pseudomonas cepacia isolated from patients with cystic fibrosis. by Sajjan SU, Forstner JF.; 1992 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=257015

•

Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. by Selman M, Pardo A.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64814

•

IL-7 inhibits fibroblast TGF-[beta] production and signaling in pulmonary fibrosis. by Huang M, Sharma S, Zhu LX, Keane MP, Luo J, Zhang L, Burdick MD, Lin YQ, Dohadwala M, Gardner B, Batra RK, Strieter RM, Dubinett SM.; 2002 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150933

•

Immunocytochemical Localization of the Cystic Fibrosis Gene Product CFTR. by Crawford I, Maloney PC, Zeitlin PL, Guggino WB, Hyde SC, Turley H, Gatter KC, Harris A, Higgins CF.; 1991 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52694

•

Impact of Heterogeneity within Cultured Cells on Bacterial Invasion: Analysis of Pseudomonas aeruginosa and Salmonella enterica Serovar Typhi Entry into MDCK cells by Using a Green Fluorescent Protein-Labelled Cystic Fibrosis Transmembrane Conductance Regulator Receptor. by Gerceker AA, Zaidi T, Marks P, Golan DE, Pier GB.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97215

•

Impact of Microbiology Practice on Cumulative Prevalence of Respiratory Tract Bacteria in Patients with Cystic Fibrosis. by Shreve MR, Butler S, Kaplowitz HJ, Rabin HR, Stokes D, Light M, Regelmann WE.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84543

•

Impaired Cell Volume Regulation in Intestinal Crypt Epithelia of Cystic Fibrosis Mice. by Valverde MA, O'Brien JA, Sepulveda FV, Ratcliff RA, Evans MJ, Colledge WH.; 1995 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40919

•

In vitro activities of combinations of aztreonam, ciprofloxacin, and ceftazidime against clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from patients with cystic fibrosis. by Bosso JA, Saxon BA, Matsen JM.; 1990 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=171623

•

In Vitro Activities of Designed Antimicrobial Peptides against Multidrug-Resistant Cystic Fibrosis Pathogens. by Schwab U, Gilligan P, Jaynes J, Henke D.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89292

82

Fibrosis

•

In vitro activity of amiloride combined with tobramycin against Pseudomonas isolates from patients with cystic fibrosis. by Cohn RC, Jacobs M, Aronoff SC.; 1988 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=172183

•

In vitro activity of aztreonam combined with tobramycin and gentamicin against clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from patients with cystic fibrosis. by Bosso JA, Saxon BA, Matsen JM.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=174950

•

In vitro activity of BMY-28142 against pediatric pathogens, including isolates from cystic fibrosis sputum. by Conrad DA, Scribner RK, Weber AH, Marks MI.; 1985 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=176310

•

In vitro activity of E-1040, a 3-substituted cephalosporin, against pathogens from cystic fibrosis sputum. by Stutman HR, Akaniro JC, Vidaurre CE, Marks MI.; 1990 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=175982

•

In vitro activity of tosufloxacin, a new quinolone, against respiratory pathogens derived from cystic fibrosis sputum. by Arguedas AG, Akaniro JC, Stutman HR, Marks MI.; 1990 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=172026

•

In vitro correction of cystic fibrosis epithelial cell lines by small fragment homologous replacement (SFHR) technique. by Sangiuolo F, Bruscia E, Serafino A, Nardone AM, Bonifazi E, Lais M, Gruenert DC, Novelli G.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130050

•

In Vitro Pharmacodynamic Properties of Colistin and Colistin Methanesulfonate against Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis. by Li J, Turnidge J, Milne R, Nation RL, Coulthard K.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90373

•

In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant [Delta]F508 in murine nasal epithelium. by Kelley TJ, Thomas K, Milgram LJ, Drumm ML.; 1997 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20135

•

In vivo bradykinin B2 receptor activation reduces renal fibrosis. by Schanstra JP, Neau E, Drogoz P, Arevalo Gomez MA, Lopez Novoa JM, Calise D, Pecher C, Bader M, Girolami JP, Bascands JL.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151090

•

In vivo inhibition of rat stellate cell activation by soluble transforming growth factor [beta] type II receptor: A potential new therapy for hepatic fibrosis. by George J, Roulot D, Koteliansky VE, Bissell DM.; 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23066

Studies 83

•

Increased oral bioavailability of ciprofloxacin in cystic fibrosis patients. by Christensson BA, Nilsson-Ehle I, Ljungberg B, Lindblad A, Malmborg AS, Hjelte L, Strandvik B.; 1992 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284363

•

Increased Trypanosoma cruzi Invasion and Heart Fibrosis Associated with High Transforming Growth Factor [beta] Levels in Mice Deficient in [alpha]2Macroglobulin. by Waghabi MC, Coutinho CM, Soeiro MN, Pereira MC, Feige JJ, Keramidas M, Cosson A, Minoprio P, Van Leuven F, Araujo-Jorge TC.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128220

•

Infection-induced airway fibrosis in two rat strains with differential susceptibility. by McIntosh JC, Simecka JW, Ross SE, Davis JK, Miller EJ, Cassell GH.; 1992 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=257257

•

Innate Lung Defenses and Compromised Pseudomonas aeruginosa Clearance in the Malnourished Mouse Model of Respiratory Infections in Cystic Fibrosis. by Yu H, Nasr SZ, Deretic V.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97396

•

Intrinsic Anion Channel Activity of the Recombinant First Nucleotide Binding Fold Domain of the Cystic Fibrosis Transmembrane Regulator Protein. by Arispe N, Rojas E, Hartman J, Sorscher EJ, Pollard HB.; 1992 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48487

•

Isolation of a novel Helicobacter species, Helicobacter cholecystus sp. nov., from the gallbladders of Syrian hamsters with cholangiofibrosis and centrilobular pancreatitis. by Franklin CL, Beckwith CS, Livingston RS, Riley LK, Gibson SV, Besch-Williford CL, Hook RR Jr.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229440

•

Ketoconazole Activates Cl- Conductance and Blocks Cl- and Fluid Absorption by Cultured Cystic Fibrosis (CFPAC-1) Cells. by Kersting U, Kersting D, Spring KR.; 1993 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46443

•

Laboratory proficiency test results on use of selective media for isolating Pseudomonas cepacia from simulated sputum specimens of patients with cystic fibrosis. by Tablan OC, Carson LA, Cusick LB, Bland LA, Martone WJ, Jarvis WR.; 1987 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265959

•

Longitudinal study of antibody response to lipopolysaccharides during chronic Pseudomonas aeruginosa lung infection in cystic fibrosis. by Fomsgaard A, Hoiby N, Shand GH, Conrad RS, Galanos C.; 1988 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=259560

•

Lung Infections Associated with Cystic Fibrosis. by Lyczak JB, Cannon CL, Pier GB.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=118069

84

Fibrosis

•

Magnetic Resonance Imaging of Myocardial Fibrosis in Hypertrophic Cardiomyopathy. by Wilson JM, Villareal RP, Hariharan R, Massumi A, Muthupillai R, Flamm SD.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124756

•

Marked phenotypic variability in Pseudomonas cepacia isolated from a patient with cystic fibrosis. by Larsen GY, Stull TL, Burns JL.; 1993 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263564

•

Mechanism of Conversion to Mucoidy in Pseudomonas aeruginosa Infecting Cystic Fibrosis Patients. by Martin DW, Schurr MJ, Mudd MH, Govan JR, Holloway BW, Deretic V.; 1993 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47359

•

Membrane targeting of cGMP-dependent protein kinase is required for cystic fibrosis transmembrane conductance regulator Cl[minus sign] channel activation. by Vaandrager AB, Smolenski A, Tilly BC, Houtsmuller AB, Ehlert EM, Bot AG, Edixhoven M, Boomaars WE, Lohmann SM, de Jonge HR.; 1998 Feb 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19047

•

Microbial Pathogenesis in Cystic Fibrosis: Pulmonary Clearance of Mucoid Pseudomonas aeruginosa and Inflammation in a Mouse Model of Repeated Respiratory Challenge. by Yu H, Hanes M, Chrisp CE, Boucher JC, Deretic V.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107888

•

Mixed-morphotype broth microdilution susceptibility testing of Pseudomonas aeruginosa from cystic fibrosis patients. by Van Horn KG.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=262789

•

Modifications of plasma fibronectin in cystic fibrosis patients. by Stanislawski L, Sorin M.; 1991 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=258351

•

Molecular Analysis of Burkholderia cepacia Complex Isolates from a Portuguese Cystic Fibrosis Center: a 7-Year Study. by Cunha MV, Leitao JH, Mahenthiralingam E, Vandamme P, Lito L, Barreto C, Salgado MJ, Sa-Correia I.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=193798

•

Molecular Analysis of the Ovine Cystic Fibrosis Transmembrane Conductanvce Regulator Gene. by Tebbutt SJ, Wardle CJ, Hill DF, Harris A.; 1995 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42470

•

Molecular basis for defective glycosylation and Pseudomonas pathogenesis in cystic fibrosis lung. by Poschet JF, Boucher JC, Tatterson L, Skidmore J, Van Dyke RW, Deretic V.; 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61151

•

Molecular Epidemiology of Stenotrophomonas maltophilia Isolated from Clinical Specimens from Patients with Cystic Fibrosis and Associated Environmental Samples. by Denton M, Todd NJ, Kerr KG, Hawkey PM, Littlewood JM.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104959

Studies 85

•

Molecular Mechanisms of Fluoroquinolone Resistance in Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients. by Jalal S, Ciofu O, Hoiby N, Gotoh N, Wretlind B.; 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89751

•

Molecular Typing and Exopolysaccharide Biosynthesis of Burkholderia cepacia Isolates from a Portuguese Cystic Fibrosis Center. by Richau JA, Leitao JH, Correia M, Lito L, Salgado MJ, Barreto C, Cescutti P, Sa-Correia I.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86514

•

Mucinophilic and chemotactic properties of Pseudomonas aeruginosa in relation to pulmonary colonization in cystic fibrosis. by Nelson JW, Tredgett MW, Sheehan JK, Thornton DJ, Notman D, Govan JR.; 1990 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=258659

•

Mutant Cystic Fibrosis Transmembrane Conductance Regulator Inhibits Acidification and Apoptosis in C127 Cells: Possible Relevance to Cystic Fibrosis. by Gottlieb RA, Dosanjh A.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39654

•

Mutation Detection by Mismatch Binding Protein, MutS, in Amplified DNA: Application to the Cystic Fibrosis Gene. by Lishanski A, Ostrander EA, Rine J.; 1994 Mar 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43432

•

N-acetyl-D-glucosamine medium improves recovery of Haemophilus influenzae from sputa of patients with cystic fibrosis. by Moller LV, van Alphen L, Grasselier H, Dankert J.; 1993 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265670

•

NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. by Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA.; 2003 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=228420

•

Nonmotility and phagocytic resistance of Pseudomonas aeruginosa isolates from chronically colonized patients with cystic fibrosis. by Mahenthiralingam E, Campbell ME, Speert DP.; 1994 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=186146

•

Nonopsonic phagocytosis of strains of Pseudomonas aeruginosa from cystic fibrosis patients. by Speert DP, Eftekhar F, Puterman ML.; 1984 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=264285

•

Nosocomial acquisition of Pseudomonas aeruginosa by cystic fibrosis patients. by Tummler B, Koopmann U, Grothues D, Weissbrodt H, Steinkamp G, von der Hardt H.; 1991 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=271975

86

Fibrosis

•

Novel Bacterium Isolated from a Lung Transplant Patient with Cystic Fibrosis. by Pitulle C, Citron DM, Bochner B, Barbers R, Appleman MD.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85827

•

Occurrence and Risk of Cochleotoxicity in Cystic Fibrosis Patients Receiving Repeated High-Dose Aminoglycoside Therapy. by Mulheran M, Degg C, Burr S, Morgan DW, Stableforth DE.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90684

•

Optimum use of selective plated media in primary processing of respiratory tract specimens from patients with cystic fibrosis. by Doern GV, Brogden-Torres B.; 1992 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=270512

•

Osteoporosis in Canadian adult cystic fibrosis patients: A descriptive study. by Brenckmann C, Papaioannou A, Freitag A, Hennessey R, Hansen S, Ioannidis G, Webber C, Adachi J.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=198278

•

Outer membrane permeability in Pseudomonas cepacia: diminished porin content in a beta-lactam-resistant mutant and in resistant cystic fibrosis isolates. by Aronoff SC.; 1988 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=175943

•

P-113d, an Antimicrobial Peptide Active against Pseudomonas aeruginosa, Retains Activity in the Presence of Sputum from Cystic Fibrosis Patients. by Sajjan US, Tran LT, Sole N, Rovaldi C, Akiyama A, Friden PM, Forstner JF, Rothstein DM.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90850

•

P2Z-Independent and P2Z Receptor-Mediated Macrophage Killing by Pseudomonas aeruginosa Isolated from Cystic Fibrosis Patients. by Zaborina O, Misra N, Kostal J, Kamath S, Kapatral V, El-Idrissi ME, Prabhakar BS, Chakrabarty AM.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96875

•

PCR-Based Detection and Identification of Burkholderia cepacia Complex Pathogens in Sputum from Cystic Fibrosis Patients. by McDowell A, Mahenthiralingam E, Moore JE, Dunbar KE, Webb AK, Dodd ME, Martin SL, Millar BC, Scott CJ, Crowe M, Elborn JS.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88532

•

Persistence mechanisms in Pseudomonas aeruginosa from cystic fibrosis patients undergoing ciprofloxacin therapy. by Diver JM, Schollaardt T, Rabin HR, Thorson C, Bryan LE.; 1991 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245215

•

Pharmacokinetics and dosage requirements of netilmicin in cystic fibrosis patients. by Bosso JA, Townsend PL, Herbst JJ, Matsen JM.; 1985 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=180338

Studies 87

•

Pharmacokinetics and pharmacodynamics of ciprofloxacin in cystic fibrosis patients. by LeBel M, Bergeron MG, Vallee F, Fiset C, Chasse G, Bigonesse P, Rivard G.; 1986 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=180531

•

Pharmacokinetics of cefepime in cystic fibrosis patients. by Huls CE, Prince RA, Seilheimer DK, Bosso JA.; 1993 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=187985

•

Pharmacokinetics of ciprofloxacin in cystic fibrosis. by Davis RL, Koup JR, WilliamsWarren J, Weber A, Heggen L, Stempel D, Smith AL.; 1987 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284211

•

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients. by Schaefer HG, Stass H, Wedgwood J, Hampel B, Fischer C, Kuhlmann J, Schaad UB.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163051

•

Pharmacokinetics of Tobramycin in Adults with Cystic Fibrosis: Implications for Once-Daily Administration. by Beringer PM, Vinks AA, Jelliffe RW, Shapiro BJ.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89775

•

Pharmacokinetics of vancomycin in adult cystic fibrosis patients. by Pleasants RA, Michalets EL, Williams DM, Samuelson WM, Rehm JR, Knowles MR.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163080

•

Phenotypic conversion of Pseudomonas aeruginosa in cystic fibrosis. by Fegan M, Francis P, Hayward AC, Davis GH, Fuerst JA.; 1990 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267893

•

Pneumocystis carinii Carriage among Cystic Fibrosis Patients, as Detected by Nested PCR. by Sing A, Geiger AM, Hogardt M, Heesemann J.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88220

•

Pneumonia Due to Bordetella bronchiseptica in a Cystic Fibrosis Patient: 16S rRNA Sequencing for Diagnosis Confirmation. by Wallet F, Perez T, Armand S, Wallaert B, Courcol RJ.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130795

•

Polysaccharide surface antigens expressed by nonmucoid isolates of Pseudomonas aeruginosa from cystic fibrosis patients. by Pier GB, Desjardins D, Aguilar T, Barnard M, Speert DP.; 1986 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268873

•

Population Dynamics of Persistent Staphylococcus aureus Isolated from the Airways of Cystic Fibrosis Patients during a 6-Year Prospective Study. by Kahl BC, Duebbers A, Lubritz G, Haeberle J, Koch HG, Ritzerfeld B, Reilly M, Harms E, Proctor RA, Herrmann M, Peters G.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=193812

88

Fibrosis

•

Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis. by Montgomery MJ, Beringer PM, Aminimanizani A, Louie SG, Shapiro BJ, Jelliffe R, Gill MA.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90855

•

Population transcript accumulation of Pseudomonas aeruginosa exotoxin A and elastase in sputa from patients with cystic fibrosis. by Storey DG, Ujack EE, Rabin HR.; 1992 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=258219

•

Proficiency testing of clinical microbiology laboratories using modified decontamination procedures for detection of nontuberculous mycobacteria in sputum samples from cystic fibrosis patients. The Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. by Whittier S, Olivier K, Gilligan P, Knowles M, Della-Latta P.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230046

•

Progress toward generating a ferret model of cystic fibrosis by somatic cell nuclear transfer. by Li Z, Engelhardt JF.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=280727

•

Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator. by Travis SM, Berger HA, Welsh MJ.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23594

•

Pseudomonas aeruginosa alginate in cystic fibrosis sputum and the inflammatory response. by Pedersen SS, Kharazmi A, Espersen F, Hoiby N.; 1990 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=313661

•

Pseudomonas aeruginosa Cystic Fibrosis Isolates Induce Rapid, Type III SecretionDependent, but ExoU-Independent, Oncosis of Macrophages and Polymorphonuclear Neutrophils. by Dacheux D, Toussaint B, Richard M, Brochier G, Croize J, Attree I.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97504

•

Pseudomonas aeruginosa flagellar antibodies in patients with cystic fibrosis. by Anderson TR, Montie TC, Murphy MD, McCarthy VP.; 1989 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267127

•

Pseudomonas aeruginosa lasR Transcription Correlates with the Transcription of lasA, lasB, and toxA in Chronic Lung Infections Associated with Cystic Fibrosis. by Storey DG, Ujack EE, Rabin HR, Mitchell I.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108233

•

Pseudomonas aeruginosa Quorum-Sensing Signal Molecule N-(3-Oxododecanoyl)-lHomoserine Lactone Inhibits Expression of P2Y Receptors in Cystic Fibrosis Tracheal Gland Cells. by Saleh A, Figarella C, Kammouni W, Marchand-Pinatel S, Lazdunski A, Tubul A, Brun P, Merten MD.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96855

Studies 89

•

Pseudomonas aeruginosa Quorum-Sensing Systems May Control Virulence Factor Expression in the Lungs of Patients with Cystic Fibrosis. by Erickson DL, Endersby R, Kirkham A, Stuber K, Vollman DD, Rabin HR, Mitchell I, Storey DG.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127834

•

Pulmonary Outcome in Cystic Fibrosis Is Influenced Primarily by Mucoid Pseudomonas aeruginosa Infection and Immune Status and Only Modestly by Genotype. by Parad RB, Gerard CJ, Zurakowski D, Nichols DP, Pier GB.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96804

•

Purification, characterization, and immunological cross-reactivity of alginates produced by mucoid Pseudomonas aeruginosa from patients with cystic fibrosis. by Pedersen SS, Espersen F, Hoiby N, Shand GH.; 1989 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267399

•

Quantitative proteomic analysis indicates increased synthesis of a quinolone by Pseudomonas aeruginosa isolates from cystic fibrosis airways. by Guina T, Purvine SO, Yi EC, Eng J, Goodlett DR, Aebersold R, Miller SI.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151416

•

Rapid Endocytosis of the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel. by Prince LS, Workman RB Jr, Marchase RB.; 1994 May 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43958

•

Recombinant Human DNase I Reduces the Viscosity of Cystic Fibrosis Sputum. by Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL.; 1990 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=55129

•

Recovery of Mycobacteria from Patients with Cystic Fibrosis. by Bange FC, Kirschner P, Bottger EC.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85755

•

Recovery of Pseudomonas gladioli from respiratory tract specimens of patients with cystic fibrosis. by Christenson JC, Welch DF, Mukwaya G, Muszynski MJ, Weaver RE, Brenner DJ.; 1989 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267290

•

Regulation of Cl- Channels in Normal and Cystic Fibrosis Airway Epithelial Cells by Extracellular ATP. by Stutts MJ, Chinet TC, Mason SJ, Fullton JM, Clarke LL, Boucher RC.; 1992 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48504

•

Regulation of cystic fibrosis transmembrane conductance regulator single-channel gating by bivalent PDZ-domain-mediated interaction. by Raghuram V, Mak DO, Foskett JK.; 2001 Jan 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14749

•

Regulation of the Gating of Cystic Fibrosis Transmembrane Conductance Regulator C1 Channels by Phosphorylation and ATP Hydrolysis. by Hwang T, Nagel G, Nairn AC, Gadsby DC.; 1994 May 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43855

90

Fibrosis

•

Relationship of a Non-Cystic Fibrosis Transmembrane Conductance RegulatorMediated Chloride Conductance to Organ-Level Disease in Cftr(-/-) Mice. by Clarke LL, Grubb BR, Yankaskas JR, Cotton CU, McKenzie A, Boucher RC.; 1994 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42972

•

Renal fibrosis: not just PAI-1 in the sky. by Fogo AB.; 2003 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166301

•

Renal interstitial fibrosis: Remembrance of things past? by Herzlinger D.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151098

•

Repeated Chlamydia trachomatis infection of Macaca nemestrina fallopian tubes produces a Th1-like cytokine response associated with fibrosis and scarring. by Van Voorhis WC, Barrett LK, Sweeney YT, Kuo CC, Patton DL.; 1997 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175300

•

Rescuing protein conformation: prospects for pharmacological therapy in cystic fibrosis. by Gelman MS, Kopito RR.; 2002 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151638

•

Retrovirus-mediated gene transfer to cystic fibrosis airway epithelial cells: effect of selectable marker sequences on long-term expression. by Olsen JC, Johnson LG, WongSun ML, Moore KL, Swanstrom R, Boucher RC.; 1993 Feb 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=309167

•

Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes. by Beggah AT, Escoubet B, Puttini S, Cailmail S, Delage V, Ouvrard-Pascaud A, Bocchi B, Peuchmaur M, Delcayre C, Farman N, Jaisser F.; 2002 May 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124545

•

Role of Pseudomonas aeruginosa exoenzymes in lung infections of patients with cystic fibrosis. by Doring G, Goldstein W, Roll A, Schiotz PO, Hoiby N, Botzenhart K.; 1985 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=261205

•

Role of sialic acid in saliva-mediated aggregation of Pseudomonas aeruginosa isolated from cystic fibrosis patients. by Komiyama K, Habbick BF, Tumber SK.; 1987 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=260714

•

Role of the cystic fibrosis transmembrane conductance regulator in innate immunity to Pseudomonas aeruginosa infections. by Pier GB.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34018

•

Routine susceptibility testing of four antibiotic combinations for improvement of laboratory guide to therapy of cystic fibrosis infections caused by Pseudomonas aeruginosa. by Weiss K, Lapointe JR.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162957

Studies 91

•

Salmonella enterica Serovar Typhi Modulates Cell Surface Expression of Its Receptor, the Cystic Fibrosis Transmembrane Conductance Regulator, on the Intestinal Epithelium. by Lyczak JB, Pier GB.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130400

•

Selective and differential medium for recovery of Pseudomonas cepacia from the respiratory tracts of patients with cystic fibrosis. by Welch DF, Muszynski MJ, Pai CH, Marcon MJ, Hribar MM, Gilligan PH, Matsen JM, Ahlin PA, Hilman BC, Chartrand SA.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269317

•

Sensitivity of a Renal K+ Channel (ROMK2) to the Inhibitory Sulfonylurea Compound Glibenclamide is Enhanced by Coexpression with the ATP-Binding Cassette Transporter Cystic Fibrosis Transmembrane Regulator. by McNicholas CM, Guggino WB, Schwiebert EM, Hebert SC, Giebisch G, Egan ME.; 1996 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38879

•

Sera from Adult Patients with Cystic Fibrosis Contain Antibodies to Pseudomonas aeruginosa Type III Apparatus. by Moss J, Ehrmantraut ME, Banwart BD, Frank DW, Barbieri JT.; 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98003

•

Siderophore presence in sputa of cystic fibrosis patients. by Haas B, Kraut J, Marks J, Zanker SC, Castignetti D.; 1991 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=258988

•

Siderophore Production by Cystic Fibrosis Isolates of Burkholderia cepacia. by Darling P, Chan M, Cox AD, Sokol PA.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107988

•

Specific and Rapid Detection by Fluorescent In Situ Hybridization of Bacteria in Clinical Samples Obtained from Cystic Fibrosis Patients. by Hogardt M, Trebesius K, Geiger AM, Hornef M, Rosenecker J, Heesemann J.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86213

•

Sputum Itraconazole Concentrations in Cystic Fibrosis Patients. by Sermet-Gaudelus I, Lesne-Hulin A, Lenoir G, Singlas E, Berche P, Hennequin C.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90579

•

Stable in vivo Expression of the Cystic Fibrosis Transmembrane Conductance Regulator with an Adeno-Associated Virus Vector. by Flotte TR, Afione SA, Conrad C, McGarth SA, Solow R, Oka H, Zeitlin PL, Guggino WB, Carter BJ.; 1993 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47827

•

State of the Art: Why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection? by Chmiel JF, Davis PB.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=203156

•

Submucosal gland secretions in airways from cystic fibrosis patients have normal [Na +] and pH but elevated viscosity. by Jayaraman S, Joo NS, Reitz B, Wine JJ, Verkman AS.; 2001 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35477

92

Fibrosis

•

Superantigens and Cystic Fibrosis: Resistance of Presenting Cells to Dexamethasone. by Ben-Ari J, Gozal D, Dorio RJ, Bowman CM, Reiff A, Walker SM.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95912

•

Synergistic Activities of Macrolide Antibiotics against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans Isolated from Patients with Cystic Fibrosis. by Saiman L, Chen Y, San Gabriel P, Knirsch C.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127106

•

Taking stock of gene therapy for cystic fibrosis. by Stern M, Geddes DM, Alton EW.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59546

•

Targeted disruption of TGF-[beta]1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. by Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A.; 2003 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=259132

•

TGF-[beta]1 induces bone marrow reticulin fibrosis in hairy cell leukemia. by Shehata M, Schwarzmeier JD, Hilgarth M, Hubmann R, Duechler M, Gisslinger H.; 2004 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=351317

•

The bone marrow leaves its scar: new concepts in pulmonary fibrosis. by Dunsmore SE, Shapiro SD.; 2004 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=311440

•

The Common Variant of Cystic Fibrosis Transmembrane Conductance Regulator is Recognized by hsp70 and Degraded in a Pre-Golgi Nonlysosomal Compartment. by Yang Y, Janich S, Cohn JA, Wilson JM.; 1993 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47592

•

The first-nucleotide binding domain of the cystic-fibrosis transmembrane conductance regulator is important for inhibition of the epithelial Na + channel. by Schreiber R, Hopf A, Mall M, Greger R, Kunzelmann K.; 1999 Apr 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21860

•

The Gene for Congenital Chloride Diarrhea Maps Close to but is Distinct from the Gene for Cystic Fibrosis Transmembrane Conductance Regulator. by Kere J, Sistonen P, Holmberg C, Chapelle AD.; 1993 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47842

•

The PEST sequence does not contribute to the stability of the cystic fibrosis transmembrane conductance regulator. by Chen EY, Clarke DM.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130031

•

The Pseudomonas aeruginosa Secretory Product Pyocyanin Inactivates [alpha]1 Protease Inhibitor: Implications for the Pathogenesis of Cystic Fibrosis Lung Disease. by Britigan BE, Railsback MA, Cox CD.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96448

•

The role of the Grb2 --p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. by Zhang S, Weinheimer C, Courtois M, Kovacs A, Zhang CE, Cheng AM, Wang Y, Muslin AJ.; 2003 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153766

Studies 93

•

Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. by Pawlinski R, Fernandes A, Kehrle B, Pedersen B, Parry G, Erlich J, Pyo R, Gutstein D, Zhang J, Castellino F, Melis E, Carmeliet P, Baretton G, Luther T, Taubman M, Rosen E, Mackman N.; 2002 Nov 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137717

•

Toward an Animal Model of Cystic Fibrosis: Targeted Interruption of Exon 10 of the Cystic Fibrosis Transmembrane Regulator Gene in Embryonic Stem Cells. by Koller BH, Kim H, Latour AM, Brigman K, Boucher RC Jr, Scambler P, Wainwright B, Smithies O.; 1991 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53004

•

Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. by Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB.; 1997 Feb 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19623

•

Transfer of a constitutive viral promoter-cystic fibrosis transmembrane conductance regulator cDNA to human epithelial cells conveys resistance to down-regulation of cAMP-regulated Cl- secretion in the presence of inflammatory stimuli. by Kobayashi N, Rosenthal ER, Yoshimura K, Crystal RG.; 1994 Oct 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=308481

•

Transforming Growth Factor [beta]1 is Present at Sites of Extracellular Matrix Gene Expression in Human Pulmonary Fibrosis. by Broekelmann TJ, Limper AH, Colby TV, McDonald JA.; 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52144

•

Two Cystic Fibrosis Transmembrane Conductance Regulator Mutations Have Different Effects on Both Pulmonary Phenotype and Regulation of Outwardly Rectified Chloride Currents. by Fulmer SB, Schwiebert EM, Morales MM, Guggino WB, Cutting GR.; 1995 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41423

•

Unexpected news in renal fibrosis. by Oliver JA.; 2002 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151660

•

Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR? by Boyle MP.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59552

•

Uptake of Fluorescent Dyes Associated with the Functional Expression of the Cystic Fibrosis Transmembrane Conductance Regulator in Epithelial Cells. by Wersto RP, Rosenthal ER, Crystal RG, Spring KR.; 1996 Feb 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40050

•

Use of 16S rRNA Gene Sequencing for Identification of Nonfermenting GramNegative Bacilli Recovered from Patients Attending a Single Cystic Fibrosis Center. by Ferroni A, Sermet-Gaudelus I, Abachin E, Quesne G, Lenoir G, Berche P, Gaillard JL.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130867

94

Fibrosis

•

Use of Random Amplified Polymorphic DNA PCR To Examine Epidemiology of Stenotrophomonas maltophilia and Achromobacter (Alcaligenes) xylosoxidans from Patients with Cystic Fibrosis. by Krzewinski JW, Nguyen CD, Foster JM, Burns JL.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88395

•

Use of Subtractive Hybridization To Identify a Diagnostic Probe for a Cystic Fibrosis Epidemic Strain of Pseudomonas aeruginosa. by Parsons YN, Panagea S, Smart CH, Walshaw MJ, Hart CA, Winstanley C.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154653

•

Utility of Commercial Systems for Identification of Burkholderia cepacia Complex from Cystic Fibrosis Sputum Culture. by Shelly DB, Spilker T, Gracely EJ, Coenye T, Vandamme P, LiPuma JJ.; 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87204

•

Utility of gram stain in evaluation of sputa from patients with cystic fibrosis. by Sadeghi E, Matlow A, MacLusky I, Karmali MA.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=262969

•

Utility of Gram Staining for Evaluation of the Quality of Cystic Fibrosis Sputum Samples. by Nair B, Stapp J, Stapp L, Bugni L, Van Dalfsen J, Burns JL.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120690

•

Variation in the Composition and Pore Function of Major Outer Membrane Pore Protein P2 of Haemophilus influenzae from Cystic Fibrosis Patients. by Regelink AG, Dahan D, Moller LV, Coulton JW, Eijk P, Van Ulsen P, Dankert J, Van Alphen L.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89055

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 fibrosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “fibrosis” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for fibrosis (hyperlinks lead to article summaries):

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.

Studies 95

•

A comparison of nutrient intake between infants and toddlers with and without cystic fibrosis. Author(s): Powers SW, Patton SR. Source: Journal of the American Dietetic Association. 2003 December; 103(12): 1620-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14647088&dopt=Abstract

•

A phase I trial of intranasal Moli1901 for cystic fibrosis. Author(s): Zeitlin PL, Boyle MP, Guggino WB, Molina L. Source: Chest. 2004 January; 125(1): 143-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718433&dopt=Abstract

•

A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. Author(s): Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr; Idiopathic Pulmonary Fibrosis Study Group. Source: The New England Journal of Medicine. 2004 January 8; 350(2): 125-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14711911&dopt=Abstract

•

A rare case of idiopathic retroperitoneal fibrosis involving obstruction of the mesenteric arteries, duodenum, common bile duct, and inferior vena cava. Author(s): Tamura S, Yokoyama Y, Nakajo K, Morita T, Wada K, Onishi S. Source: Intern Med. 2003 September; 42(9): 812-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14518667&dopt=Abstract

•

A scoring system for the early detection of oral submucous fibrosis based on a selfadministered questionnaire. Author(s): Chiu CJ, Lee WC, Chiang CP, Hahn LJ, Kuo YS, Chen CJ. Source: J Public Health Dent. 2002 Winter; 62(1): 28-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14700086&dopt=Abstract

•

A unique presentation of calcinosis cutis in a patient with cystic fibrosis after double lung transplants. Author(s): Friedman JS, Fulghum Walters R, Woosley J, Fine JD. Source: Journal of the American Academy of Dermatology. 2003 December; 49(6): 11316. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14639400&dopt=Abstract

•

Abnormal osteoclasts and bone marrow fibrosis in Paget's disease of the bone. Author(s): Murrin RJ, Harrison P. Source: British Journal of Haematology. 2004 January; 124(1): 3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14675402&dopt=Abstract

96

Fibrosis

•

Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Author(s): Ambrosini V, Cancellieri A, Chilosi M, Zompatori M, Trisolini R, Saragoni L, Poletti V. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 November; 22(5): 821-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14621091&dopt=Abstract

•

agr-dependent bacterial interference has no impact on long-term colonization of Staphylococcus aureus during persistent airway infection of cystic fibrosis patients. Author(s): Kahl BC, Becker K, Friedrich AW, Clasen J, Sinha B, Von Eiff C, Peters G. Source: Journal of Clinical Microbiology. 2003 November; 41(11): 5199-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14605162&dopt=Abstract

•

Airway-centered interstitial fibrosis: a distinct form of aggressive diffuse lung disease. Author(s): Churg A, Myers J, Suarez T, Gaxiola M, Estrada A, Mejia M, Selman M. Source: The American Journal of Surgical Pathology. 2004 January; 28(1): 62-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14707865&dopt=Abstract

•

Allergic bronchopulmonary aspergillosis in cystic fibrosis--state of the art: Cystic Fibrosis Foundation Consensus Conference. Author(s): Stevens DA, Moss RB, Kurup VP, Knutsen AP, Greenberger P, Judson MA, Denning DW, Crameri R, Brody AS, Light M, Skov M, Maish W, Mastella G; Participants in the Cystic Fibrosis Foundation Consensus Conference. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 October 1; 37 Suppl 3: S225-64. Review. Erratum In: Clin Infect Dis. 2004 January 1; 38(1): 158. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975753&dopt=Abstract

•

Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors. Author(s): Kawaguchi Y, Takagi K, Hara M, Fukasawa C, Sugiura T, Nishimagi E, Harigai M, Kamatani N. Source: Arthritis and Rheumatism. 2004 January; 50(1): 216-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14730619&dopt=Abstract

•

Antibiotic treatment of multidrug-resistant organisms in cystic fibrosis. Author(s): Conway SP, Brownlee KG, Denton M, Peckham DG. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2003; 2(4): 321-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14719998&dopt=Abstract

Studies 97

•

Antimicrobial susceptibility and synergy studies of Stenotrophomonas maltophilia isolates from patients with cystic fibrosis. Author(s): San Gabriel P, Zhou J, Tabibi S, Chen Y, Trauzzi M, Saiman L. Source: Antimicrobial Agents and Chemotherapy. 2004 January; 48(1): 168-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14693535&dopt=Abstract

•

Asbestosis and idiopathic pulmonary fibrosis: comparison of thin-section CT features. Author(s): Copley SJ, Wells AU, Sivakumaran P, Rubens MB, Lee YC, Desai SR, MacDonald SL, Thompson RI, Colby TV, Nicholson AG, du Bois RM, Musk AW, Hansell DM. Source: Radiology. 2003 December; 229(3): 731-6. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14576443&dopt=Abstract

•

Assessment of tidal breathing parameters in infants with cystic fibrosis. Author(s): Ranganathan SC, Goetz I, Hoo AF, Lum S, Castle R, Stocks J; London Collaborative Cystic Fibrosis Group. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 November; 22(5): 761-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14621082&dopt=Abstract

•

Association of cystic fibrosis with abnormalities in fatty acid metabolism. Author(s): Freedman SD, Blanco PG, Zaman MM, Shea JC, Ollero M, Hopper IK, Weed DA, Gelrud A, Regan MM, Laposata M, Alvarez JG, O'Sullivan BP. Source: The New England Journal of Medicine. 2004 February 5; 350(6): 560-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14762183&dopt=Abstract

•

Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis). Author(s): Baker LR. Source: Bju International. 2003 November; 92(7): 663-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14616440&dopt=Abstract

•

Autoimmune pancreatitis associated with idiopathic retroperitoneal fibrosis. Author(s): Fukukura Y, Fujiyoshi F, Nakamura F, Hamada H, Nakajo M. Source: Ajr. American Journal of Roentgenology. 2003 October; 181(4): 993-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500215&dopt=Abstract

98

Fibrosis

•

Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. Author(s): Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd; Macrolide Study Group. Source: Jama : the Journal of the American Medical Association. 2003 October 1; 290(13): 1749-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519709&dopt=Abstract

•

Bacterial diversity in cases of lung infection in cystic fibrosis patients: 16S ribosomal DNA (rDNA) length heterogeneity PCR and 16S rDNA terminal restriction fragment length polymorphism profiling. Author(s): Rogers GB, Hart CA, Mason JR, Hughes M, Walshaw MJ, Bruce KD. Source: Journal of Clinical Microbiology. 2003 August; 41(8): 3548-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904354&dopt=Abstract

•

Basic science research vs. clinical research in cystic fibrosis: Has the pendulum swung too far? Author(s): Coates AL, Bush A. Source: Pediatric Pulmonology. 2003 September; 36(3): 175-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12910577&dopt=Abstract

•

Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alfa-2b and ribavirin. Author(s): Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J. Source: Hepatology (Baltimore, Md.). 2003 August; 38(2): 481-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883493&dopt=Abstract

•

Bioelectronic sensor technology for detection of cystic fibrosis and hereditary hemochromatosis mutations. Author(s): Bernacki SH, Farkas DH, Shi W, Chan V, Liu Y, Beck JC, Bailey KS, Pratt VM, Monaghan KG, Matteson KJ, Schaefer FV, Friez M, Shrimpton AE, Stenzel TT. Source: Archives of Pathology & Laboratory Medicine. 2003 December; 127(12): 1565-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14632577&dopt=Abstract

•

Bolus inhalation of rhDNase with the AERx system in subjects with cystic fibrosis. Author(s): Geller D, Thipphawong J, Otulana B, Caplan D, Ericson D, Milgram L, Okikawa J, Quan J, Bowman CM. Source: Journal of Aerosol Medicine : the Official Journal of the International Society for Aerosols in Medicine. 2003 Summer; 16(2): 175-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823911&dopt=Abstract

Studies 99

•

Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Author(s): Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA, Kalluri R. Source: American Journal of Physiology. Renal Physiology. 2003 December; 285(6): F1060-7. Epub 2003 August 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915382&dopt=Abstract

•

Bronchoalveolar lavage fluid surfactant protein-A and surfactant protein-D are inversely related to inflammation in early cystic fibrosis. Author(s): Noah TL, Murphy PC, Alink JJ, Leigh MW, Hull WM, Stahlman MT, Whitsett JA. Source: American Journal of Respiratory and Critical Care Medicine. 2003 September 15; 168(6): 685-91. Epub 2003 June 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829455&dopt=Abstract

•

Bronchopulmonary disease in children with cystic fibrosis after early or delayed diagnosis. Author(s): Farrell PM, Li Z, Kosorok MR, Laxova A, Green CG, Collins J, Lai HC, Rock MJ, Splaingard ML. Source: American Journal of Respiratory and Critical Care Medicine. 2003 November 1; 168(9): 1100-8. Epub 2003 August 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917228&dopt=Abstract

•

Burkholderia cepacia complex in cystic fibrosis: frequency of strain replacement during chronic infection. Author(s): Bernhardt SA, Spilker T, Coffey T, LiPuma JJ. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 September 15; 37(6): 780-5. Epub 2003 August 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12955638&dopt=Abstract

•

Burkholderia pseudomallei: another emerging pathogen in cystic fibrosis. Author(s): O'Carroll MR, Kidd TJ, Coulter C, Smith HV, Rose BR, Harbour C, Bell SC. Source: Thorax. 2003 December; 58(12): 1087-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14645982&dopt=Abstract

•

Carboxylated osteocalcin levels in cystic fibrosis. Author(s): Aris RM, Ontjes DA, Brown SA, Chalermskulrat W, Neuringer I, Lester GE. Source: American Journal of Respiratory and Critical Care Medicine. 2003 November 1; 168(9): 1129. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14581291&dopt=Abstract

100

Fibrosis

•

Cascade carrier-testing in cystic fibrosis. Author(s): Roberts T, Schwarz MJ, Kerr-Liddell R, Hinks JL, Super M. Source: Paediatric Respiratory Reviews. 2003 December; 4(4): 293-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14629951&dopt=Abstract

•

Case 4: assessment. An adolescent aged 14 has cystic fibrosis. Author(s): Roberts T, Schwarz MJ, Kerr-Liddell R, Hinks JL, Super M. Source: Paediatric Respiratory Reviews. 2003 December; 4(4): 348, 350. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14692404&dopt=Abstract

•

Cellular profiles of induced sputum in children with stable cystic fibrosis: comparison with BAL. Author(s): Reinhardt N, Chen CI, Loppow D, Schink T, Kleinau I, Jorres RA, Wahn U, Magnussen H, Paul KP. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 September; 22(3): 497-502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14516141&dopt=Abstract

•

CFTR molecular analysis reveals infrequent allele frequencies in nine cystic fibrosis patients from Sao Paulo State, Brazil. Author(s): Goloni-Bertollo EM, Rossit AR, Junior JB, Fett-Conte AC, Raskin S. Source: Human Biology; an International Record of Research. 2003 June; 75(3): 393-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14527202&dopt=Abstract

•

Clearance of apoptotic cells: TGF-beta in the balance between inflammation and fibrosis. Author(s): Clancy RM, Buyon JP. Source: Journal of Leukocyte Biology. 2003 December; 74(6): 959-60. Epub 2003 September 02. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12960252&dopt=Abstract

•

Combined impact of mucosal damage and of cystic fibrosis on the small intestinal brush border enzyme activities. Author(s): Van Biervliet S, Eggermont E, Marien P, Hoffman I, Veereman G. Source: Acta Clin Belg. 2003 July-August; 58(4): 220-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14635529&dopt=Abstract

•

Commentary on bronchial artery embolization for hemoptysis in young patients with cystic fibrosis. Author(s): Yovichevich S. Source: Radiology. 2003 September; 228(3): 903; Author Reply 903-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954908&dopt=Abstract

Studies 101

•

Computer-assisted quantification of fibrosis in chronic allograft nephropaty by picosirius red-staining: a new tool for predicting long-term graft function. Author(s): Pape L, Henne T, Offner G, Strehlau J, Ehrich JH, Mengel M, Grimm PC. Source: Transplantation. 2003 September 27; 76(6): 955-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14508360&dopt=Abstract

•

Copper enzyme activities in cystic fibrosis before and after copper supplementation plus or minus zinc. Author(s): Best K, McCoy K, Gemma S, Disilvestro RA. Source: Metabolism: Clinical and Experimental. 2004 January; 53(1): 37-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14681839&dopt=Abstract

•

Cruveilhier-Baumgarten syndrome associated with non cirrhotic portal fibrosis. Author(s): Pokhrana RK, Kumar S, Saini K, Kochar DK. Source: Indian J Gastroenterol. 2003 July-August; 22(4): 158. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962454&dopt=Abstract

•

CXC chemokines in vascular remodeling related to pulmonary fibrosis. Author(s): Strieter RM, Belperio JA, Keane MP. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S67-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503558&dopt=Abstract

•

Cyclosporine pharmacokinetics and dose monitoring after lung transplantation: comparison between cystic fibrosis and other conditions. Author(s): Knoop C, Vervier I, Thiry P, De Backer M, Kovarik JM, Rousseau A, Marquet P, Estenne M. Source: Transplantation. 2003 August 27; 76(4): 683-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12973109&dopt=Abstract

•

Cystic fibrosis adult care: consensus conference report. Author(s): Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Source: Chest. 2004 January; 125(1 Suppl): 1S-39S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14734689&dopt=Abstract

•

Cystic fibrosis and NOS3. Author(s): Mekus F, Tummler B. Source: American Journal of Respiratory and Critical Care Medicine. 2004 January 15; 169(2): 319-20; Author Reply 320. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718247&dopt=Abstract

102

Fibrosis

•

Cystic fibrosis newborn screening and detection of carriers. Author(s): Super M. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2003 November; 88(6): F448-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602687&dopt=Abstract

•

Cystic fibrosis patients, infertile men, and their noses. Author(s): Pradal U, Piacentini GL. Source: American Journal of Respiratory and Critical Care Medicine. 2004 January 15; 169(2): 141-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718229&dopt=Abstract

•

Cystic fibrosis: an unusual cause of chronic pancreatitis. Author(s): Vanderbruggen K, De Waele K, Van Biervliet S, Van Der Cruyssen G, Robberecht E. Source: Acta Gastroenterol Belg. 2003 July-September; 66(3): 260-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14618962&dopt=Abstract

•

Cystic fibrosis: cost of illness and considerations for the economic evaluation of potential therapies. Author(s): Krauth C, Jalilvand N, Welte T, Busse R. Source: Pharmacoeconomics. 2003; 21(14): 1001-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13129414&dopt=Abstract

•

Cystic-fibrosis-related diabetes mellitus. Author(s): Freeland BS, Micallef J. Source: Diabetes Educ. 2002 September-October; 28(5): 768-71, 774-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14625963&dopt=Abstract

•

Decreased bone mineral density in normal-growing patients with cystic fibrosis. Author(s): Gronowitz E, Garemo M, Lindblad A, Mellstrom D, Strandvik B. Source: Acta Paediatrica (Oslo, Norway : 1992). 2003 June; 92(6): 688-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856979&dopt=Abstract

•

Defect of hepatocyte growth factor secretion by fibroblasts in idiopathic pulmonary fibrosis. Author(s): Marchand-Adam S, Marchal J, Cohen M, Soler P, Gerard B, Castier Y, Leseche G, Valeyre D, Mal H, Aubier M, Dehoux M, Crestani B. Source: American Journal of Respiratory and Critical Care Medicine. 2003 November 15; 168(10): 1156-61. Epub 2003 August 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12947024&dopt=Abstract

Studies 103

•

Deferiprone and hepatic fibrosis. Author(s): Brittenham GM, Nathan DG, Olivieri NF, Porter JB, Pippard M, Vichinsky EP, Weatherall DJ. Source: Blood. 2003 June 15; 101(12): 5089-90; Author Reply 5090-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788794&dopt=Abstract

•

Detection of cystic fibrosis mutations by peptide mass signature genotyping. Author(s): Malehorn DE, Telmer CA, McEwen SB, An J, Kinsey AD, Retchless AC, Mason C, Vieta WM, Jarvik JW. Source: Clinical Chemistry. 2003 August; 49(8): 1318-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881448&dopt=Abstract

•

Detection of HCV-RNA in bronchoalveolar lavage from a woman with pulmonary fibrosis. Author(s): Brunetti G, Delmastro M, Nava S, Pignatti P, Bossi A, Gatti M, Furione M. Source: Respiratory Medicine. 2003 June; 97(6): 736-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814163&dopt=Abstract

•

Detection of novel CFTR mutations in Taiwanese cystic fibrosis patients. Author(s): Alper OM, Shu SG, Lee MH, Wang BT, Lo SY, Lin KL, Chiu YL, Wong LJ. Source: J Formos Med Assoc. 2003 May; 102(5): 287-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874665&dopt=Abstract

•

Determination of serum fibrosis indexes in patients with chronic hepatitis and its significance. Author(s): Zheng M, Cai W, Weng H, Liu R. Source: Chinese Medical Journal. 2003 March; 116(3): 346-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781034&dopt=Abstract

•

Development of a diagnostic PCR assay that targets a heat-shock protein gene (groES) for detection of Pseudomonas spp. in cystic fibrosis patients. Author(s): Clarke L, Moore JE, Millar BC, Garske L, Xu J, Heuzenroeder MW, Crowe M, Elborn JS. Source: Journal of Medical Microbiology. 2003 September; 52(Pt 9): 759-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909651&dopt=Abstract

•

Development of a Gram-negative selective agar (GNSA) for the detection of Gramnegative microflora in sputa in patients with cystic fibrosis. Author(s): Moore JE, Xu J, Millar BC, Courtney J, Elborn JS. Source: Journal of Applied Microbiology. 2003; 95(1): 160-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807467&dopt=Abstract

104

Fibrosis

•

Development of resistance in Pseudomonas aeruginosa obtained from patients with cystic fibrosis at different times. Author(s): Spencker FB, Staber L, Lietz T, Schille R, Rodloff AC. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2003 May; 9(5): 370-9. Erratum In: Clin Microbiol Infect. 2003 July; 9(7): 759-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848749&dopt=Abstract

•

Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis. Author(s): Enomoto T, Usuki J, Azuma A, Nakagawa T, Kudoh S. Source: Chest. 2003 June; 123(6): 2007-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796182&dopt=Abstract

•

Diagnostic value of platelet derived growth factor-BB, transforming growth factorbeta1, matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinase-1 in serum and peripheral blood mononuclear cells for hepatic fibrosis. Author(s): Zhang BB, Cai WM, Weng HL, Hu ZR, Lu J, Zheng M, Liu RH. Source: World Journal of Gastroenterology : Wjg. 2003 November; 9(11): 2490-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14606082&dopt=Abstract

•

Discussion on genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Author(s): Dray X, Marteau P, Bienvenu T, Dusser D, Hubert D. Source: Gastroenterology. 2003 October; 125(4): 1286. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14552321&dopt=Abstract

•

Distal intestinal obstruction syndrome after surgery in cystic fibrosis. Author(s): Boyle MP, Orens JB. Source: Chest. 2003 December; 124(6): 2408-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14665537&dopt=Abstract

•

Does deficiency of arylsulfatase B have a role in cystic fibrosis? Author(s): Tobacman JK. Source: Chest. 2003 June; 123(6): 2130-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796199&dopt=Abstract

•

Donor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C. Author(s): Machicao VI, Bonatti H, Krishna M, Aqel BA, Lukens FJ, Nguyen JH, Rosser BG, Satyanarayana R, Grewal HP, Hewitt WR, Harnois DM, Crook JE, Steers JL, Dickson RC. Source: Transplantation. 2004 January 15; 77(1): 84-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14724440&dopt=Abstract

Studies 105

•

Drug therapies for reducing gastric acidity in people with cystic fibrosis. Author(s): Ng SM, Jones AP. Source: Cochrane Database Syst Rev. 2003; (2): Cd003424. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804466&dopt=Abstract

•

Duration of effect of intravenous antibiotics on spirometry and sputum cytokines in children with cystic fibrosis. Author(s): Cunningham S, McColm JR, Mallinson A, Boyd I, Marshall TG. Source: Pediatric Pulmonology. 2003 July; 36(1): 43-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12772222&dopt=Abstract

•

Dynamics of bacterial colonisation in the respiratory tract of patients with cystic fibrosis. Author(s): Renders N, Verbrugh H, Van Belkum A. Source: Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. 2001 July; 1(1): 29-39. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798048&dopt=Abstract

•

Dynamics of fibrosis in chronic idiopathic (primary) myelofibrosis during therapy: a follow-up study on 309 patients. Author(s): Thiele J, Kvasnicka HM, Schmitt-Graeff A, Diehl V. Source: Leukemia & Lymphoma. 2003 June; 44(6): 949-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854892&dopt=Abstract

•

Early chemotherapy for non-tuberculous mycobacterial infections in patients with cystic fibrosis. Author(s): Forslow U, Geborek A, Hjelte L, Petrini B, Heurlin N. Source: Acta Paediatrica (Oslo, Norway : 1992). 2003 August; 92(8): 910-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948065&dopt=Abstract

•

Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and interstitial fibrosis in hypertensive kidney transplant patients. Author(s): el-Agroudy AE, Hassan NA, Foda MA, Ismail AM, el-Sawy EA, Mousa O, Ghoneim MA. Source: American Journal of Nephrology. 2003 September-October; 23(5): 300-6. Epub 2003 August 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904684&dopt=Abstract

•

Effect of D-penicillamine on pulmonary fibrosis in patients with systemic sclerosis. Author(s): Jinnin M, Ihn H, Asano Y, Yamane K, Yazawa N, Tamaki K. Source: Annals of the Rheumatic Diseases. 2003 October; 62(10): 1019-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12972489&dopt=Abstract

106

Fibrosis

•

Effect of ibuprofen on neutrophil migration in vivo in cystic fibrosis and healthy subjects. Author(s): Konstan MW, Krenicky JE, Finney MR, Kirchner HL, Hilliard KA, Hilliard JB, Davis PB, Hoppel CL. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 September; 306(3): 1086-91. Epub 2003 June 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807998&dopt=Abstract

•

Effects of pentoxifylline on peritoneal fibroblasts and silica-induced peritoneal fibrosis. Author(s): Fang CC, Lai MN, Chien CT, Hung KY, Tsai CC, Tsai TJ, Hsieh BS. Source: Perit Dial Int. 2003 May-June; 23(3): 228-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12938822&dopt=Abstract

•

Effects of sinus surgery in patients with cystic fibrosis after lung transplantation: a 10-year experience. Author(s): Holzmann D, Speich R, Kaufmann T, Laube I, Russi EW, Simmen D, Weder W, Boehler A. Source: Transplantation. 2004 January 15; 77(1): 134-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14724449&dopt=Abstract

•

Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Author(s): Kral JG, Thung SN, Biron S, Hould FS, Lebel S, Marceau S, Simard S, Marceau P. Source: Surgery. 2004 January; 135(1): 48-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14694300&dopt=Abstract

•

Efficacy of alendronate in adults with cystic fibrosis with low bone density. Author(s): Aris RM, Lester GE, Caminiti M, Blackwood AD, Hensler M, Lark RK, Hecker TM, Renner JB, Guillen U, Brown SA, Neuringer IP, Chalermskulrat W, Ontjes DA. Source: American Journal of Respiratory and Critical Care Medicine. 2004 January 1; 169(1): 77-82. Epub 2003 October 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563654&dopt=Abstract

•

Endogenous fecal losses of calcium compromise calcium balance in pancreaticinsufficient girls with cystic fibrosis. Author(s): Schulze KJ, O'brien KO, Germain-Lee EL, Baer DJ, Leonard AL, Rosenstein BJ. Source: The Journal of Pediatrics. 2003 December; 143(6): 765-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14657825&dopt=Abstract

Studies 107

•

Endomyocardial fibrosis in China. Author(s): Yin R. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 2000 March; 15(1): 55-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899403&dopt=Abstract

•

End-tidal carbon monoxide corrected for lung volume is elevated in patients with cystic fibrosis. Author(s): Terheggen-Lagro SW, Bink MW, Vreman HJ, van der Ent CK. Source: American Journal of Respiratory and Critical Care Medicine. 2003 November 15; 168(10): 1227-31. Epub 2003 September 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12958053&dopt=Abstract

•

Eosinophilic angiocentric fibrosis. Author(s): Tabaee A, Zadeh MH, Proytcheva M, LaBruna A. Source: The Journal of Laryngology and Otology. 2003 May; 117(5): 410-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803796&dopt=Abstract

•

Eosinophilic angiocentric fibrosis: an unusual entity of the sinonasal tract. Author(s): Onder S, Sungur A. Source: Archives of Pathology & Laboratory Medicine. 2004 January; 128(1): 90-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14692804&dopt=Abstract

•

Epithelial-mesenchymal transition and its implications for fibrosis. Author(s): Kalluri R, Neilson EG. Source: The Journal of Clinical Investigation. 2003 December; 112(12): 1776-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14679171&dopt=Abstract

•

Evidence based guidelines for the performance of the sweat test for the investigation of cystic fibrosis in the UK. Author(s): Baumer JH. Source: Archives of Disease in Childhood. 2003 December; 88(12): 1126-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14670787&dopt=Abstract

•

Evidence for newborn screening for cystic fibrosis. Author(s): Castellani C. Source: Paediatric Respiratory Reviews. 2003 December; 4(4): 278-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14629949&dopt=Abstract

108

Fibrosis

•

Evidence of transmission of Burkholderia cepacia, Burkholderia multivorans and Burkholderia dolosa among persons with cystic fibrosis. Author(s): Biddick R, Spilker T, Martin A, LiPuma JJ. Source: Fems Microbiology Letters. 2003 November 7; 228(1): 57-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612237&dopt=Abstract

•

Exercise testing in children with cystic fibrosis. Author(s): Rogers D, Prasad SA, Doull I. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 23-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906322&dopt=Abstract

•

Expansion and uncertainty: cystic fibrosis, classification and genetics. Author(s): Hedgecoe AM. Source: Sociology of Health & Illness. 2003 January; 25(1): 50-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14498944&dopt=Abstract

•

External iliac endofibrosis in endurance athletes: a novel case in an endurance runner and a review of the literature. Author(s): Ford SJ, Rehman A, Bradbury AW. Source: European Journal of Vascular and Endovascular Surgery : the Official Journal of the European Society for Vascular Surgery. 2003 December; 26(6): 629-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14603423&dopt=Abstract

•

Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection. Author(s): Wright M, Goldin R, Hellier S, Knapp S, Frodsham A, Hennig B, Hill A, Apple R, Cheng S, Thomas H, Thursz M. Source: Gut. 2003 August; 52(8): 1206-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865283&dopt=Abstract

•

Factors that influence and contribute to the regulation of fibrosis. Author(s): Razzaque MS, Taguchi T. Source: Contrib Nephrol. 2003; 139: 1-11. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854314&dopt=Abstract

•

Family life and the daily cystic fibrosis routine. Author(s): David TJ. Source: Journal of the Royal Society of Medicine. 2003 July; 96(7): 317. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835440&dopt=Abstract

Studies 109

•

Fatal interstitial pulmonary fibrosis in anti-Jo-1-negative amyopathic dermatomyositis. Author(s): High WA, Cohen JB, Murphy BA, Costner MI. Source: Journal of the American Academy of Dermatology. 2003 August; 49(2): 295-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894081&dopt=Abstract

•

Fatty acid metabolism in cystic fibrosis. Author(s): Strandvik B. Source: The New England Journal of Medicine. 2004 February 5; 350(6): 605-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14762189&dopt=Abstract

•

Fatty acids composition of plasma phospholipids and triglycerides in children with cystic fibrosis. The effect of dietary supplementation with an olive and soybean oils mixture. Author(s): Caramia G, Cocchi M, Gagliardini R, Malavolta M, Mozzon M, Frega NG. Source: Pediatr Med Chir. 2003 January-February; 25(1): 42-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920976&dopt=Abstract

•

FCP (http://fibro.biobitfield.com/fcp.php): a bioinformatic tool assisting in PubMed searches for literature on fibrosis-related cytokines. Author(s): Atamas SP. Source: Arthritis and Rheumatism. 2003 July; 48(7): 2083-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847712&dopt=Abstract

•

Fibroblast phenotypes in pulmonary fibrosis. Author(s): Phan SH. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S87-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503563&dopt=Abstract

•

Fibrosis and inflammatory activity in noncancerous tissue and mitotic index of cancer tissue in patients with hepatocellular carcinoma: relationship to clinicopathological factors and prognosis after hepatic resection. Author(s): Nanashima A, Tanaka K, Yamaguchi H, Shibasaki S, Morino S, Yoshinaga M, Sawai T, Nakagoe T, Ayabe H. Source: Digestive Diseases and Sciences. 2003 August; 48(8): 1517-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12924646&dopt=Abstract

•

Fibrosis in hypertensive heart disease: role of the renin-angiotensin-aldosterone system. Author(s): Gonzalez A, Lopez B, Diez J. Source: The Medical Clinics of North America. 2004 January; 88(1): 83-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14871052&dopt=Abstract

110

Fibrosis

•

Fibrosis in ocular allergic inflammation: recent concepts in the pathogenesis of ocular allergy. Author(s): Solomon A, Puxeddu I, Levi-Schaffer F. Source: Current Opinion in Allergy and Clinical Immunology. 2003 October; 3(5): 38993. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501440&dopt=Abstract

•

Fibrosis in scleroderma. Author(s): Kissin EY, Korn JH. Source: Rheumatic Diseases Clinics of North America. 2003 May; 29(2): 351-69. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841299&dopt=Abstract

•

Fibrosis of the upper lobes: a newly identified late-onset complication after lung transplantation? Author(s): Konen E, Weisbrod GL, Pakhale S, Chung T, Paul NS, Hutcheon MA. Source: Ajr. American Journal of Roentgenology. 2003 December; 181(6): 1539-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14627569&dopt=Abstract

•

Fibrosis-associated gene expression in renal transplant glomeruli after acute renal allograft rejection. Author(s): Brook NR, White SA, Waller JR, Bicknell GR, Nicholson ML. Source: The British Journal of Surgery. 2003 August; 90(8): 1009-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905557&dopt=Abstract

•

Five-year prospective analysis of dietary intake and clinical status in malnourished cystic fibrosis patients. Author(s): Walkowiak J, Przyslawski J. Source: Journal of Human Nutrition and Dietetics : the Official Journal of the British Dietetic Association. 2003 August; 16(4): 225-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859704&dopt=Abstract

•

Fluorescent in situ hybridization (FISH) of the FHIT gene in idiopathic pulmonary fibrosis (IPF) lesions. Author(s): Uematsu K, Yoshimura A, Gemma A, Hosoya Y, Kudoh S. Source: Journal of Nippon Medical School = Nihon Ika Daigaku Zasshi. 2003 August; 70(4): 298-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12928708&dopt=Abstract

•

Focal fatty sparing of the pancreatic head in cystic fibrosis: CT findings. Author(s): Carucci LR, Jacobs JE. Source: Abdominal Imaging. 2003 November-December; 28(6): 853-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14753605&dopt=Abstract

Studies 111

•

Forestalling fibrosis. Author(s): Ingelfinger JR. Source: The New England Journal of Medicine. 2003 December 4; 349(23): 2265-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14657436&dopt=Abstract

•

Free secretory component from cystic fibrosis sputa displays the cystic fibrosis glycosylation phenotype. Author(s): Marshall LJ, Perks B, Bodey K, Suri R, Bush A, Shute JK. Source: American Journal of Respiratory and Critical Care Medicine. 2004 February 1; 169(3): 399-406. Epub 2003 November 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597481&dopt=Abstract

•

Function and bulk of respiratory and limb muscles in patients with cystic fibrosis. Author(s): Pinet C, Cassart M, Scillia P, Lamotte M, Knoop C, Casimir G, Melot C, Estenne M. Source: American Journal of Respiratory and Critical Care Medicine. 2003 October 15; 168(8): 989-94. Epub 2003 June 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829457&dopt=Abstract

•

Genetic counseling in assisted reproduction: a case of cystic fibrosis identified after two successful intracytoplasmic sperm-injection pregnancies. Author(s): Kujat A, Alexander H, Glander HJ, Froster UG. Source: Archives of Andrology. 2003 May-June; 49(3): 165-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746094&dopt=Abstract

•

Genetic factors in idiopathic pulmonary fibrosis: transforming growth factor-beta implicated at last. Author(s): Whyte MK. Source: American Journal of Respiratory and Critical Care Medicine. 2003 August 15; 168(4): 410-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912730&dopt=Abstract

•

Genetic features of Pseudomonas aeruginosa isolates from cystic fibrosis patients compared with those of isolates from other origins. Author(s): Lanotte P, Watt S, Mereghetti L, Dartiguelongue N, Rastegar-Lari A, Goudeau A, Quentin R. Source: Journal of Medical Microbiology. 2004 January; 53(Pt 1): 73-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14663109&dopt=Abstract

112

Fibrosis

•

Genetic testing for cystic fibrosis: a personal perspective. Author(s): Tomlinson SP. Source: Harv J Law Technol. 1998 Summer; 11(3): 551-64. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731545&dopt=Abstract

•

Genome mosaicism is conserved but not unique in Pseudomonas aeruginosa isolates from the airways of young children with cystic fibrosis. Author(s): Ernst RK, D'Argenio DA, Ichikawa JK, Bangera MG, Selgrade S, Burns JL, Hiatt P, McCoy K, Brittnacher M, Kas A, Spencer DH, Olson MV, Ramsey BW, Lory S, Miller SI. Source: Environmental Microbiology. 2003 December; 5(12): 1341-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14641578&dopt=Abstract

•

Genomovar distribution of the Burkholderia cepacia complex differs significantly between Czech and Slovak patients with cystic fibrosis. Author(s): Drevinek P, Cinek O, Melter J, Langsadl L, Navesnakova Y, Vavrova V. Source: Journal of Medical Microbiology. 2003 July; 52(Pt 7): 603-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12808084&dopt=Abstract

•

Genomovar diversity amongst Burkholderia cepacia complex isolates from an Australian adult cystic fibrosis unit. Author(s): Kidd TJ, Bell SC, Coulter C. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 July; 22(7): 434-7. Epub 2003 June 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884074&dopt=Abstract

•

Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. Author(s): Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, Bebok Z, Shushi L, Kerem B, Kerem E. Source: The New England Journal of Medicine. 2003 October 9; 349(15): 1433-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14534336&dopt=Abstract

•

Grading and staging of hepatic fibrosis, and its relationship with noninvasive diagnostic parameters. Author(s): Lu LG, Zeng MD, Wan MB, Li CZ, Mao YM, Li JQ, Qiu DK, Cao AP, Ye J, Cai X, Chen CW, Wang JY, Wu SM, Zhu JS, Zhou XQ. Source: World Journal of Gastroenterology : Wjg. 2003 November; 9(11): 2574-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14606100&dopt=Abstract

Studies 113

•

Growing up and living with cystic fibrosis: everyday life and encounters with the health care and social services--a qualitative study. Author(s): Gjengedal E, Rustoen T, Wahl AK, Hanesta BR. Source: Ans. Advances in Nursing Science. 2003 April-June; 26(2): 149-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795543&dopt=Abstract

•

Growing up with chronic illness: psychosocial adjustment of children and adolescents with cystic fibrosis. Author(s): Christian B. Source: Annu Rev Nurs Res. 2003; 21: 151-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858696&dopt=Abstract

•

Growth and growth charts in cystic fibrosis. Author(s): Patel L, Dixon M, David TJ. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 35-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906324&dopt=Abstract

•

Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. Author(s): Konstan MW, Butler SM, Wohl ME, Stoddard M, Matousek R, Wagener JS, Johnson CA, Morgan WJ; Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Source: The Journal of Pediatrics. 2003 June; 142(6): 624-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838189&dopt=Abstract

•

Growth factors in cystic fibrosis - when more is not enough. Author(s): Shute J, Marshall L, Bodey K, Bush A. Source: Paediatric Respiratory Reviews. 2003 June; 4(2): 120-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758049&dopt=Abstract

•

Growth failure and diabetes in cystic fibrosis: have you considered Turner syndrome? Author(s): Steppberger K, Schuster V, Kiess W. Source: Acta Paediatrica (Oslo, Norway : 1992). 2003 September; 92(9): 1111. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14599080&dopt=Abstract

•

Hepatic fibrosis and survival in biliary atresia. Author(s): Weerasooriya VS, White FV, Shepherd RW. Source: The Journal of Pediatrics. 2004 January; 144(1): 123-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14722530&dopt=Abstract

114

Fibrosis

•

Hepatic stellate cells (HSC): architects of hepatic fibrosis. Author(s): Solis-Herruzo JA, de la Torre P, Munoz-Yague MT. Source: Rev Esp Enferm Dig. 2003 June; 95(6): 438-9, 436-7. English, Spanish. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918537&dopt=Abstract

•

Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis, and liver fibrosis. Author(s): Petit JM, Benichou M, Duvillard L, Jooste V, Bour JB, Minello A, Verges B, Brun JM, Gambert P, Hillon P. Source: The American Journal of Gastroenterology. 2003 May; 98(5): 1150-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809841&dopt=Abstract

•

Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. Author(s): Tang YW, Johnson JE, Browning PJ, Cruz-Gervis RA, Davis A, Graham BS, Brigham KL, Oates JA Jr, Loyd JE, Stecenko AA. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2633-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791891&dopt=Abstract

•

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Author(s): Yamada K, Andrews C, Chan WM, McKeown CA, Magli A, de Berardinis T, Loewenstein A, Lazar M, O'Keefe M, Letson R, London A, Ruttum M, Matsumoto N, Saito N, Morris L, Del Monte M, Johnson RH, Uyama E, Houtman WA, de Vries B, Carlow TJ, Hart BL, Krawiecki N, Shoffner J, Vogel MC, Katowitz J, Goldstein SM, Levin AV, Sener EC, Ozturk BT, Akarsu AN, Brodsky MC, Hanisch F, Cruse RP, Zubcov AA, Robb RM, Roggenkaemper P, Gottlob I, Kowal L, Battu R, Traboulsi EI, Franceschini P, Newlin A, Demer JL, Engle EC. Source: Nature Genetics. 2003 December; 35(4): 318-21. Epub 2003 November 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14595441&dopt=Abstract

•

Hidden depletion of fat-free mass and bone mineral density in adults with cystic fibrosis. Author(s): Ionescu AA, Evans WD, Pettit RJ, Nixon LS, Stone MD, Shale DJ. Source: Chest. 2003 December; 124(6): 2220-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14665504&dopt=Abstract

•

High rate of macrolide resistance in Staphylococcus aureus strains from patients with cystic fibrosis reveals high proportions of hypermutable strains. Author(s): Prunier AL, Malbruny B, Laurans M, Brouard J, Duhamel JF, Leclercq R. Source: The Journal of Infectious Diseases. 2003 June 1; 187(11): 1709-16. Epub 2003 May 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12751028&dopt=Abstract

Studies 115

•

High-resolution CT of asbestosis and idiopathic pulmonary fibrosis. Author(s): Akira M, Yamamoto S, Inoue Y, Sakatani M. Source: Ajr. American Journal of Roentgenology. 2003 July; 181(1): 163-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818850&dopt=Abstract

•

High-resolution CT: what is it good for in pulmonary fibrosis? Author(s): Wilcox A. Source: Current Opinion in Pulmonary Medicine. 2003 September; 9(5): 431-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904716&dopt=Abstract

•

Hodgkin's disease of bone marrow masquerading as a heavy plasma cell infiltration and fibrosis. Author(s): Joshi A, Aqel NM. Source: British Journal of Haematology. 2003 August; 122(3): 343. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12877660&dopt=Abstract

•

Holistic approach of a child with cystic fibrosis: a case report. Author(s): da Costa CC, Cardoso L, de Carvalho Rocha MJ. Source: J Dent Child (Chic). 2003 January-April; 70(1): 86-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762618&dopt=Abstract

•

Hypothesis: vitamin E complements polyunsaturated fatty acids in essential fatty acid deficiency in cystic fibrosis. Author(s): Wood LG, Fitzgerald DA, Garg ML. Source: Journal of the American College of Nutrition. 2003 August; 22(4): 253-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897038&dopt=Abstract

•

Idiopathic pulmonary fibrosis in transplantation. Author(s): Jankowich MD. Source: Chest. 2003 December; 124(6): 2404; Author Reply 2404-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14665532&dopt=Abstract

•

Idiopathic pulmonary fibrosis. New insights into classification and pathogenesis usher in a new era therapeutic approaches. Author(s): Noble PW. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S27-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503550&dopt=Abstract

116

Fibrosis

•

Idiopathic pulmonary fibrosis: current and future treatment options. Author(s): Davies HR, Richeldi L. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2002; 1(3): 211-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14720059&dopt=Abstract

•

Idiopathic pulmonary fibrosis: the inflammation hypothesis revisited. Author(s): Kamp DW. Source: Chest. 2003 October; 124(4): 1187-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555542&dopt=Abstract

•

Idiopathic pulmonary fibrosis--a disorder of alveolar wound repair? Author(s): Geiser T. Source: Swiss Medical Weekly : Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology. 2003 July 26; 133(29-30): 405-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14562190&dopt=Abstract

•

IFN-gamma polymorphisms (IFN-gamma +2109 and IFN-gamma +3810) are associated with severe hepatic fibrosis in human hepatic schistosomiasis (Schistosoma mansoni). Author(s): Chevillard C, Moukoko CE, Elwali NE, Bream JH, Kouriba B, Argiro L, Rahoud S, Mergani A, Henri S, Gaudart J, Mohamed-Ali Q, Young HA, Dessein AJ. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 November 15; 171(10): 5596-601. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14607968&dopt=Abstract

•

Images in clinical medicine. Progression of idiopathic pulmonary fibrosis. Author(s): Abou Jawde RM, Al-Ashkar F. Source: The New England Journal of Medicine. 2004 January 8; 350(2): 165. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14711915&dopt=Abstract

•

Imatinib mesylate in idiopathic and postpolycythemic myelofibrosis. Author(s): Hasselbalch HC, Bjerrum OW, Jensen BA, Clausen NT, Hansen PB, Birgens H, Therkildsen MH, Ralfkiaer E. Source: American Journal of Hematology. 2003 December; 74(4): 238-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14635203&dopt=Abstract

Studies 117

•

Immunosuppressive therapy for idiopathic retroperitoneal fibrosis: a retrospective analysis of 26 cases. Author(s): Marcolongo R, Tavolini IM, Laveder F, Busa M, Noventa F, Bassi P, Semenzato G. Source: The American Journal of Medicine. 2004 February 1; 116(3): 194-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14749165&dopt=Abstract

•

Implications of carrier identification in newborn screening for cystic fibrosis. Author(s): Parsons EP, Clarke AJ, Bradley DM. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2003 November; 88(6): F467-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602692&dopt=Abstract

•

In celebration of expectoration: induced sputum indices as outcome measures in cystic fibrosis. Author(s): Armstrong DS. Source: American Journal of Respiratory and Critical Care Medicine. 2003 December 15; 168(12): 1412-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14668253&dopt=Abstract

•

Incidence and predictors of severe liver fibrosis in human immunodeficiency virusinfected patients with chronic hepatitis C: a European collaborative study. Author(s): Martin-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Quereda C, Arizcorreta A, Gonzalez A, Rockstroh J, Asensi V, Miralles P, Laguno M, Moreno L, Giron JA, Vogel M, Garcia-Samaniego J, Nunez M, Romero M, Moreno S, de la Cruz JJ, Soriano V. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2004 January 1; 38(1): 128-33. Epub 2003 December 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14679458&dopt=Abstract

•

Increased plasma homocysteine and S-adenosylhomocysteine and decreased methionine is associated with altered phosphatidylcholine and phosphatidylethanolamine in cystic fibrosis. Author(s): Innis SM, Davidson AG, Chen A, Dyer R, Melnyk S, James SJ. Source: The Journal of Pediatrics. 2003 September; 143(3): 351-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517519&dopt=Abstract

•

Individualized daily schedules for hospitalized adolescents with cystic fibrosis. Author(s): Weiland J, Schoettker PJ, Byczkowski T, Britto MT, Pandzik G, Kotagal UR. Source: Journal of Pediatric Health Care : Official Publication of National Association of Pediatric Nurse Associates & Practitioners. 2003 November-December; 17(6): 284-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14610441&dopt=Abstract

118

Fibrosis

•

Inflammatory markers in cystic fibrosis patients with transmissible Pseudomonas aeruginosa. Author(s): Jones AM, Martin L, Bright-Thomas RJ, Dodd ME, McDowell A, Moffitt KL, Elborn JS, Webb AK. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 September; 22(3): 503-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14516142&dopt=Abstract

•

Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression. Author(s): Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan GW, George J. Source: Gastroenterology. 2003 December; 125(6): 1695-704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14724822&dopt=Abstract

•

Insulin-like growth factor I correlates with lean body mass in cystic fibrosis patients. Author(s): Sermet-Gaudelus I, Souberbielle JC, Azhar I, Ruiz JC, Magnine P, Colomb V, Le Bihan C, Folio D, Lenoir G. Source: Archives of Disease in Childhood. 2003 November; 88(11): 956-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612353&dopt=Abstract

•

Interferon-gamma response by peripheral blood mononuclear cells to hepatitis C virus core antigen is reduced in patients with liver fibrosis. Author(s): Watson MW, Jaksic A, Price P, Cheng W, McInerney M, French MA, Fisher S, Lee S, Flexman JP. Source: The Journal of Infectious Diseases. 2003 November 15; 188(10): 1533-6. Epub 2003 Nov 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14624379&dopt=Abstract

•

Interferon-gamma toxicity in idiopathic pulmonary fibrosis. Author(s): O'Connor TM, Bredin CP. Source: American Journal of Respiratory and Critical Care Medicine. 2004 February 1; 169(3): 428. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14739137&dopt=Abstract

•

Interstitial nephritis associated with perianeurysmal retroperitoneal fibrosis. Author(s): Igbokwe UO, Barnard SM, Marshall RJ, Parry RG. Source: Clinical Nephrology. 2003 September; 60(3): 201-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14524584&dopt=Abstract

Studies 119

•

Laboratory aspects of management of chronic pulmonary infections in patients with cystic fibrosis. Author(s): Miller MB, Gilligan PH. Source: Journal of Clinical Microbiology. 2003 September; 41(9): 4009-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12958218&dopt=Abstract

•

Laboratory tests for the diagnosis of cystic fibrosis. Author(s): Wang L, Freedman SD. Source: American Journal of Clinical Pathology. 2002 June; 117 Suppl: S109-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14569807&dopt=Abstract

•

Laminin-5 gamma2 chain in cryptogenic organizing pneumonia and idiopathic pulmonary fibrosis. Author(s): Lappi-Blanco E, Kaarteenaho-Wiik R, Salo S, Sormunen R, Maatta M, AutioHarmainen H, Soini Y, Paakko P. Source: American Journal of Respiratory and Critical Care Medicine. 2004 January 1; 169(1): 27-33. Epub 2003 September 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500258&dopt=Abstract

•

Late radiation-related fibrosis: pathogenesis, manifestations, and current management. Author(s): O'Sullivan B, Levin W. Source: Seminars in Radiation Oncology. 2003 July; 13(3): 274-89. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12903016&dopt=Abstract

•

Lean body mass in children with cystic fibrosis. Author(s): Sood M, Adams JE, Mughal MZ. Source: Archives of Disease in Childhood. 2003 September; 88(9): 836. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937118&dopt=Abstract

•

Left ventricular diastolic function in patients with advanced cystic fibrosis. Author(s): Koelling TM, Dec GW, Ginns LC, Semigran MJ. Source: Chest. 2003 May; 123(5): 1488-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12740265&dopt=Abstract

•

Life on a slippery slope: perceptions of health in adults with cystic fibrosis. Author(s): Lowton K, Gabe J. Source: Sociology of Health & Illness. 2003 May; 25(4): 289-319. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14498923&dopt=Abstract

120

Fibrosis

•

Linezolid pharmacokinetics in adult patients with cystic fibrosis. Author(s): Bosso JA, Flume PA, Gray SL. Source: Antimicrobial Agents and Chemotherapy. 2004 January; 48(1): 281-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14693551&dopt=Abstract

•

Liver cirrhosis and portal hypertension in cystic fibrosis. Author(s): Efrati O, Barak A, Modan-Moses D, Augarten A, Vilozni D, Katznelson D, Szeinberg A, Yahav J, Bujanover Y. Source: European Journal of Gastroenterology & Hepatology. 2003 October; 15(10): 10738. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501614&dopt=Abstract

•

Liver fibrosis grade classification with B-mode ultrasound. Author(s): Yeh WC, Huang SW, Li PC. Source: Ultrasound in Medicine & Biology. 2003 September; 29(9): 1229-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14553797&dopt=Abstract

•

Liver fibrosis in chronic viral hepatitis: an ultrasonographic study. Author(s): Zheng RQ, Wang QH, Lu MD, Xie SB, Ren J, Su ZZ, Cai YK, Yao JL. Source: World Journal of Gastroenterology : Wjg. 2003 November; 9(11): 2484-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14606081&dopt=Abstract

•

Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C. Author(s): Asselah T, Boyer N, Guimont MC, Cazals-Hatem D, Tubach F, Nahon K, Daikha H, Vidaud D, Martinot M, Vidaud M, Degott C, Valla D, Marcellin P. Source: Gut. 2003 November; 52(11): 1638-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14570735&dopt=Abstract

•

Liver histology and progression of fibrosis in individuals with chronic hepatitis C and persistently normal ALT. Author(s): Kyrlagkitsis I, Portmann B, Smith H, O'Grady J, Cramp ME. Source: The American Journal of Gastroenterology. 2003 July; 98(7): 1588-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873583&dopt=Abstract

•

Liver transplantation in children with cystic fibrosis: a long-term longitudinal review of a single center's experience. Author(s): Fridell JA, Bond GJ, Mazariegos GV, Orenstein DM, Jain A, Sindhi R, Finder JD, Molmenti E, Reyes J. Source: Journal of Pediatric Surgery. 2003 August; 38(8): 1152-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891484&dopt=Abstract

Studies 121

•

Liver ultrasound and faecal copper estimation in oral submucous fibrosis. Author(s): Rajendran R, Kumari KR, Kumar AS. Source: Indian J Dent Res. 2003 January-March; 14(1): 13-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800753&dopt=Abstract

•

Longitudinal changes in growth parameters are correlated with changes in pulmonary function in children with cystic fibrosis. Author(s): Peterson ML, Jacobs DR Jr, Milla CE. Source: Pediatrics. 2003 September; 112(3 Pt 1): 588-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12949289&dopt=Abstract

•

Longitudinal determinants of peak aerobic performance in children with cystic fibrosis. Author(s): Klijn PH, van der Net J, Kimpen JL, Helders PJ, van der Ent CK. Source: Chest. 2003 December; 124(6): 2215-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14665503&dopt=Abstract

•

Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis. Author(s): Farrell PM, Li Z, Kosorok MR, Laxova A, Green CG, Collins J, Lai HC, Makholm LM, Rock MJ, Splaingard ML. Source: Pediatric Pulmonology. 2003 September; 36(3): 230-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12910585&dopt=Abstract

•

Low-dose radiotherapy for the inhibition of peridural fibrosis after reexploratory nerve root decompression for postlaminectomy syndrome. Author(s): Gerszten PC, Moossy JJ, Flickinger JC, Welch WC. Source: Journal of Neurosurgery. 2003 October; 99(3 Suppl): 271-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563144&dopt=Abstract

•

Lung function impairment in relation to asbestos-induced pleural lesions with reference to the extent of the lesions and the initial parenchymal fibrosis. Author(s): Lebedova J, Dlouha B, Rychla L, Neuwirth J, Brabec M, Pelclova D, Fenclova Z. Source: Scand J Work Environ Health. 2003 October; 29(5): 388-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14584519&dopt=Abstract

•

Macrolide antibiotics for cystic fibrosis. Author(s): Southern KW, Barker PM, Solis A. Source: Cochrane Database Syst Rev. 2003; (3): Cd002203. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917924&dopt=Abstract

122

Fibrosis

•

Macrolides in cystic fibrosis: is there a role? Author(s): Wolter JM, Seeney SL, McCormack JG. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2002; 1(4): 235-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14720043&dopt=Abstract

•

Marrow fibrosis, indicator of therapy failure in chronic myeloid leukemia prospective long-term results from a randomized-controlled trial. Author(s): Buesche G, Hehlmann R, Hecker H, Heimpel H, Heinze B, Schmeil A, Pfirrmann M, Gomez G, Tobler A, Herrmann H, Kappler M, Hasford J, Buhr T, Kreipe HH, Georgii A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 December; 17(12): 2444-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14562117&dopt=Abstract

•

Mast cells and tubulointerstitial fibrosis in patients with ANCA-associated glomerulonephritis. Author(s): Otsubo S, Nitta K, Uchida K, Yumura W, Nihei H. Source: Clinical and Experimental Nephrology. 2003 March; 7(1): 41-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14586742&dopt=Abstract

•

Methicillin-resistant Staphylococcus aureus in children with cystic fibrosis: An eradication protocol. Author(s): Solis A, Brown D, Hughes J, Van Saene HK, Heaf DP. Source: Pediatric Pulmonology. 2003 September; 36(3): 189-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12910579&dopt=Abstract

•

Microarray analysis of idiopathic pulmonary fibrosis. Author(s): Kaminski N. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S32-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503551&dopt=Abstract

•

Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL. Author(s): Cheng J, Wang H, Guggino WB. Source: The Journal of Biological Chemistry. 2004 January 16; 279(3): 1892-8. Epub 2003 October 21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14570915&dopt=Abstract

Studies 123

•

Molecular analysis of Burkholderia cepacia complex isolates from a Portuguese cystic fibrosis center: a 7-year study. Author(s): Cunha MV, Leitao JH, Mahenthiralingam E, Vandamme P, Lito L, Barreto C, Salgado MJ, Sa-Correia I. Source: Journal of Clinical Microbiology. 2003 September; 41(9): 4113-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12958234&dopt=Abstract

•

Molecular characterization of Burkholderia cepacia isolates from cystic fibrosis (CF) patients in an Italian CF center. Author(s): Petrucca A, Cipriani P, Valenti P, Santapaola D, Cimmino C, Scoarughi GL, Santino I, Stefani S, Sessa R, Nicoletti M. Source: Research in Microbiology. 2003 September; 154(7): 491-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14499935&dopt=Abstract

•

Molecular comparison of isolates of Burkholderia multivorans from patients with cystic fibrosis in the United Kingdom. Author(s): Turton JF, Kaufmann ME, Mustafa N, Kawa S, Clode FE, Pitt TL. Source: Journal of Clinical Microbiology. 2003 December; 41(12): 5750-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14662975&dopt=Abstract

•

Molecular diagnosis of cystic fibrosis in South African populations. Author(s): Goldman A, Graf C, Ramsay M, Leisegang F, Westwood AT. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2003 July; 93(7): 518-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939925&dopt=Abstract

•

Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Author(s): Klion AD, Robyn J, Akin C, Noel P, Brown M, Law M, Metcalfe DD, Dunbar C, Nutman TB. Source: Blood. 2004 January 15; 103(2): 473-8. Epub 2003 September 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14504092&dopt=Abstract

•

Molecular targets in drugs discovery in idiopathic pulmonary fibrosis. Work in progress. Author(s): Bitterman PB. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S98-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503565&dopt=Abstract

124

Fibrosis

•

Molecular typing of the bacterial flora in sputum of cystic fibrosis patients. Author(s): Kolak M, Karpati F, Monstein HJ, Jonasson J. Source: International Journal of Medical Microbiology : Ijmm. 2003 August; 293(4): 30917. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503795&dopt=Abstract

•

Mothers in postdivorce families caring for a child with cystic fibrosis. Author(s): Ganong L, Doty ME, Gayer D. Source: Journal of Pediatric Nursing. 2003 October; 18(5): 332-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14569581&dopt=Abstract

•

MR imaging findings of bone marrow changes in patients with cystic fibrosis. Author(s): De Maeseneer M, Desprechins B, Dab I, Machiels F, Shahabpour M, Osteaux M. Source: Jbr-Btr. 2003 September-October; 86(5): 265-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14651080&dopt=Abstract

•

Multicenter characterization and validation of the intron-8 poly(T) tract (IVS8-T) status in 25 Coriell cell repository cystic fibrosis reference cell lines for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation assays. Author(s): Sebastian S, Spitzer SG, Grosso LE, Amos J, Schaefer FV, Lyon E, Wolff DJ, Hajianpour A, Taylor AK, Millson A, Stenzel TT. Source: Clinical Chemistry. 2004 January; 50(1): 251-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14709668&dopt=Abstract

•

Muscle function and resting energy expenditure in female athletes with cystic fibrosis. Author(s): Selvadurai HC, Allen J, Sachinwalla T, Macauley J, Blimkie CJ, Van Asperen PP. Source: American Journal of Respiratory and Critical Care Medicine. 2003 December 15; 168(12): 1476-80. Epub 2003 September 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500260&dopt=Abstract

•

Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Author(s): Olbrich H, Fliegauf M, Hoefele J, Kispert A, Otto E, Volz A, Wolf MT, Sasmaz G, Trauer U, Reinhardt R, Sudbrak R, Antignac C, Gretz N, Walz G, Schermer B, Benzing T, Hildebrandt F, Omran H. Source: Nature Genetics. 2003 August; 34(4): 455-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12872122&dopt=Abstract

Studies 125

•

Myelofibrosis with myeloid metaplasia. Author(s): Barosi G. Source: Hematology/Oncology Clinics of North America. 2003 October; 17(5): 1211-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14560783&dopt=Abstract

•

NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. Author(s): Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA. Source: The Journal of Clinical Investigation. 2003 November; 112(9): 1383-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597764&dopt=Abstract

•

Nasal airway ion transport and lung function in young people with cystic fibrosis. Author(s): Wallace HL, Barker PM, Southern KW. Source: American Journal of Respiratory and Critical Care Medicine. 2003 September 1; 168(5): 594-600. Epub 2003 June 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829453&dopt=Abstract

•

Natural history of glucose tolerance, beta-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia. Author(s): Lombardo F, De Luca F, Rosano M, Sferlazzas C, Lucanto C, Arrigo T, Messina MF, Crisafulli G, Wasniewska M, Valenzise M, Cucinotta D. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 July; 149(1): 53-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824866&dopt=Abstract

•

Natural history of pancreatitis associated with cystic fibrosis gene mutations. Author(s): Frulloni L, Castellani C, Bovo P, Vaona B, Calore B, Liani C, Mastella G, Cavallini G. Source: Dig Liver Dis. 2003 March; 35(3): 179-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779072&dopt=Abstract

•

Nebulised anti-pseudomonal antibiotics for cystic fibrosis. Author(s): Ryan G, Mukhopadhyay S, Singh M. Source: Cochrane Database Syst Rev. 2003; (3): Cd001021. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917897&dopt=Abstract

•

Neutrophilic inflammation in induced sputum of patients with idiopathic pulmonary fibrosis. Author(s): Beeh KM, Beier J, Kornmann O, Buhl R. Source: Sarcoidosis Vasc Diffuse Lung Dis. 2003 June; 20(2): 138-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870724&dopt=Abstract

126

Fibrosis

•

Newborn screening for cystic fibrosis. Author(s): Wagener JS, Sontag MK, Accurso FJ. Source: Current Opinion in Pediatrics. 2003 June; 15(3): 309-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806263&dopt=Abstract

•

Newborn screening for cystic fibrosis. Author(s): Parad RB, Comeau AM. Source: Pediatric Annals. 2003 August; 32(8): 528-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12942895&dopt=Abstract

•

Newborn screening for cystic fibrosis: ensuring more good than harm. Author(s): Farrell MH, Farrell PM. Source: The Journal of Pediatrics. 2003 December; 143(6): 707-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14657812&dopt=Abstract

•

Newborn screening methods for cystic fibrosis. Author(s): Wilcken B, Wiley V. Source: Paediatric Respiratory Reviews. 2003 December; 4(4): 272-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14629948&dopt=Abstract

•

Newborn screening programmes for cystic fibrosis. Author(s): Southern KW, Littlewood JM. Source: Paediatric Respiratory Reviews. 2003 December; 4(4): 299-305. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14629952&dopt=Abstract

•

No evidence for a major effect of tumor necrosis factor alpha gene polymorphisms in periportal fibrosis caused by Schistosoma mansoni infection. Author(s): Moukoko CE, El Wali N, Saeed OK, Mohamed-Ali Q, Gaudart J, Dessein AJ, Chevillard C. Source: Infection and Immunity. 2003 October; 71(10): 5456-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500462&dopt=Abstract

•

Non invasive mechanical ventilation in cystic fibrosis: physiological effects and monitoring. Author(s): Fauroux B, Hart N, Lofaso F. Source: Monaldi Arch Chest Dis. 2002 October-December; 57(5-6): 268-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814039&dopt=Abstract

•

Non-cirrhotic portal fibrosis (NCPF) is a vanishing disease in India. Author(s): Chawla Y, Duseja A. Source: Trop Gastroenterol. 2003 April-June; 24(2): 45-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14603819&dopt=Abstract

Studies 127

•

Noninvasive diagnosis of fibrosis: the truth is rarely pure and never simple. Author(s): Giannini E, Testa R. Source: Hepatology (Baltimore, Md.). 2003 November; 38(5): 1312-3; Author Reply 1313. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578874&dopt=Abstract

•

Non-invasive ventilation assists chest physiotherapy in adults with acute exacerbations of cystic fibrosis. Author(s): Holland AE, Denehy L, Ntoumenopoulos G, Naughton MT, Wilson JW. Source: Thorax. 2003 October; 58(10): 880-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14514944&dopt=Abstract

•

Non-invasive ventilation for cystic fibrosis. Author(s): Moran F, Bradley J. Source: Cochrane Database Syst Rev. 2003; (2): Cd002769. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804435&dopt=Abstract

•

Nontuberculous mycobacterial pulmonary infection in patients with cystic fibrosis: diagnosis and treatment. Author(s): Carro LM, Elorza EN. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2002; 1(2): 107-17. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14720065&dopt=Abstract

•

Normal and pathologic soft tissue remodeling: role of the myofibroblast, with special emphasis on liver and kidney fibrosis. Author(s): Desmouliere A, Darby IA, Gabbiani G. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2003 December; 83(12): 1689-707. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14691287&dopt=Abstract

•

Nutritional management of children with cystic fibrosis. Author(s): Sharma M, Singh M. Source: Indian Pediatrics. 2003 November; 40(11): 1055-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14660836&dopt=Abstract

•

Of fertility, cystic fibrosis and the bicarbonate ion. Author(s): Sutton KA, Jungnickel MK, Florman HM. Source: Nature Cell Biology. 2003 October; 5(10): 857-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14523397&dopt=Abstract

128

Fibrosis

•

Offering preconceptional cystic fibrosis carrier couple screening in the absence of established preconceptional care services. Author(s): Henneman L, Bramsen I, van Kempen L, van Acker MB, Pals G, van der Horst HE, Ader HJ, van der Ploeg HM, ten Kate LP. Source: Community Genetics. 2003; 6(1): 5-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12748433&dopt=Abstract

•

Onset and progression of idiopathic pulmonary fibrosis in a renal transplant recipient. A case report. Author(s): Battista G, Zompatori M, Fasano L, Campieri C, Di Scioscio V. Source: Radiol Med (Torino). 2003 July-August; 106(1-2): 103-7. English, Italian. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12951557&dopt=Abstract

•

Operation for lung cancer in patients with idiopathic pulmonary fibrosis: surgical contraindication? Author(s): Fujimoto T, Okazaki T, Matsukura T, Hanawa T, Yamashita N, Nishimura K, Kuwabara M, Matsubara Y. Source: The Annals of Thoracic Surgery. 2003 November; 76(5): 1674-8; Discussion 1679. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602310&dopt=Abstract

•

Oral administration of specific yolk antibodies (IgY) may prevent Pseudomonas aeruginosa infections in patients with cystic fibrosis: a phase I feasibility study. Author(s): Kollberg H, Carlander D, Olesen H, Wejaker PE, Johannesson M, Larsson A. Source: Pediatric Pulmonology. 2003 June; 35(6): 433-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746939&dopt=Abstract

•

Oral health and related factors in cystic fibrosis and other chronic respiratory disorders. Author(s): Narang A, Maguire A, Nunn JH, Bush A. Source: Archives of Disease in Childhood. 2003 August; 88(8): 702-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876168&dopt=Abstract

•

Organic solutes rescue the functional defect in delta F508 cystic fibrosis transmembrane conductance regulator. Author(s): Zhang XM, Wang XT, Yue H, Leung SW, Thibodeau PH, Thomas PJ, Guggino SE. Source: The Journal of Biological Chemistry. 2003 December 19; 278(51): 51232-42. Epub 2003 October 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14532265&dopt=Abstract

Studies 129

•

Organotypic liver culture in a fluid-air interface using slices of neonatal rat and adult human tissue--a model of fibrosis in vitro. Author(s): Verrill C, Davies J, Millward-Sadler H, Sundstrom L, Sheron N. Source: Journal of Pharmacological and Toxicological Methods. 2002 SeptemberOctober; 48(2): 103-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14565567&dopt=Abstract

•

Otago Glaucoma Surgery Outcome Study: factors controlling capsule fibrosis around Molteno implants with histopathological correlation. Author(s): Molteno AC, Fucik M, Dempster AG, Bevin TH. Source: Ophthalmology. 2003 November; 110(11): 2198-206. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597530&dopt=Abstract

•

Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta. Author(s): Fujita M, Shannon JM, Morikawa O, Gauldie J, Hara N, Mason RJ. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 December; 29(6): 669-76. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816730&dopt=Abstract

•

Overlap connective tissue disease, pulmonary fibrosis, and extensive subcutaneous calcification. Author(s): Chan AT, Wordsworth BP, McNally J. Source: Annals of the Rheumatic Diseases. 2003 July; 62(7): 690-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810445&dopt=Abstract

•

Oxidant stress and regulation of chemokines in the development of renal interstitial fibrosis. Author(s): Cochrane AL, Ricardo SD. Source: Contrib Nephrol. 2003; 139: 102-19. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854321&dopt=Abstract

•

Pancreatitis leading to retroperitoneal fibrosis and ureteric obstruction. Author(s): Tan HM, Khoo J, Pang KP. Source: Med J Malaysia. 2003 June; 58(2): 286-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14569752&dopt=Abstract

•

Pathophysiology and management of pulmonary infections in cystic fibrosis. Author(s): Gibson RL, Burns JL, Ramsey BW. Source: American Journal of Respiratory and Critical Care Medicine. 2003 October 15; 168(8): 918-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555458&dopt=Abstract

130

Fibrosis

•

Pediatrics, surfactant, and cystic fibrosis in AJRCCM 2003. Author(s): Tobin MJ. Source: American Journal of Respiratory and Critical Care Medicine. 2004 January 15; 169(2): 277-87. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718241&dopt=Abstract

•

Pharmacologic approaches to correcting the basic defect in cystic fibrosis. Author(s): Lukacs GL, Durie PR. Source: The New England Journal of Medicine. 2003 October 9; 349(15): 1401-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14534332&dopt=Abstract

•

Pharmacotherapy of the ion transport defect in cystic fibrosis: role of purinergic receptor agonists and other potential therapeutics. Author(s): Kunzelmann K, Mall M. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2003; 2(4): 299-309. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14719996&dopt=Abstract

•

Population pharmacokinetics of high dose ibuprofen in cystic fibrosis. Author(s): Arranz I, Martin-Suarez A, Lanao JM, Mora F, Vazquez C, Escribano A, Juste M, Mercader J, Ripoll E. Source: Archives of Disease in Childhood. 2003 December; 88(12): 1128-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14670788&dopt=Abstract

•

Possibilities and barriers in the implementation of a preconceptional screening programme for cystic fibrosis carriers: a focus group study. Author(s): Poppelaars FA, van der Wal G, Braspenning JC, Cornel MC, Henneman L, Langendam MW, ten Kate LP. Source: Public Health. 2003 November; 117(6): 396-403. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522154&dopt=Abstract

•

Possible roles for apoptosis and apoptotic cell recognition in inflammation and fibrosis. Author(s): Henson PM. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S70-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503559&dopt=Abstract

•

Predictive factors for the severity of liver fibrosis in patients with chronic hepatitis C and moderate alcohol consumption. Author(s): Vadan R, Gheorghe L, Becheanu G, Iacob R, Iacob S, Gheorghe C. Source: Rom J Gastroenterol. 2003 September; 12(3): 183-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14502317&dopt=Abstract

Studies 131

•

Prenatal cystic fibrosis screening in Mexican Americans: an economic analysis. Author(s): Doyle NM, Gardner MO. Source: American Journal of Obstetrics and Gynecology. 2003 September; 189(3): 769-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14526311&dopt=Abstract

•

Presentation of idiopathic retroperitoneal fibrosis in the pediatric population. Author(s): Miller OF, Smith LJ, Ferrara EX, McAleer IM, Kaplan GW. Source: Journal of Pediatric Surgery. 2003 November; 38(11): 1685-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14614727&dopt=Abstract

•

Progression of liver fibrosis in patients with chronic hepatitis C after orthotopic liver transplantation. Author(s): Chopra KB, Demetris AJ, Blakolmer K, Dvorchik I, Laskus T, Wang LF, Araya VR, Dodson F, Fung JJ, Rakela J, Vargas HE. Source: Transplantation. 2003 November 27; 76(10): 1487-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14657691&dopt=Abstract

•

Pro-inflammatory effects of Burkholderia cepacia on cystic fibrosis respiratory epithelium. Author(s): Fink J, Steer JH, Joyce DA, McWilliam AS, Stewart GA. Source: Fems Immunology and Medical Microbiology. 2003 October 15; 38(3): 273-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522463&dopt=Abstract

•

Prospective randomised treatment with recombinant human growth hormone in cystic fibrosis. Author(s): Schibler A, von der Heiden R, Birrer P, Mullis PE. Source: Archives of Disease in Childhood. 2003 December; 88(12): 1078-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14670773&dopt=Abstract

•

Pseudomonas aeruginosa chromosomal beta-lactamase in patients with cystic fibrosis and chronic lung infection. Mechanism of antibiotic resistance and target of the humoral immune response. Author(s): Ciofu O. Source: Apmis. Supplementum. 2003; (116): 1-47. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14692154&dopt=Abstract

•

Pseudomonas cross-infection from cystic fibrosis patients to non-cystic fibrosis patients: implications for inpatient care of respiratory patients. Author(s): Robinson P, Carzino R, Armstrong D, Olinsky A. Source: Journal of Clinical Microbiology. 2003 December; 41(12): 5741. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14662972&dopt=Abstract

132

Fibrosis

•

Psychosocial issues in newborn screening for cystic fibrosis. Author(s): Parsons EP, Bradley DM. Source: Paediatric Respiratory Reviews. 2003 December; 4(4): 285-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14629950&dopt=Abstract

•

Pulmonary fibrosis in a tool sharpener. Author(s): Rao U, Ganeshalingam K, Davies BH. Source: Hosp Med. 2003 August; 64(8): 491. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12958763&dopt=Abstract

•

Pulmonary fibrosis in families. Author(s): Loyd JE. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S47-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503554&dopt=Abstract

•

Pulmonary fibrosis of sarcoidosis. New approaches, old ideas. Author(s): Moller DR. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S37-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14503552&dopt=Abstract

•

Quantitative analysis of testicular interstitial fibrosis after vasectomy in humans. Author(s): Shiraishi K, Takihara H, Naito K. Source: Aktuelle Urologie. 2003 July; 34(4): 262-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14566680&dopt=Abstract

•

Quantitative CT indexes in idiopathic pulmonary fibrosis: relationship with physiologic impairment. Author(s): Best AC, Lynch AM, Bozic CM, Miller D, Grunwald GK, Lynch DA. Source: Radiology. 2003 August; 228(2): 407-14. Epub 2003 June 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12802000&dopt=Abstract

•

Radiographic evidence of pulmonary fibrosis and possible etiologic factors at a nickel refinery in Norway. Author(s): Berge SR, Skyberg K. Source: Journal of Environmental Monitoring : Jem. 2003 August; 5(4): 681-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948249&dopt=Abstract

Studies 133

•

Ralstonia respiraculi sp. nov., isolated from the respiratory tract of cystic fibrosis patients. Author(s): Coenye T, Vandamme P, LiPuma JJ. Source: International Journal of Systematic and Evolutionary Microbiology. 2003 September; 53(Pt 5): 1339-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13130016&dopt=Abstract

•

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Author(s): Fubini B, Hubbard A. Source: Free Radical Biology & Medicine. 2003 June 15; 34(12): 1507-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788471&dopt=Abstract

•

Recombinant human deoxyribonuclease for cystic fibrosis. Author(s): Jones AP, Wallis CE. Source: Cochrane Database Syst Rev. 2003; (3): Cd001127. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917899&dopt=Abstract

•

Recurrent fevers in a five-year-old boy with cystic fibrosis. Author(s): Kohn AS, Conrad DA. Source: The Pediatric Infectious Disease Journal. 2003 May; 22(5): 474, 478-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797319&dopt=Abstract

•

Regarding “External iliac artery endofibrosis: a new possible predisposing factor”. Author(s): Mosimann F. Source: Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2003 December; 38(6): 1446; Author Reply 1446-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14689609&dopt=Abstract

•

Regression of fibrosis in chronic hepatitis C after therapy with interferon and ribavirin. Author(s): Arif A, Levine RA, Sanderson SO, Bank L, Velu RP, Shah A, Mahl TC, Gregory DH. Source: Digestive Diseases and Sciences. 2003 July; 48(7): 1425-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870807&dopt=Abstract

•

Relation between pancreatic lipase activity and gastric emptying rate in children with cystic fibrosis. Author(s): Symonds EL, Omari TI, Webster JM, Davidson GP, Butler RN. Source: The Journal of Pediatrics. 2003 December; 143(6): 772-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14657826&dopt=Abstract

134

Fibrosis

•

Rescue of defective pancreatic secretion in cystic-fibrosis cells by suppression of a novel isoform of phospholipase C. Author(s): Zhu H, Zhu JX, Lo PS, Li J, Leung KM, Rowlands DK, Tsang LL, Yu MK, Jiang JL, Lam SY, Chung YW, Zhou Z, Sha J, Chang Chan H. Source: Lancet. 2003 December 20; 362(9401): 2059-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14697805&dopt=Abstract

•

Respective roles of porto-septal fibrosis and centrilobular fibrosis in alcoholic liver disease. Author(s): Michalak S, Rousselet MC, Bedossa P, Pilette C, Chappard D, Oberti F, Gallois Y, Cales P. Source: The Journal of Pathology. 2003 September; 201(1): 55-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12950017&dopt=Abstract

•

Respiratory epithelium in usual interstitial pneumonia/idiopathic pulmonary fibrosis: spark or destructive flame? Author(s): Myers JL, Selman M. Source: American Journal of Respiratory and Critical Care Medicine. 2004 January 1; 169(1): 3-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14695101&dopt=Abstract

•

Respiratory reovirus 1/L induction of intraluminal fibrosis, a model of bronchiolitis obliterans organizing pneumonia, is dependent on T lymphocytes. Author(s): Majeski EI, Paintlia MK, Lopez AD, Harley RA, London SD, London L. Source: American Journal of Pathology. 2003 October; 163(4): 1467-79. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507654&dopt=Abstract

•

Role of coagulation cascade proteases in lung repair and fibrosis. Author(s): Chambers RC. Source: Eur Respir J Suppl. 2003 September; 44: 33S-35S. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14582899&dopt=Abstract

•

Sampling variability of liver fibrosis in chronic hepatitis C. Author(s): Bedossa P, Dargere D, Paradis V. Source: Hepatology (Baltimore, Md.). 2003 December; 38(6): 1449-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14647056&dopt=Abstract

•

Septo-optic dysplasia with congenital hepatic fibrosis. Author(s): Minami K, Izumi G, Yanagawa T, Shimoyamada Y, Yoshikawa N. Source: Pediatric Neurology. 2003 August; 29(2): 157-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14580661&dopt=Abstract

Studies 135

•

Serum hyaluronic acid, procollagen type III and IV in histological diagnosis of liver fibrosis. Author(s): Xie SB, Yao JL, Zheng RQ, Peng XM, Gao ZL. Source: Hepatobiliary Pancreat Dis Int. 2003 February; 2(1): 69-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14607650&dopt=Abstract

•

Sildenafil improved pulmonary hypertension and peripheral blood flow in a patient with scleroderma-associated lung fibrosis and the raynaud phenomenon. Author(s): Rosenkranz S, Diet F, Karasch T, Weihrauch J, Wassermann K, Erdmann E. Source: Annals of Internal Medicine. 2003 November 18; 139(10): 871-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623635&dopt=Abstract

•

Spectrum and diagnosis of idiopathic pulmonary fibrosis. Author(s): Maheshwari U, Gupta D, Aggarwal AN, Jindal SK. Source: Indian J Chest Dis Allied Sci. 2004 January-March; 46(1): 23-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14870865&dopt=Abstract

•

Stenotrophomonas maltophilia contamination of nebulizers used to deliver aerosolized therapy to inpatients with cystic fibrosis. Author(s): Denton M, Rajgopal A, Mooney L, Qureshi A, Kerr KG, Keer V, Pollard K, Peckham DG, Conway SP. Source: The Journal of Hospital Infection. 2003 November; 55(3): 180-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14572484&dopt=Abstract

•

Stimulatory and inhibitory protein kinase C consensus sequences regulate the cystic fibrosis transmembrane conductance regulator. Author(s): Chappe V, Hinkson DA, Howell LD, Evagelidis A, Liao J, Chang XB, Riordan JR, Hanrahan JW. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 January 6; 101(1): 390-5. Epub 2003 December 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14695900&dopt=Abstract

•

Sublingual tacrolimus for immunosuppression in lung transplantation: a potentially important therapeutic option in cystic fibrosis. Author(s): Reams BD, Palmer SM. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2002; 1(2): 91-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14720063&dopt=Abstract

•

Successful meropenem desensitization in a patient with cystic fibrosis. Author(s): Wilson DL, Owens RC Jr, Zuckerman JB. Source: The Annals of Pharmacotherapy. 2003 October; 37(10): 1424-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519038&dopt=Abstract

136

Fibrosis

•

Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors. Author(s): Lenaerts C, Lapierre C, Patriquin H, Bureau N, Lepage G, Harel F, Marcotte J, Roy CC. Source: The Journal of Pediatrics. 2003 September; 143(3): 343-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517517&dopt=Abstract

•

The assessment of anti-endothelial cell antibodies in scleroderma-associated pulmonary fibrosis. A study of indirect immunofluorescent and western blot analysis in 49 patients with scleroderma. Author(s): Wusirika R, Ferri C, Marin M, Knight DA, Waldman WJ, Ross P Jr, Magro CM. Source: American Journal of Clinical Pathology. 2003 October; 120(4): 596-606. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14560571&dopt=Abstract

•

The bone marrow leaves its scar: new concepts in pulmonary fibrosis. Author(s): Dunsmore SE, Shapiro SD. Source: The Journal of Clinical Investigation. 2004 January; 113(2): 180-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14722608&dopt=Abstract

•

The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Author(s): Bonacchi A, Petrai I, Defranco RM, Lazzeri E, Annunziato F, Efsen E, Cosmi L, Romagnani P, Milani S, Failli P, Batignani G, Liotta F, Laffi G, Pinzani M, Gentilini P, Marra F. Source: Gastroenterology. 2003 October; 125(4): 1060-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517790&dopt=Abstract

•

The effect of pregnancy on survival in women with cystic fibrosis. Author(s): Goss CH, Rubenfeld GD, Otto K, Aitken ML. Source: Chest. 2003 October; 124(4): 1460-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555580&dopt=Abstract

•

The glycosylation of airway mucins in cystic fibrosis and its relationship with lung infection by Pseudomonas aeruginosa. Author(s): Roussel P, Lamblin G. Source: Advances in Experimental Medicine and Biology. 2003; 535: 17-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14714886&dopt=Abstract

Studies 137

•

The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis. Author(s): Tajima S, Oshikawa K, Tominaga S, Sugiyama Y. Source: Chest. 2003 October; 124(4): 1206-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555548&dopt=Abstract

•

The potential of recombinant surfactant protein D therapy to reduce inflammation in neonatal chronic lung disease, cystic fibrosis, and emphysema. Author(s): Clark H, Reid K. Source: Archives of Disease in Childhood. 2003 November; 88(11): 981-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612363&dopt=Abstract

•

The repeatability of forced expiratory volume measurements in adults with cystic fibrosis. Author(s): Stanbrook MB, Corey M, Tullis DE. Source: Chest. 2004 January; 125(1): 150-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718434&dopt=Abstract

•

The reticulin stain in bone marrow biopsies--beyond marrow fibrosis. Author(s): Ahluwalia J, Garewal G, Das R, Vaiphei K. Source: British Journal of Haematology. 2003 November; 123(3): 379. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14616994&dopt=Abstract

•

Towards preimplantation diagnosis of cystic fibrosis using microarrays. Author(s): Salvado CS, Trounson AO, Cram DS. Source: Reproductive Biomedicine Online. 2004 January; 8(1): 107-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14759297&dopt=Abstract

•

Unusually common cystic fibrosis mutation in Portugal encodes a misprocessed protein. Author(s): Mendes F, Roxo Rosa M, Dragomir A, Farinha CM, Roomans GM, Amaral MD, Penque D. Source: Biochemical and Biophysical Research Communications. 2003 November 21; 311(3): 665-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623323&dopt=Abstract

•

Upper lobe pulmonary fibrosis associated with high-dose chemotherapy containing BCNU for bone marrow transplantation. Author(s): Parish JM, Muhm JR, Leslie KO. Source: Mayo Clinic Proceedings. 2003 May; 78(5): 630-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12744552&dopt=Abstract

138

Fibrosis

•

Uptake of 18fluorodeoxyglucose in the cystic fibrosis lung: a measure of lung inflammation? Author(s): Labiris NR, Nahmias C, Freitag AP, Thompson ML, Dolovich MB. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 May; 21(5): 848-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765432&dopt=Abstract

•

Urinary amino-terminal propeptide of type III procollagen (PIIINP) as a marker of interstitial fibrosis in renal transplant recipients. Author(s): Teppo AM, Tornroth T, Honkanen E, Gronhagen-Riska C. Source: Transplantation. 2003 June 27; 75(12): 2113-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829921&dopt=Abstract

•

Use of amplified ribosomal DNA restriction analysis for identification of Ralstonia and Pandoraea species: interest in determination of the respiratory bacterial flora in patients with cystic fibrosis. Author(s): Segonds C, Paute S, Chabanon G. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 3415-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843108&dopt=Abstract

•

Use of real-time PCR with multiple targets to identify Pseudomonas aeruginosa and other nonfermenting gram-negative bacilli from patients with cystic fibrosis. Author(s): Qin X, Emerson J, Stapp J, Stapp L, Abe P, Burns JL. Source: Journal of Clinical Microbiology. 2003 September; 41(9): 4312-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12958262&dopt=Abstract

•

Using disease registries for pharmacoepidemiological research: a case study of data from a cystic fibrosis registry. Author(s): Strobl J, Enzer I, Bagust A, Haycox A, Smyth R, Ashby D, Walley T. Source: Pharmacoepidemiology and Drug Safety. 2003 September; 12(6): 467-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14513660&dopt=Abstract

•

Utility of the breathing reserve index at the anaerobic threshold in determining ventilatory-limited exercise in adult cystic fibrosis patients. Author(s): Sexauer WP, Cheng HK, Fiel SB. Source: Chest. 2003 October; 124(4): 1469-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555581&dopt=Abstract

•

Validation of a disease-specific measure of health-related quality of life for children with cystic fibrosis. Author(s): Modi AC, Quittner AL. Source: Journal of Pediatric Psychology. 2003 December; 28(8): 535-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602844&dopt=Abstract

Studies 139

•

Validation of a simple predictive model for the identification of mild hepatic fibrosis in chronic hepatitis C patients. Author(s): Patel K, Muir AJ, McHutchison JG. Source: Hepatology (Baltimore, Md.). 2003 May; 37(5): 1222; Author Reply 1222-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717404&dopt=Abstract

•

Validation of interstitial fluid continuous glucose monitoring in cystic fibrosis. Author(s): Dobson L, Sheldon CD, Hattersley AT. Source: Diabetes Care. 2003 June; 26(6): 1940-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12766139&dopt=Abstract

•

Ventilatory function of progressive massive fibrosis among bituminous coal miners in Taiwan. Author(s): Yang SC, Yang SP. Source: Archives of Environmental Health. 2003 May; 58(5): 290-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14738275&dopt=Abstract

•

Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Author(s): Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Source: The American Journal of Gastroenterology. 2003 November; 98(11): 2485-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14638353&dopt=Abstract

•

Vitamin K deficient bleeding in cystic fibrosis. Author(s): Verghese T, Beverley D. Source: Archives of Disease in Childhood. 2003 June; 88(6): 553. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765934&dopt=Abstract

•

Vitamin K supplementation in cystic fibrosis. Author(s): van Hoorn JH, Hendriks JJ, Vermeer C, Forget PP. Source: Archives of Disease in Childhood. 2003 November; 88(11): 974-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612359&dopt=Abstract

•

Worsening of steatosis and fibrosis progression in hepatitis C. Author(s): Castera L, Pawlotsky JM, Dhumeaux D. Source: Gut. 2003 October; 52(10): 1531. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970153&dopt=Abstract

Academic Periodicals covering Fibrosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to fibrosis. To find the latest

140

Fibrosis

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, 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.”

Dissertations on Fibrosis 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 fibrosis. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “fibrosis” (or a synonym) in their titles. The following covers recent dissertations found when using this search procedure: •

A Comparative Study to Assess an Educational Curriculum Designed for Preschool Chronically Ill Children Suffering from Cystic Fibrosis and/or Atopic Diseases. by Tanner, Lillian Catherine, EDD from The University of Mississippi, 1979, 362 pages http://wwwlib.umi.com/dissertations/fullcit/7921525

•

Development and Chronic Disease: Functional Adaptation in Cystic Fibrosis (Maturation, Growth, Auxology) by Mahaney, Michael Charles, PhD from The Ohio State University, 1984, 227 pages http://wwwlib.umi.com/dissertations/fullcit/8504050

•

Family Adaptation to Chronic Illness: The Case of Cystic Fibrosis by Patterson, Joan Marie Engel, PhD from University of Minnesota, 1983, 218 pages http://wwwlib.umi.com/dissertations/fullcit/8318114

•

Perceived Efficacy of Symptom-Oriented Hypnotherapy in Pediatric Cancer and Cystic Fibrosis Patients (Pediatric Patients) by Dorr, Constance Joan, PhD from The University of Toledo, 1991, 134 pages http://wwwlib.umi.com/dissertations/fullcit/9216428

•

Smoking Cessation Counseling for Cystic Fibrosis Patient Caregivers and Significant Others: Perceptions of Care Center Directors and Nurse Coordinators by Strasser, Sheryl Marie, PhD from University of Alabama and University of Alabama at Birmingham, 2003, 123 pages http://wwwlib.umi.com/dissertations/fullcit/3101585

•

Studies on Plasma Membranes and Glycoproteins in Cells Cultured from Patients with Cystic Fibrosis by Maler, Thomas; PhD from University of Toronto (Canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NL07931

•

The Development of Pulmonary Radiation Fibrosis in Man by Prato, Frank S; PhD from University of Toronto (Canada), 1976 http://wwwlib.umi.com/dissertations/fullcit/NK35105

141

CHAPTER 2. NUTRITION AND FIBROSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and fibrosis.

Finding Nutrition Studies on Fibrosis 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. Once you have entered 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 “fibrosis” (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.

142

Fibrosis

The following is a typical result when searching for recently indexed consumer information on fibrosis: •

Identification and treatment of cystic fibrosis-related diabetes. A survey of current medical practice in the U.S. Author(s): Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts, USA. [email protected] Source: Allen, H F Gay, E C Klingensmith, G J Hamman, R F Diabetes-Care. 1998 June; 21(6): 943-8 0149-5992

•

Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes. Author(s): Division of Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA. [email protected] Source: Moran, A Phillips, J Milla, C Diabetes-Care. 2001 October; 24(10): 1706-10 01495992

•

Nutrition in cystic fibrosis. Source: Schorah, C.J. Smithells, R.W. Nutr-Res-Rev. Cambridge [England] : Cambridge University Press. 1991. volume (4) page 51-67. 0954-4224

•

Nutrition support in cystic fibrosis. Source: Gerson, W T Swan, P Walker, W A Nutr-Revolume 1987 December; 45(12): 35360 0029-6643

•

Taurine supplementation in cystic fibrosis. Source: Anonymous Nutr-Revolume 1988 July; 46(7): 257-8 0029-6643

•

Vitamin E therapy in cystic fibrosis. Source: Anonymous Nutr-Revolume 1988 August; 46(8): 289-90 0029-6643

The following information is typical of that found when using the “Full IBIDS Database” to search for “fibrosis” (or a synonym): •

Abnormal bone turnover in cystic fibrosis adults. Author(s): Divisions of Pulmonary Medicine,The University of North Carolina at Chapel Hill, 27599-7524, USA. [email protected] Source: Aris, R M Ontjes, D A Buell, H E Blackwood, A D Lark, R K Caminiti, M Brown, S A Renner, J B Chalermskulrat, W Lester, G E Osteoporos-Int. 2002; 13(2): 151-7 0937941X

•

Activation of hepatic stellate cells--a key issue in liver fibrosis. Author(s): Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029-6574, USA. [email protected] Source: Reeves, Helen L Friedman, Scott L Front-Biosci. 2002 April 1; 7: d808-26 10934715

•

Anti-inflammatory approaches to the treatment of cystic fibrosis lung disease: past, present and future. Author(s): Pediatric Pulmonology Service, Baylor College of Medicine, TCH Feigin Center, Houston, TX, 77030 USA. [email protected] Source: Oermann, C M Curr-Opin-Investig-Drugs. 2001 July; 2(7): 900-6 1472-4472

•

Antioxidant status in erythrocytes of cystic fibrosis children. Author(s): Department of Biochemistry, National Research Institute of Mother and Child, Warszawa, Poland. [email protected]

Nutrition

143

Source: Laskowska Klita, T Chelchowska, M Acta-Biochim-Pol. 2001; 48(1): 283-5 0001527X •

Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated with suppression of transforming growth factor-beta1 gene expression but not prevention of mitochondrial dysfunction. Author(s): Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada. Source: Card, J W Racz, W J Brien, J F Massey, T E J-Pharmacol-Exp-Ther. 2003 January; 304(1): 277-83 0022-3565

•

Body mass index, tobacco chewing, alcohol drinking and the risk of oral submucous fibrosis in Kerala, India. Author(s): Department of Epidemiology, UCLA School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095-1772, USA. Source: Hashibe, Mia Sankaranarayanan, Rengaswamy Thomas, Gigi Kuruvilla, Binu Mathew, Babu Somanathan, Thara Parkin, Donald Maxwell Zhang, Zuo Feng CancerCauses-Control. 2002 February; 13(1): 55-64 0957-5243

•

Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B. Author(s): Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. [email protected] Source: Liu, P Hu, Y Y Liu, C Zhu, D Y Xue, H M Xu, Z Q Xu, L M Liu, C H Gu, H T Zhang, Z Q World-J-Gastroenterol. 2002 August; 8(4): 679-85 1007-9327

•

Consideration of mycophenolate mofetil for idiopathic pulmonary fibrosis. Author(s): Brain and Perception Laboratory, University of California, San Diego, La Jolla 92093-0109, USA. [email protected] Source: Altschuler, E L Med-Hypotheses. 2001 December; 57(6): 701-2 0306-9877

•

Detection of Pseudomonas aeruginosa cell-to-cell signals in lung tissue of cystic fibrosis patients. Author(s): Department of Genetics and Microbiology, Medical School, CH-1211 Geneva 4, Switzerland. Source: Favre Bonte, Sabine Pache, Jean Claude Robert, John Blanc, Dominique Pechere, Jean Claude van Delden, Christian Microb-Pathog. 2002 March; 32(3): 143-7 0882-4010

•

Development of hepatocellular adenomas and carcinomas associated with fibrosis in C57BL/6J male mice given a choline-deficient, L-amino acid-defined diet. Author(s): Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Nara 634-8521, Japan. [email protected] Source: Denda, Ayumi Kitayama, Wakashi Kishida, Hideki Murata, Nao Tsutsumi, Masahiro Tsujiuchi, Toshifumi Nakae, Dai Konishi, Yoichi Jpn-J-Cancer-Res. 2002 February; 93(2): 125-32 0910-5050

•

Dietary fish oil protects against lung and liver inflammation and fibrosis in monocrotaline treated rats. Author(s): Department of Human Nutrition, Kansas State University, Justin Hall, Manhattan, KS 66502-1407, USA. [email protected] Source: Baybutt, Richard C Rosales, Cecilia Brady, Heather Molteni, Agostino Toxicology. 2002 June 14; 175(1-3): 1-13 0300-483X

144

Fibrosis

•

Different activation mechanisms of cystic fibrosis transmembrane conductance regulator expressed in Xenopus laevis oocytes. Author(s): Laboratory of Physiology, K U Leuven, Belgium. [email protected] Source: Webe W, M Segal, A Vankeerberghen, A Cassiman J, J Van Driessche, W CompBiochem-Physiol-A-Mol-Integr-Physiol. 2001 October; 130(3): 521-31 1095-6433

•

Effects of glycyrrhetinic acid on collagen metabolism of hepatic stellate cells at different stages of liver fibrosis in rats. Author(s): Department of Internal Medicine, Zhongshan Hospital, Medical Center, Fu Dan University, Shanghai 200032, China. Source: Wang, J Y Zhang, Q S Guo, J S Hu, M Y World-J-Gastroenterol. 2001 February; 7(1): 115-9 1007-9327

•

Effects of Tanshinone VI on the Hypertrophy of Cardiac Myocytes and Fibrosis of Cardiac Fibroblasts of Neonatal Rats. Author(s): Department of Pharmacology, Tokyo University of Pharmacy and Life Science, Hachioji, Japan. Source: Maki, T Kawahara, Y Tanonaka, K Yagi, A Takeo, S Planta-Med. 2002 December; 68(12): 1103-7 0032-0943

•

Endoscopic sinus surgery in cystic fibrosis: do patients benefit from surgery? Author(s): Southern California Permanente Medical Group, Department of Head and Neck Surgery, 6th Floor, 4900 Sunset Boulevard, Los Angeles, CA 90027, USA. Source: Rosbe, K W Jones, D T Rahbar, R Lahiri, T Auerbach, A D Int-J-PediatrOtorhinolaryngol. 2001 November 1; 61(2): 113-9 0165-5876

•

Estrogen reduces CCL4- induced liver fibrosis in rats. Author(s): Department of Gastroenterology, Second Hospital of Xi'an Jiaotong University, Xi'an 710031, Shaanxi Province, China. [email protected] Source: Xu, J W Gong, J Chang, X M Luo, J Y Dong, L Hao, Z M Jia, A Xu, G P World-JGastroenterol. 2002 October; 8(5): 883-7 1007-9327

•

Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis. Author(s): Department of Pediatrics, Gastroenterology and Paediatric Oncology, Medical University of Gdansk, Poland. Source: Brodzicki, J Trawinska Bartnicka, M Korzon, M Med-Sci-Monit. 2002 July; 8(7): CR529-37 1234-1010

•

Further on the causation of oral submucous fibrosis. Author(s): Department of Oral Pathology and Microbiology, Dental Wing, Medical College, Trivandrum-695011, India. [email protected] Source: Rajendran, R Karunakaran, A Indian-J-Dent-Res. 2002 Apr-June; 13(2): 74-81 0970-9290

•

Gadolinium as an opener of the outwardly rectifying Cl(-) channel (ORCC). Is there relevance for cystic fibrosis therapy? Author(s): Max-Planck-Institut fur Experimentelle Medizin, Abteilung Immunchemie, Hermann-Rein-Strasse 3, 37075 Gottingen, Germany. [email protected] Source: Thinnes, F P Walter, G Hellmann, K P Hellmann, T Merker, R Kiafard, Z Eben Brunnen, J Schwarzer, C Gotz, H Hilschmann, N Pflugers-Arch. 2001; 443 Suppl 1: S1116 0031-6768

Nutrition

145

•

Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities. Author(s): Institute for Molecular Biosciences, Imperial College of Medicine at the National Heart and Lung Institute, Manresa Road, London SW3 6LR, UK. Source: Oceandy, D McMorran, B J Smith, S N Schreiber, R Kunzelmann, K Alton, E W Hume, D A Wainwright, B J Hum-Mol-Genet. 2002 May 1; 11(9): 1059-67 0964-6906

•

Glucose intolerance in cystic fibrosis patients. Author(s): Department of Paediatrics, Rigshospitalet, CF Centre Copenhagen, Copenhagen, Denmark. [email protected] Source: Lanng, S Paediatr-Respir-Revolume 2001 September; 2(3): 253-9 1526-0542

•

Growth problems and growth hormone treatment in children with cystic fibrosis. Author(s): Department of Pediatrics, University of Texas Southwestern Medical School, Dallas 75390-9063, USA. [email protected] Source: Hardin, D S J-Pediatr-Endocrinol-Metab. 2002 May; 15 Suppl 2: 731-5

•

Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis. Author(s): Department of Medicine, Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles, California 90095, USA. Source: Belperio, J A Dy, M Burdick, M D Xue, Y Y Li, K Elias, J A Keane, M P Am-JRespir-Cell-Mol-Biol. 2002 October; 27(4): 419-27 1044-1549

•

Intracellular cysteines of the cystic fibrosis transmembrane conductance regulator (CFTR) modulate channel gating. Author(s): Department of Physiology, Johns Hopkins University School of Medicine, Baltimore MD 21205, USA. Source: Ketchum, Christian J Yue, Hongwen Alessi, Karen A Devidas, Shreenivas Guggino, William B Maloney, Peter C Cell-Physiol-Biochem. 2002; 12(1): 1-8 1015-8987

•

Intracellular rate-limiting steps of gene transfer using glycosylated polylysines in cystic fibrosis airway epithelial cells. Author(s): Laboratoire de Physiologie Respiratoire, CHU Cochin, AP-HP-Universite Paris V, France. Source: Grosse, S Tremeau Bravard, A Aron, Y Briand, P Fajac, I Gene-Ther. 2002 August; 9(15): 1000-7 0969-7128

•

Low fasting serum triglyceride and high free fatty acid levels in pulmonary fibrosis: a previously unreported finding. Author(s): Department of Medicina Interna e Patologie Sistemiche, University of Catania Medical School, Garibaldi Hospital, 95123 Catania, Italy. Source: Iannello, Silvia Cavaleri, Antonina Camuto, Massimo Pisano, Maria Grazia Milazzo, Paolina Belfiore, Francesco MedGenMed. 2002 June 14; 4(2): 5 1531-0132

•

Multifocal myocardial necrosis: a distinctive cardiac lesion in cystic fibrosis, lipomatous pancreatic atrophy, and Keshan disease. Author(s): Department of Pathology, Hjpital Edouard Herriot, Lyon, France. Source: Nezelof, C Bouvier, R Dijoud, F Pediatr-Pathol-Mol-Med. 2002 May-June; 21(3): 343-52 1522-7952

•

Omega-3 fatty acids (from fish oils) for cystic fibrosis. Author(s): Department of Nutrition and Dietetics, Sheffield Children's Hospital NHS Trust, Western Bank, Sheffield, UK, S10 2TH. [email protected] Source: Beckles, W I Elliott, T M Everard, M L Cochrane-Database-Syst-Revolume 2002; (3): CD002201 1469-493X

146

Fibrosis

•

Oxidative stress, plant-derived antioxidants and liver fibrosis. Author(s): Institut of Biochemistry, University of Leipzig, [email protected] Source: Gebhardt, R Planta-Med. 2002 April; 68(4): 289-96 0032-0943

•

Periportal fibrosis and other liver ultrasonography findings in vinyl chloride workers. Author(s): Department of Occupational Medicine, School of Medicine and Surgery, University of Milan, Italy. [email protected] Source: Maroni, M Mocci, F Visentin, S Preti, G Fanetti, A C Occup-Environ-Med. 2003 January; 60(1): 60-5 1351-0711

•

Pharmacological intervention in renal fibrosis and vascular sclerosis. Author(s): Department of Nephrology, The Royal Melbourne Hospital, Vic., Australia. [email protected] Source: Becker, G J Perkovic, V Hewitson, T D J-Nephrol. 2001 Sep-October; 14(5): 332-9 1120-3625

•

Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Author(s): Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, USA. [email protected] Source: Shihab, F S Bennett, W M Yi, H Andoh, T F Am-J-Transplant. 2002 February; 2(2): 111-9 1600-6135

•

Progress of intervention of renal interstitial fibrosis with Chinese traditional herbal medicine. Author(s): Department of Traditional Chinese Medicine, Nanfang Hospital, First Military Medical University, Guangzhou 510515, China. Source: Wei, L B Ma, Z G Ye, R G Chen, B T Zhan, S C Huang, H Di-Yi-Jun-Yi-Da-XueXue-Bao. 2002 October; 22(10): 946-8 1000-2588

•

Renal interstitial fibrosis and urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). Author(s): Department of Nephrology, Erasme Hospital, Universite Libre de Bruxelles, 808 Route de Lennik, B-1070 Brussels, Belgium. [email protected] Source: Nortier, J L Vanherweghem, J L Toxicology. 2002 December 27; 181-182: 577-80 0300-483X

•

Retinoids in liver fibrosis and cancer. Author(s): First Department of the Internal Medicine, Gifu University School of Medicine, Gifu, Japan. [email protected] Source: Okuno, Masataka Kojima, Soichi Akita, Kuniharu Matsushima Nishiwaki, Rie Adachi, Seiji Sano, Tetsuro Takano, Yukihiko Takai, Koji Obora, Akihiro Yasuda, Ichiro Shiratori, Yoshimune Okano, Yukio Shimada, June Suzuki, Yasuhiro Muto, Yasutoshi Moriwaki, Yasutoshi Front-Biosci. 2002 January 1; 7: d204-18 1093-4715

•

Retrospective clinical comparison of Celsior solution to modified blood Wallwork solution in lung transplantation for cystic fibrosis. Author(s): Thoracic Transplantation Unit, Cardiovascular Surgery Department, Laennec Hospital, Nantes, France. Source: Baron, O Fabre, S Haloun, A Treilhaud, M al Habasch, O Duveau, D Michaud, J L Despins, P Prog-Transplant. 2002 September; 12(3): 176-80 1526-9248

Germany.

Nutrition

147

•

Scutellaria baicalensis inhibits liver fibrosis induced by bile duct ligation or carbon tetrachloride in rats. Author(s): Department of Pharmacy, Wonkwang University, Iksan, Cheonbuk, South Korea. Source: Nan, J X Park, E J Kim, Y C Ko, G Sohn, D H J-Pharm-Pharmacol. 2002 April; 54(4): 555-63 0022-3573

•

Studies of the molecular basis for cystic fibrosis using purified reconstituted CFTR protein. Author(s): Programme in Cell Biology, Research Institute, Hospital for Sick Children, Department of Physiology, Faculty of Medicine, Toronto, Ontario, Canada. Source: Kogan, Ilana Ramjeesingh, Mohabir Li, Canhui Bear, Christine E Methods-MolMed. 2002; 70: 143-57

•

Targeting hepatic stellate cells for cell-specific treatment of liver fibrosis. Author(s): Groningen University Institute for Drug Exploration, Dept. of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, Groningen, The Netherlands. [email protected] Source: Beljaars, Leonie Meijer, Dirk K F Poelstra, Klaas Front-Biosci. 2002 May 1; 7: e214-22 1093-4715

•

The role of sodium cromolyn in treatment of paraquat-induced pulmonary fibrosis in rat. Author(s): Department of Pharmacology and Toxicology, School of Pharmacy, Ahwaz University of Medical Sciences, Ahwaz, Iran. [email protected] Source: Hemmati, A A Nazari, Z Motlagh, M E Goldasteh, S Pharmacol-Res. 2002 September; 46(3): 229-34 1043-6618

•

Treatment of severe small airways disease in children with cystic fibrosis: alternatives to corticosteroids. Author(s): Department of Respiratory Medicine, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. [email protected] Source: Jaffe, A Balfour Lynn, I M Paediatr-Drugs. 2002; 4(6): 381-9 1174-5878

•

Zeaxanthin dipalmitate from Lycium chinense fruit reduces experimentally induced hepatic fibrosis in rats. Author(s): College of Pharmacy, Seoul National University, Korea. Source: Kim, H P Lee, E J Kim, Y C Kim, J Kim, H K Park, J H Kim, S Y Kim, Y C BiolPharm-Bull. 2002 March; 25(3): 390-2 0918-6158

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

•

The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

•

The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

148

Fibrosis

•

The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

•

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/

•

Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

•

Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

•

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

•

Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

•

Google: http://directory.google.com/Top/Health/Nutrition/

•

Healthnotes: http://www.healthnotes.com/

•

Open Directory Project: http://dmoz.org/Health/Nutrition/

•

Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

•

WebMD®Health: http://my.webmd.com/nutrition

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

The following is a specific Web list relating to fibrosis; 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 A Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin D Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com

Nutrition

Vitamin K Source: Healthnotes, Inc.; www.healthnotes.com •

Minerals Zinc Source: Healthnotes, Inc.; www.healthnotes.com

•

Food and Diet Low-Salt Diet Source: Healthnotes, Inc.; www.healthnotes.com Polyunsaturated Fats Source: Healthnotes, Inc.; www.healthnotes.com

149

151

CHAPTER 3. ALTERNATIVE MEDICINE AND FIBROSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to fibrosis. At the conclusion of this chapter, we will provide additional sources.

The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “fibrosis” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •

Alternative Medicine Update Source: Alternative Health Practitioner. 3(3): 157-160. Fall/Winter 1997. Summary: This journal article reports the results of 12 studies funded by the Office of Alternative Medicine in 1993 and 1994. The studies were classified as either mind/body interventions or as pharmacological or biological treatments. The 10 mind/body intervention studies include the following therapies: biofeedback, dance movement therapy, guided imagery, hypnotic imagery, music therapy, prayer, and yoga. Conditions studied include pain, diabetes mellitus, cystic fibrosis, asthma, immunity, cancer, AIDS, brain injury, and drug abuse. The two pharmacological and biological studies were 'Enzyme Therapy and Experimental Memory Metastasis' and 'Pharmacological Treatment of Cancer by Antioxidants.'.

152

Fibrosis

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 fibrosis 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 “fibrosis” (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 fibrosis: •

A common mechanism for cystic fibrosis transmembrane conductance regulator protein activation by genistein and benzimidazolone analogs. Author(s): Al-Nakkash L, Hu S, Li M, Hwang TC. Source: The Journal of Pharmacology and Experimental Therapeutics. 2001 February; 296(2): 464-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11160632&dopt=Abstract

•

A disciplined approach to spiritual care giving for adults living with cystic fibrosis. Author(s): Palmer C. Source: Journal of Health Care Chaplaincy. 2001; 11(1): 95-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11398539&dopt=Abstract

•

Activation of cystic fibrosis transmembrane conductance regulator in rat epididymal epithelium by genistein. Author(s): Leung GP, Wong PY. Source: Biology of Reproduction. 2000 January; 62(1): 143-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10611078&dopt=Abstract

•

Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4phenylbutyrate, genistein and CPX. Author(s): Andersson C, Roomans GM. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2000 May; 15(5): 937-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10853862&dopt=Abstract

•

Acute respiratory infection in patients with cystic fibrosis with mild pulmonary impairment: comparison of two physiotherapy regimens. Author(s): Williams MT, Parsons DW, Frick RA, Ellis ER, Martin AJ, Giles SE, Grant ER. Source: The Australian Journal of Physiotherapy. 2001; 47(4): 227-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11722291&dopt=Abstract

•

Altered channel properties of porins from Haemophilus influenzae: isolates from cystic fibrosis patients. Author(s): Arbing MA, Hanrahan JW, Coulton JW.

Alternative Medicine

153

Source: The Journal of Membrane Biology. 2002 September 15; 189(2): 131-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12235488&dopt=Abstract •

Antifibrotic effect of extracellular biopolymer from submerged mycelial cultures of Cordyceps militaris on liver fibrosis induced by bile duct ligation and scission in rats. Author(s): Nan JX, Park EJ, Yang BK, Song CH, Ko G, Sohn DH. Source: Arch Pharm Res. 2001 August; 24(4): 327-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11534766&dopt=Abstract

•

Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1. Author(s): Jia JD, Bauer M, Cho JJ, Ruehl M, Milani S, Boigk G, Riecken EO, Schuppan D. Source: Journal of Hepatology. 2001 September; 35(3): 392-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11592601&dopt=Abstract

•

Antifibrotic effect of Stephania tetrandra on experimental liver fibrosis induced by bile duct ligation and scission in rats. Author(s): Nan JX, Park EJ, Lee SH, Park PH, Kim JY, Ko G, Sohn DH. Source: Arch Pharm Res. 2000 October; 23(5): 501-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11059831&dopt=Abstract

•

Anti-fibrotic effects of a hot-water extract from Salvia miltiorrhiza roots on liver fibrosis induced by biliary obstruction in rats. Author(s): Nan JX, Park EJ, Kang HC, Park PH, Kim JY, Sohn DH. Source: The Journal of Pharmacy and Pharmacology. 2001 February; 53(2): 197-204. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11273016&dopt=Abstract

•

Antifibrotic effects of matrine on in vitro and in vivo models of liver fibrosis in rats. Author(s): Zhang JP, Zhang M, Zhou JP, Liu FT, Zhou B, Xie WF, Guo C. Source: Acta Pharmacologica Sinica. 2001 February; 22(2): 183-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11741525&dopt=Abstract

•

Aristolochic acids induce chronic renal failure with interstitial fibrosis in saltdepleted rats. Author(s): Debelle FD, Nortier JL, De Prez EG, Garbar CH, Vienne AR, Salmon IJ, Deschodt-Lanckman MM, Vanherweghem JL. Source: Journal of the American Society of Nephrology : Jasn. 2002 February; 13(2): 4316. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11805172&dopt=Abstract

154

Fibrosis

•

Assessment of CFTR chloride channel openers in intact normal and cystic fibrosis murine epithelia. Author(s): Cuthbert AW. Source: British Journal of Pharmacology. 2001 February; 132(3): 659-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11159718&dopt=Abstract

•

Association of cystic fibrosis with abnormalities in fatty acid metabolism. Author(s): Freedman SD, Blanco PG, Zaman MM, Shea JC, Ollero M, Hopper IK, Weed DA, Gelrud A, Regan MM, Laposata M, Alvarez JG, O'Sullivan BP. Source: The New England Journal of Medicine. 2004 February 5; 350(6): 560-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14762183&dopt=Abstract

•

Bak Foong Pills stimulate anion secretion across normal and cystic fibrosis pancreatic duct epithelia. Author(s): Zhu JX, Lo PS, Zhao WC, Tang N, Zhou Q, Rowlands DK, Gou YL, Chung YW, Chan HC. Source: Cell Biology International. 2002; 26(12): 1011-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468376&dopt=Abstract

•

Benefits of music therapy as an adjunct to chest physiotherapy in infants and toddlers with cystic fibrosis. Author(s): Grasso MC, Button BM, Allison DJ, Sawyer SM. Source: Pediatric Pulmonology. 2000 May; 29(5): 371-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10790249&dopt=Abstract

•

Changes of liver fibrosis in chronic hepatitis C patients with no response to interferon-alpha therapy: including quantitative assessment by a morphometric method. Author(s): Yagura M, Murai S, Kojima H, Tokita H, Kamitsukasa H, Harada H. Source: Journal of Gastroenterology. 2000; 35(2): 105-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10680665&dopt=Abstract

•

Cholestasis-induced fibrosis is reduced by interferon alpha-2a and is associated with elevated liver metalloprotease activity. Author(s): Bueno MR, Daneri A, Armendariz-Borunda J. Source: Journal of Hepatology. 2000 December; 33(6): 915-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11131453&dopt=Abstract

•

Cholesterol esterase activities in commercial pancreatic enzyme preparations and implications for use in pancreatic insufficient cystic fibrosis. Author(s): Walters MP, Conway SP.

Alternative Medicine

155

Source: Journal of Clinical Pharmacy and Therapeutics. 2001 December; 26(6): 425-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11722679&dopt=Abstract •

Clinical and functional staging of oral submucous fibrosis. Author(s): Haider SM, Merchant AT, Fikree FF, Rahbar MH. Source: The British Journal of Oral & Maxillofacial Surgery. 2000 February; 38(1): 12-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10783440&dopt=Abstract

•

Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B. Author(s): Liu P, Hu YY, Liu C, Zhu DY, Xue HM, Xu ZQ, Xu LM, Liu CH, Gu HT, Zhang ZQ. Source: World Journal of Gastroenterology : Wjg. 2002 August; 8(4): 679-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174378&dopt=Abstract

•

Clinical observation on the long-term therapeutic effects of traditional Chinese medicine for treatment of liver fibrosis. Author(s): Yang H, Chen Y, Xu R, Shen W, Chen G. Source: J Tradit Chin Med. 2000 December; 20(4): 247-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11263273&dopt=Abstract

•

Clinical studies with silymarin: fibrosis progression is the end point. Author(s): Schuppan D, Hahn EG. Source: Hepatology (Baltimore, Md.). 2001 February; 33(2): 483-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11172360&dopt=Abstract

•

Clinical study on the treatment of liver fibrosis due to hepatitis B by IFN-alpha(1) and traditional medicine preparation. Author(s): Cheng ML, Wu YY, Huang KF, Luo TY, Ding YS, Lu YY, Liu RC, Wu J. Source: World Journal of Gastroenterology : Wjg. 1999 June; 5(3): 267-269. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11819444&dopt=Abstract

•

Co-expression of colligin and collagen in oral submucous fibrosis: plausible role in pathogenesis. Author(s): Kaur J, Rao M, Chakravarti N, Mathur M, Shukla NK, Sanwal BD, Ralhan R. Source: Oral Oncology. 2001 April; 37(3): 282-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11287283&dopt=Abstract

•

Copper enzyme activities in cystic fibrosis before and after copper supplementation plus or minus zinc. Author(s): Best K, McCoy K, Gemma S, Disilvestro RA.

156

Fibrosis

Source: Metabolism: Clinical and Experimental. 2004 January; 53(1): 37-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14681839&dopt=Abstract •

Copper stimulates human oral fibroblasts in vitro: a role in the pathogenesis of oral submucous fibrosis. Author(s): Trivedy C, Meghji S, Warnakulasuriya KA, Johnson NW, Harris M. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2001 September; 30(8): 465-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11545237&dopt=Abstract

•

Cutaneous fibrosis induced by docetaxel: a case report. Author(s): Cleveland MG, Ajaikumar BS, Reganti R. Source: Cancer. 2000 March 1; 88(5): 1078-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10699898&dopt=Abstract

•

Cystic fibrosis-related diabetes. Author(s): Mackie AD, Thornton SJ, Edenborough FP. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 June; 20(6): 425-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12786675&dopt=Abstract

•

Development and evaluation of a multi-family psychoeducational program for cystic fibrosis. Author(s): Goldbeck L, Babka C. Source: Patient Education and Counseling. 2001 August; 44(2): 187-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11479059&dopt=Abstract

•

Dietary fish oil protects against lung and liver inflammation and fibrosis in monocrotaline treated rats. Author(s): Baybutt RC, Rosales C, Brady H, Molteni A. Source: Toxicology. 2002 June 14; 175(1-3): 1-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12049831&dopt=Abstract

•

Directed modification instead of normalization of fatty acid patterns in cystic fibrosis: an emerging concept. Author(s): Christophe A, Robberecht E. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 2001 March; 4(2): 1113. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11224654&dopt=Abstract

Alternative Medicine

157

•

Does the control of alanine aminotransferase levels lead to a regression of liver fibrosis in chronic hepatitis C patients? Author(s): Yagura M, Murai S, Kojima H, Tokita H, Kamitsukasa H, Harada H. Source: Hepatology Research : the Official Journal of the Japan Society of Hepatology. 2001 February; 19(2): 144-157. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11164739&dopt=Abstract

•

Dystroglycan expression in hepatic stellate cells: role in liver fibrosis. Author(s): Bedossa P, Ferlicot S, Paradis V, Dargere D, Bonvoust F, Vidaud M. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2002 August; 82(8): 1053-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12177244&dopt=Abstract

•

Effect of an 8-month treatment with omega-3 fatty acids (eicosapentaenoic and docosahexaenoic) in patients with cystic fibrosis. Author(s): De Vizia B, Raia V, Spano C, Pavlidis C, Coruzzo A, Alessio M. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 2003 January-February; 27(1): 52-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12549599&dopt=Abstract

•

Effect of an organized lipid matrix on lipid absorption and clinical outcomes in patients with cystic fibrosis. Author(s): Lepage G, Yesair DW, Ronco N, Champagne J, Bureau N, Chemtob S, Berube D, Roy CC. Source: The Journal of Pediatrics. 2002 August; 141(2): 178-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183711&dopt=Abstract

•

Effect of compound rhodiola sachalinensis A Bor on CCl4-induced liver fibrosis in rats and its probable molecular mechanisms. Author(s): Wu XL, Zeng WZ, Wang PL, Lei CT, Jiang MD, Chen XB, Zhang Y, Xu H, Wang Z. Source: World Journal of Gastroenterology : Wjg. 2003 July; 9(7): 1559-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854163&dopt=Abstract

•

Effect of Holotrichia diomphalia larvae on liver fibrosis and hepatotoxicity in rats. Author(s): Oh WY, Pyo S, Lee KR, Lee BK, Shin DH, Cho SI, Lee SM. Source: Journal of Ethnopharmacology. 2003 August; 87(2-3): 175-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860304&dopt=Abstract

•

Effect of sea buckthorn on liver fibrosis: a clinical study. Author(s): Gao ZL, Gu XH, Cheng FT, Jiang FH.

158

Fibrosis

Source: World Journal of Gastroenterology : Wjg. 2003 July; 9(7): 1615-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12854177&dopt=Abstract •

Effect of Sho-saiko-to extract on hepatic inflammation and fibrosis in dimethylnitrosamine induced liver injury rats. Author(s): Kusunose M, Qiu B, Cui T, Hamada A, Yoshioka S, Ono M, Miyamura M, Kyotani S, Nishioka Y. Source: Biological & Pharmaceutical Bulletin. 2002 November; 25(11): 1417-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12419951&dopt=Abstract

•

Effect of tetrandrine on experimental hepatic fibrosis induced by bile duct ligation and scission in rats. Author(s): Park PH, Nan JX, Park EJ, Kang HC, Kim JY, Ko G, Sohn DH. Source: Pharmacology & Toxicology. 2000 December; 87(6): 261-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11140824&dopt=Abstract

•

Effects of beta-carotene supplementation for six months on clinical and laboratory parameters in patients with cystic fibrosis. Author(s): Renner S, Rath R, Rust P, Lehr S, Frischer T, Elmadfa I, Eichler I. Source: Thorax. 2001 January; 56(1): 48-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11120904&dopt=Abstract

•

Effects of da ding feng zhu decoction in 30 cases of liver fibrosis. Author(s): Li W, Wang C, Zhang J. Source: J Tradit Chin Med. 2003 December; 23(4): 251-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14719288&dopt=Abstract

•

Effects of L-carnitine and ginkgo biloba extract (EG b 761) in experimental bleomycin-induced lung fibrosis. Author(s): Daba MH, Abdel-Aziz AA, Moustafa AM, Al-Majed AA, Al-Shabanah OA, El-Kashef HA. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 2002 June; 45(6): 461-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12162946&dopt=Abstract

•

Effects of tanshinone VI on the hypertrophy of cardiac myocytes and fibrosis of cardiac fibroblasts of neonatal rats. Author(s): Maki T, Kawahara Y, Tanonaka K, Yagi A, Takeo S. Source: Planta Medica. 2002 December; 68(12): 1103-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12494338&dopt=Abstract

Alternative Medicine

159

•

End of life issues in a palliative care framework for a critically ill adult African American with cystic fibrosis: a case study. Author(s): McNeal GJ. Source: J Cult Divers. 2002 Winter; 9(4): 118-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674889&dopt=Abstract

•

Energy supplements rich in linoleic acid improve body weight and essential fatty acid status of cystic fibrosis patients. Author(s): Steinkamp G, Demmelmair H, Ruhl-Bagheri I, von der Hardt H, Koletzko B. Source: Journal of Pediatric Gastroenterology and Nutrition. 2000 October; 31(4): 418-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11045840&dopt=Abstract

•

Enteral tube feeding for cystic fibrosis. Author(s): Conway SP, Morton A, Wolfe S. Source: Cochrane Database Syst Rev. 2000; (2): Cd001198. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10796753&dopt=Abstract

•

Epidemiological survey of oral submucous fibrosis and leukoplakia in aborigines of Taiwan. Author(s): Yang YH, Lee HY, Tung S, Shieh TY. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2001 April; 30(4): 213-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11302240&dopt=Abstract

•

Essential fatty acid deficiency and nutritional supplementation in cystic fibrosis. Author(s): Lloyd-Still JD. Source: The Journal of Pediatrics. 2002 August; 141(2): 157-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183705&dopt=Abstract

•

Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis. Author(s): Strandvik B, Gronowitz E, Enlund F, Martinsson T, Wahlstrom J. Source: The Journal of Pediatrics. 2001 November; 139(5): 650-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713441&dopt=Abstract

•

Estrogen inhibition of cystic fibrosis transmembrane conductance regulator-mediated chloride secretion. Author(s): Singh AK, Schultz BD, Katzenellenbogen JA, Price EM, Bridges RJ, Bradbury NA. Source: The Journal of Pharmacology and Experimental Therapeutics. 2000 October; 295(1): 195-204. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10991979&dopt=Abstract

160

Fibrosis

•

Experimental study of effect of Ganyanping on fibrosis in rat livers. Author(s): Tang WX, Dan ZL, Yan HM, Wu CH, Zhang G, Liu M, Li Q, Li SB. Source: World Journal of Gastroenterology : Wjg. 2003 June; 9(6): 1292-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800243&dopt=Abstract

•

Expression of p53 protein in oral submucous fibrosis, oral epithelial hyperkeratosis, and oral epithelial dysplasia. Author(s): Chiang CP, Lang MJ, Liu BY, Wang JT, Leu JS, Hahn LJ, Kuo MY. Source: J Formos Med Assoc. 2000 March; 99(3): 229-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10820956&dopt=Abstract

•

Expression of proliferating cell nuclear antigen (PCNA) in oral submucous fibrosis, oral epithelial hyperkeratosis and oral epithelial dysplasia in Taiwan. Author(s): Chiang CP, Lang MJ, Liu BY, Wang JT, Leu JS, Hahn LJ, Kuo MY. Source: Oral Oncology. 2000 July; 36(4): 353-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10899674&dopt=Abstract

•

Faecal elastase-1 and fat-soluble vitamin profiles in patients with cystic fibrosis in Western Norway. Author(s): Dorlochter L, Aksnes L, Fluge G. Source: European Journal of Nutrition. 2002 August; 41(4): 148-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12242582&dopt=Abstract

•

Fatal pulmonary fibrosis associated with induction chemotherapy with carboplatin and vinorelbine followed by CHART radiotherapy for locally advanced non-small cell lung cancer. Author(s): Kirkbride P, Hatton M, Lorigan P, Joyce P, Fisher P. Source: Clin Oncol (R Coll Radiol). 2002 October; 14(5): 361-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12555874&dopt=Abstract

•

Fatty acid metabolism in cystic fibrosis. Author(s): Strandvik B. Source: The New England Journal of Medicine. 2004 February 5; 350(6): 605-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14762189&dopt=Abstract

•

Fatty acids composition of plasma phospholipids and triglycerides in children with cystic fibrosis. The effect of dietary supplementation with an olive and soybean oils mixture. Author(s): Caramia G, Cocchi M, Gagliardini R, Malavolta M, Mozzon M, Frega NG. Source: Pediatr Med Chir. 2003 January-February; 25(1): 42-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920976&dopt=Abstract

Alternative Medicine

161

•

Fatty acids in cystic fibrosis. Author(s): Freedman SD, Shea JC, Blanco PG, Alvarez JG. Source: Current Opinion in Pulmonary Medicine. 2000 November; 6(6): 530-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11100964&dopt=Abstract

•

Fatty acids, alpha-fetoprotein, and cystic fibrosis. Author(s): Mizejewski GJ, Pass KA. Source: Pediatrics. 2001 December; 108(6): 1370-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731663&dopt=Abstract

•

Fibrosing colonopathy revealing cystic fibrosis in a neonate before any pancreatic enzyme supplementation. Author(s): Serban DE, Florescu P, Miu N. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 September; 35(3): 3569. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12352527&dopt=Abstract

•

Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets? Author(s): Schuppan D, Koda M, Bauer M, Hahn EG. Source: Acta Gastroenterol Belg. 2000 October-December; 63(4): 366-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11233519&dopt=Abstract

•

Future pharmacological treatment of cystic fibrosis. Author(s): Zeitlin PL. Source: Respiration; International Review of Thoracic Diseases. 2000; 67(4): 351-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10940786&dopt=Abstract

•

Genistein improves regulatory interactions between G551D-cystic fibrosis transmembrane conductance regulator and the epithelial sodium channel in Xenopus oocytes. Author(s): Suaud L, Carattino M, Kleyman TR, Rubenstein RC. Source: The Journal of Biological Chemistry. 2002 December 27; 277(52): 50341-7. Epub 2002 October 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386156&dopt=Abstract

•

HCO(3)(-)-dependent soluble adenylyl cyclase activates cystic fibrosis transmembrane conductance regulator in corneal endothelium. Author(s): Sun XC, Zhai CB, Cui M, Chen Y, Levin LR, Buck J, Bonanno JA. Source: American Journal of Physiology. Cell Physiology. 2003 May; 284(5): C1114-22. Epub 2003 January 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519749&dopt=Abstract

162

Fibrosis

•

Hepatic fibrosis: From bench to bedside. Author(s): Schuppan D, Porov Y. Source: Journal of Gastroenterology and Hepatology. 2002 December; 17 Suppl 3: S300S305. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472954&dopt=Abstract

•

Hepatic stellate cells: a target for the treatment of liver fibrosis. Author(s): Wu J, Zern MA. Source: Journal of Gastroenterology. 2000; 35(9): 665-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11023037&dopt=Abstract

•

Hepatitis C and liver fibrosis. Author(s): Schuppan D, Krebs A, Bauer M, Hahn EG. Source: Cell Death and Differentiation. 2003 January; 10 Suppl 1: S59-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12655347&dopt=Abstract

•

Herbal medicine Inchin-ko-to (TJ-135) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Author(s): Sakaida I, Tsuchiya M, Kawaguchi K, Kimura T, Terai S, Okita K. Source: Journal of Hepatology. 2003 June; 38(6): 762-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763369&dopt=Abstract

•

Holistic approach of a child with cystic fibrosis: a case report. Author(s): da Costa CC, Cardoso L, de Carvalho Rocha MJ. Source: J Dent Child (Chic). 2003 January-April; 70(1): 86-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762618&dopt=Abstract

•

Hopkins Teen Central: Assessment of an internet-based support system for children with cystic fibrosis. Author(s): Johnson KB, Ravert RD, Everton A. Source: Pediatrics. 2001 February; 107(2): E24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11158498&dopt=Abstract

•

Hydrogen peroxide and nitric oxide in exhaled air of children with cystic fibrosis during antibiotic treatment. Author(s): Jobsis Q, Raatgeep HC, Schellekens SL, Kroesbergen A, Hop WC, de Jongste JC. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2000 July; 16(1): 95-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10933092&dopt=Abstract

•

Hypnosis, Theodore Roosevelt, and the patient with cystic fibrosis. Author(s): Anbar RD.

Alternative Medicine

163

Source: Pediatrics. 2000 August; 106(2 Pt 1): 339-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10920161&dopt=Abstract •

Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function. Author(s): Wood LG, Fitzgerald DA, Lee AK, Garg ML. Source: The American Journal of Clinical Nutrition. 2003 January; 77(1): 150-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499335&dopt=Abstract

•

Inhibition of liver fibrosis in LEC rats by a carotenoid, lycopene, or a herbal medicine, Sho-saiko-to. Author(s): Kitade Y, Watanabe S, Masaki T, Nishioka M, Nishino H. Source: Hepatology Research : the Official Journal of the Japan Society of Hepatology. 2002 March; 22(3): 196-205. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11882416&dopt=Abstract

•

Inhibitive effect of cordyceps sinensis on experimental hepatic fibrosis and its possible mechanism. Author(s): Liu YK, Shen W. Source: World Journal of Gastroenterology : Wjg. 2003 March; 9(3): 529-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12632512&dopt=Abstract

•

Inspiratory muscle training in patients with cystic fibrosis. Author(s): de Jong W, van Aalderen WM, Kraan J, Koeter GH, van der Schans CP. Source: Respiratory Medicine. 2001 January; 95(1): 31-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11207014&dopt=Abstract

•

Interferon gamma (IFN-gamma) may reverse oral submucous fibrosis. Author(s): Haque MF, Meghji S, Nazir R, Harris M. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2001 January; 30(1): 12-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11140895&dopt=Abstract

•

Iron-induced oxidant stress in nonparenchymal liver cells: mitochondrial derangement and fibrosis in acutely iron-dosed gerbils and its prevention by silybin. Author(s): Pietrangelo A, Montosi G, Garuti C, Contri M, Giovannini F, Ceccarelli D, Masini A. Source: Journal of Bioenergetics and Biomembranes. 2002 February; 34(1): 67-79. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11860182&dopt=Abstract

164

Fibrosis

•

Iron-induced oxidant stress leads to irreversible mitochondrial dysfunctions and fibrosis in the liver of chronic iron-dosed gerbils. The effect of silybin. Author(s): Masini A, Ceccarelli D, Giovannini F, Montosi G, Garuti C, Pietrangelo A. Source: Journal of Bioenergetics and Biomembranes. 2000 April; 32(2): 175-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11768750&dopt=Abstract

•

Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Author(s): Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, Gamberini MR, Schwartz E, Cohen AR. Source: Blood. 2002 September 1; 100(5): 1566-9. Erratum In: Blood. 2003 April 1; 101(7): 2460. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12176871&dopt=Abstract

•

L-arginine supplementation accelerates renal fibrosis and shortens life span in experimental lupus nephritis. Author(s): Peters H, Border WA, Ruckert M, Kramer S, Neumayer HH, Noble NA. Source: Kidney International. 2003 April; 63(4): 1382-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12631354&dopt=Abstract

•

Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachlorideinduced hepatic fibrosis in rats. Author(s): Lee TY, Wang GJ, Chiu JH, Lin HC. Source: The Journal of Pharmacy and Pharmacology. 2003 November; 55(11): 1561-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14713368&dopt=Abstract

•

Long-term oral beta-carotene supplementation in patients with cystic fibrosis - effects on antioxidative status and pulmonary function. Author(s): Rust P, Eichler I, Renner S, Elmadfa I. Source: Annals of Nutrition & Metabolism. 2000; 44(1): 30-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10838464&dopt=Abstract

•

Mechanisms by which bradykinin promotes fibrosis in vascular smooth muscle cells: role of TGF-beta and MAPK. Author(s): Douillet CD, Velarde V, Christopher JT, Mayfield RK, Trojanowska ME, Jaffa AA. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2000 December; 279(6): H2829-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11087238&dopt=Abstract

•

Molecular diagnosis of cystic fibrosis in Indian patients--a preliminary report. Author(s): Ashavaid TF, Dherai AJ, Kondkar AA, Raghavan R, Udani SV, Udwadia ZF, Desai D.

Alternative Medicine

165

Source: J Assoc Physicians India. 2003 April; 51: 345-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723646&dopt=Abstract •

Mutations in the nucleotide binding domain 1 signature motif region rescue processing and functional defects of cystic fibrosis transmembrane conductance regulator delta f508. Author(s): DeCarvalho AC, Gansheroff LJ, Teem JL. Source: The Journal of Biological Chemistry. 2002 September 27; 277(39): 35896-905. Epub 2002 July 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12110684&dopt=Abstract

•

Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. Author(s): Dona M, Dell'Aica I, Calabrese F, Benelli R, Morini M, Albini A, Garbisa S. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 April 15; 170(8): 4335-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682270&dopt=Abstract

•

New and emerging therapies for pulmonary complications of cystic fibrosis. Author(s): Tonelli MR, Aitken ML. Source: Drugs. 2001; 61(10): 1379-85. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11558827&dopt=Abstract

•

Non-invasive ventilation assists chest physiotherapy in adults with acute exacerbations of cystic fibrosis. Author(s): Holland AE, Denehy L, Ntoumenopoulos G, Naughton MT, Wilson JW. Source: Thorax. 2003 October; 58(10): 880-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14514944&dopt=Abstract

•

Norepinephrine enhances fibrosis mediated by TGF-beta in cardiac fibroblasts. Author(s): Akiyama-Uchida Y, Ashizawa N, Ohtsuru A, Seto S, Tsukazaki T, Kikuchi H, Yamashita S, Yano K. Source: Hypertension. 2002 August; 40(2): 148-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12154105&dopt=Abstract

•

Nutrition and growth in cystic fibrosis. Author(s): Hankard R, Munck A, Navarro J. Source: Hormone Research. 2002; 58 Suppl 1: 16-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12373008&dopt=Abstract

•

Nutritional status of patients with cystic fibrosis with meconium ileus: a comparison with patients without meconium ileus and diagnosed early through neonatal screening. Author(s): Lai HC, Kosorok MR, Laxova A, Davis LA, FitzSimmon SC, Farrell PM.

166

Fibrosis

Source: Pediatrics. 2000 January; 105(1 Pt 1): 53-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10617704&dopt=Abstract •

Omega-3 fatty acids (from fish oils) for cystic fibrosis. Author(s): Beckles Willson N, Elliott TM, Everard ML. Source: Cochrane Database Syst Rev. 2002; (3): Cd002201. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12137649&dopt=Abstract

•

Oral calorie supplements for cystic fibrosis. Author(s): Smyth R, Walters S. Source: Cochrane Database Syst Rev. 2000; (2): Cd000406. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10796716&dopt=Abstract

•

Oral submucous fibrosis in a 11-year-old Bangladeshi girl living in the United Kingdom. Author(s): Shah B, Lewis MA, Bedi R. Source: British Dental Journal. 2001 August 11; 191(3): 130-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11523884&dopt=Abstract

•

Oral submucous fibrosis patients have altered levels of cytokine production. Author(s): Haque MF, Meghji S, Khitab U, Harris M. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2000 March; 29(3): 123-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10738939&dopt=Abstract

•

Oxidative stress, plant-derived antioxidants and liver fibrosis. Author(s): Gebhardt R. Source: Planta Medica. 2002 April; 68(4): 289-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11988849&dopt=Abstract

•

Percutaneous release of abductor pollicis brevis muscle fibrosis in a bowler--a case report. Author(s): Yen HH, Lin GT, Tien YC, Fu YC, Lin SY. Source: Kaohsiung J Med Sci. 2000 November; 16(11): 592-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11294067&dopt=Abstract

•

PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis. Author(s): Krishna G, Liu K, Shigemitsu H, Gao M, Raffin TA, Rosen GD. Source: American Journal of Pathology. 2001 March; 158(3): 997-1004. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11238047&dopt=Abstract

Alternative Medicine

167

•

Pharmacological approaches to correcting the ion transport defect in cystic fibrosis. Author(s): Roomans GM. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2003; 2(5): 413-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14719993&dopt=Abstract

•

Pharmacological treatment of the ion transport defect in cystic fibrosis. Author(s): Roomans GM. Source: Expert Opinion on Investigational Drugs. 2001 January; 10(1): 1-19. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11116277&dopt=Abstract

•

Pharmacotherapy of the ion transport defect in cystic fibrosis. Author(s): Kunzelmann K, Mall M. Source: Clinical and Experimental Pharmacology & Physiology. 2001 November; 28(11): 857-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11703384&dopt=Abstract

•

Physiotherapy in cystic fibrosis. Author(s): Prasad SA, Tannenbaum EL, Mikelsons C. Source: Journal of the Royal Society of Medicine. 2000; 93 Suppl 38: 27-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10911816&dopt=Abstract

•

Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats. Author(s): Zhong Z, Froh M, Lehnert M, Schoonhoven R, Yang L, Lind H, Lemasters JJ, Thurman RG. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2003 November; 285(5): G1004-13. Epub 2003 June 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791596&dopt=Abstract

•

Posture and cystic fibrosis. Author(s): Tattersall R, Walshaw MJ. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 18-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906321&dopt=Abstract

•

Present situation in preventing and treating liver fibrosis with TCM drugs. Author(s): Du B, You S. Source: J Tradit Chin Med. 2001 June; 21(2): 147-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11498907&dopt=Abstract

•

Prevention of permanent arthrofibrosis after anterior cruciate ligament reconstruction alone or combined with associated procedures: a prospective study in 443 knees. Author(s): Noyes FR, Berrios-Torres S, Barber-Westin SD, Heckmann TP.

168

Fibrosis

Source: Knee Surgery, Sports Traumatology, Arthroscopy : Official Journal of the Esska. 2000; 8(4): 196-206. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10975259&dopt=Abstract •

Progress of intervention of renal interstitial fibrosis with Chinese traditional herbal medicine. Author(s): Wei LB, Ma ZG, Ye RG, Chen BT, Zhan SC, Huang H. Source: Di Yi June Yi Da Xue Xue Bao. 2002 October; 22(10): 946-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12377630&dopt=Abstract

•

Progressive interstitial renal fibrosis due to Chinese herbs in a patient with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome. Author(s): Nishimagi E, Kawaguchi Y, Terai C, Kajiyama H, Hara M, Kamatani N. Source: Intern Med. 2001 October; 40(10): 1059-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11688835&dopt=Abstract

•

Providing services for families with a genetic condition: a contrast between cystic fibrosis and Down syndrome. Author(s): Collins V, Williamson R. Source: Pediatrics. 2003 November; 112(5): 1177-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14595065&dopt=Abstract

•

Psychological interventions for cystic fibrosis. Author(s): Glasscoe CA, Quittner AL. Source: Cochrane Database Syst Rev. 2003; (3): Cd003148. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917948&dopt=Abstract

•

Quality of life in children and adolescents with cystic fibrosis: implications for optimizing treatments and clinical trial design. Author(s): Abbott J, Gee L. Source: Paediatric Drugs. 2003; 5(1): 41-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12513105&dopt=Abstract

•

Raised tissue copper levels in oral submucous fibrosis. Author(s): Trivedy CR, Warnakulasuriya KA, Peters TJ, Senkus R, Hazarey VK, Johnson NW. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2000 July; 29(6): 241-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10890553&dopt=Abstract

Alternative Medicine

169

•

Rapidly progressive interstitial renal fibrosis associated with Chinese herbal medications. Author(s): Chang CH, Wang YM, Yang AH, Chiang SS. Source: American Journal of Nephrology. 2001 November-December; 21(6): 441-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11799260&dopt=Abstract

•

Regulation of the hepatic endothelin system in advanced biliary fibrosis in rats. Author(s): Rothermund L, Leggewie S, Schwarz A, Thone-Reinecke C, Cho JJ, Bauer C, Paul M, Neumayer HH, Schuppan D, Hocher B. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2000 June; 38(6): 507-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10987198&dopt=Abstract

•

Religious/spiritual coping in childhood cystic fibrosis: a qualitative study. Author(s): Pendleton SM, Cavalli KS, Pargament KI, Nasr SZ. Source: Pediatrics. 2002 January; 109(1): E8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11773576&dopt=Abstract

•

Renal interstitial fibrosis and urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). Author(s): Nortier JL, Vanherweghem JL. Source: Toxicology. 2002 December 27; 181-182: 577-80. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12505369&dopt=Abstract

•

Riboflavin deficiency in cystic fibrosis: three case reports. Author(s): McCabe H. Source: Journal of Human Nutrition and Dietetics : the Official Journal of the British Dietetic Association. 2001 October; 14(5): 365-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11906577&dopt=Abstract

•

Sclerosing malignant lymphoma mimicking idiopathic retroperitoneal fibrosis: importance of clonality study. Author(s): Chim CS, Liang R, Chan AC. Source: The American Journal of Medicine. 2001 August 15; 111(3): 240-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11545095&dopt=Abstract

•

Scutellaria baicalensis inhibits liver fibrosis induced by bile duct ligation or carbon tetrachloride in rats. Author(s): Nan JX, Park EJ, Kim YC, Ko G, Sohn DH. Source: The Journal of Pharmacy and Pharmacology. 2002 April; 54(4): 555-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999134&dopt=Abstract

170

Fibrosis

•

Self-hypnosis for patients with cystic fibrosis. Author(s): Anbar RD. Source: Pediatric Pulmonology. 2000 December; 30(6): 461-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11109057&dopt=Abstract

•

Sex differences in weight perception and nutritional behaviour in adults with cystic fibrosis. Author(s): Walters S. Source: Journal of Human Nutrition and Dietetics : the Official Journal of the British Dietetic Association. 2001 April; 14(2): 83-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11330265&dopt=Abstract

•

Sho-saiko-to: Japanese herbal medicine for protection against hepatic fibrosis and carcinoma. Author(s): Shimizu I. Source: Journal of Gastroenterology and Hepatology. 2000 March; 15 Suppl: D84-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10759225&dopt=Abstract

•

Silymarin retards the progression of alcohol-induced hepatic fibrosis in baboons. Author(s): Lieber CS, Leo MA, Cao Q, Ren C, DeCarli LM. Source: Journal of Clinical Gastroenterology. 2003 October; 37(4): 336-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506392&dopt=Abstract

•

Steroid therapy in chronic interstitial renal fibrosis: the case of Chinese-herb nephropathy. Author(s): Martinez MC, Nortier J, Vereerstraeten P, Vanherweghem JL. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 November; 17(11): 2033-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12401870&dopt=Abstract

•

Superior vena cava syndrome caused by chemotherapy-induced fibrosis. Author(s): Turk HM, Camci C, Buyukberber S, Tuncozgur B, Sivrikoz C, Elbeyli L, Sari I. Source: J Chemother. 2002 August; 14(4): 417-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12420862&dopt=Abstract

•

Suppression of Rat Stellate Cell Activation and Liver Fibrosis by a Japanese Herbal Medicine, Inchinko-to (TJ135). Author(s): Imanishi Y, Maeda N, Matsui H, Takashima T, Seki S, Arakawa T, Kawada N. Source: Comparative Hepatology [electronic Resource]. 2004 January 14; 3 Suppl 1: S11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14960163&dopt=Abstract

Alternative Medicine

171

•

Tetrandrine prevents tissue inhibitor of metalloproteinase-1 messenger RNA expression in rat liver fibrosis. Author(s): Lee SH, Nan JX, Sohn DH. Source: Pharmacology & Toxicology. 2001 October; 89(4): 214-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11881973&dopt=Abstract

•

Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammation. Author(s): Brewer GJ. Source: Journal of Cellular and Molecular Medicine. 2003 January-March; 7(1): 11-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767257&dopt=Abstract

•

The collagenolytic effects of the traditional Chinese medicine preparation, Han-DanGan-Le, contribute to reversal of chemical-induced liver fibrosis in rats. Author(s): Li C, Luo J, Li L, Cheng M, Huang N, Liu J, Waalkes MP. Source: Life Sciences. 2003 February 21; 72(14): 1563-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12551745&dopt=Abstract

•

The cystic fibrosis mutation G551D alters the non-Michaelis-Menten behavior of the cystic fibrosis transmembrane conductance regulator (CFTR) channel and abolishes the inhibitory Genistein binding site. Author(s): Derand R, Bulteau-Pignoux L, Becq F. Source: The Journal of Biological Chemistry. 2002 September 27; 277(39): 35999-6004. Epub 2002 July 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12124395&dopt=Abstract

•

The ethanol-soluble part of a hot-water extract from Artemisia iwayomogi inhibits liver fibrosis induced by carbon tetrachloride in rats. Author(s): Park EJ, Nan JX, Kim JY, Kang HC, Choi JH, Lee SJ, Lee BH, Kim SJ, Lee JH, Kim YC, Sohn DH. Source: The Journal of Pharmacy and Pharmacology. 2000 July; 52(7): 875-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10933139&dopt=Abstract

•

The role of antioxidant vitamins (C and E), selenium and Nigella sativa in the prevention of liver fibrosis and cirrhosis in rabbits: new hopes. Author(s): Turkdogan MK, Agaoglu Z, Yener Z, Sekeroglu R, Akkan HA, Avci ME. Source: Dtsch Tierarztl Wochenschr. 2001 February; 108(2): 71-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11367885&dopt=Abstract

•

The role of vitamins in cystic fibrosis. Author(s): Carr SB, McBratney J.

172

Fibrosis

Source: Journal of the Royal Society of Medicine. 2000; 93 Suppl 38: 14-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10911814&dopt=Abstract •

Therapeutic effect of gypenoside on chronic liver injury and fibrosis induced by CCl4 in rats. Author(s): Chen JC, Tsai CC, Chen LD, Chen HH, Wang WC. Source: The American Journal of Chinese Medicine. 2000; 28(2): 175-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10999436&dopt=Abstract

•

Therapeutic effect of Zijin capsule in liver fibrosis in rats. Author(s): Cai DY, Zhao G, Chen JC, Ye GM, Bing FH, Fan BW. Source: World Journal of Gastroenterology : Wjg. 1998 June; 4(3): 260-263. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11819291&dopt=Abstract

•

Two mechanisms of genistein inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in murine cell line. Author(s): Lansdell KA, Cai Z, Kidd JF, Sheppard DN. Source: The Journal of Physiology. 2000 April 15; 524 Pt 2: 317-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10766914&dopt=Abstract

•

Upregulation of cystic fibrosis transmembrane conductance regulator expression by oestrogen and Bak Foong Pill in mouse uteri. Author(s): Rowlands DK, Tsang LL, Cui YG, Chung YW, Chan LN, Liu CQ, James T, Chan HC. Source: Cell Biology International. 2001; 25(10): 1033-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11589624&dopt=Abstract

•

Visceral organ involvement is infrequent in oral submucous fibrosis (OSF). Author(s): Rajendra R, George B, Sivakaran S, Narendranathan N. Source: Indian J Dent Res. 2001 January-March; 12(1): 7-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11441804&dopt=Abstract

•

Vitamin K supplementation in cystic fibrosis. Author(s): van Hoorn JH, Hendriks JJ, Vermeer C, Forget PP. Source: Archives of Disease in Childhood. 2003 November; 88(11): 974-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612359&dopt=Abstract

Alternative Medicine

173

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/

•

AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

•

Chinese Medicine: http://www.newcenturynutrition.com/

•

drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html

•

Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

•

Google: http://directory.google.com/Top/Health/Alternative/

•

Healthnotes: http://www.healthnotes.com/

•

MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

•

Open Directory Project: http://dmoz.org/Health/Alternative/

•

HealthGate: http://www.tnp.com/

•

WebMD®Health: http://my.webmd.com/drugs_and_herbs

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

•

Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to fibrosis; 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 Bone Marrow Disorders Source: Integrative Medicine Communications; www.drkoop.com Chronic Myelogenous Leukemia Source: Integrative Medicine Communications; www.drkoop.com Cystic Fibrosis Source: Healthnotes, Inc.; www.healthnotes.com Cystic Fibrosis Source: Integrative Medicine Communications; www.drkoop.com Depression Source: Integrative Medicine Communications; www.drkoop.com Hepatitis Source: Healthnotes, Inc.; www.healthnotes.com

174

Fibrosis

Leukoplakia Source: Healthnotes, Inc.; www.healthnotes.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Lymphoma Source: Integrative Medicine Communications; www.drkoop.com Malabsorption Source: Healthnotes, Inc.; www.healthnotes.com Myelofibrosis Source: Integrative Medicine Communications; www.drkoop.com Myeloproliferative Disorders Source: Integrative Medicine Communications; www.drkoop.com Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com Polycythemia Vera Source: Integrative Medicine Communications; www.drkoop.com Thrombocytosis Source: Integrative Medicine Communications; www.drkoop.com •

Alternative Therapy Hypnotherapy Source: Integrative Medicine Communications; www.drkoop.com Massage Source: Integrative Medicine Communications; www.drkoop.com

•

Herbs and Supplements Aloe Alternative names: Aloe vera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Angelica sinensis Source: Integrative Medicine Communications; www.drkoop.com Aristolochia Alternative names: Snakeroot, Guaco; Aristolochia sp Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Astragalus Mem Alternative names: Huang-Qi; Astragalus membranaceus Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

Alternative Medicine

175

Astragalus Sp Alternative names: Vetch, Rattlepod, Locoweed; Astragalus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Borago Alternative names: Borage; Borago officinalis Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Chinese Angelica Source: Integrative Medicine Communications; www.drkoop.com Curcuma Alternative names: Turmeric; Curcuma longa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Danggui Alternative names: Angelica sinensis, Chinese Angelica, Dang Gui, Danngui, Dong Qua, Tang Kuei, Tan Kue Bai zhi(Note: Dong quai should not be confused with Angelica root or Angelica seed.) Source: Integrative Medicine Communications; www.drkoop.com Digestive Enzymes Source: Healthnotes, Inc.; www.healthnotes.com Dong Quai Alternative names: Angelica sinensis, Chinese Angelica, Dang Gui, Danngui, Dong Qua, Tang Kuei, Tan Kue Bai zhi(Note: Dong quai should not be confused with Angelica root or Angelica seed.) Source: Integrative Medicine Communications; www.drkoop.com Glutamine Source: Integrative Medicine Communications; www.drkoop.com Glutathione Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Lecithin Source: Prima Communications, Inc.www.personalhealthzone.com Lipase Source: Healthnotes, Inc.; www.healthnotes.com Milk Thistle Alternative names: Silybum marianum, Carduus marianus Source: Healthnotes, Inc.; www.healthnotes.com

176

Fibrosis

Musa Banana Alternative names: Plantain, Banana; Musa sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Tang Kuei Source: Integrative Medicine Communications; www.drkoop.com Taurine Source: Healthnotes, Inc.; www.healthnotes.com Tribulus Puncture Alternative names: Puncture Vine, Goathead; Tribulus terrestris L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

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.

177

CHAPTER 4. CLINICAL TRIALS AND FIBROSIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning fibrosis.

Recent Trials on Fibrosis The following is a list of recent trials dedicated to fibrosis.8 Further information on a trial is available at the Web site indicated. •

A Pilot Trial of Phenylbutyrate/Genistein Duotherapy (for Cystic Fibrosis) Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Cystic Fibrosis Foundation Therapeutics Purpose - Excerpt: We are testing a new combination of medicines, to determine if they could be used to treat cystic fibrosis (CF). Subjects with CF who have two copies of the most common mutation (change) found in patients with CF called DF508. CF is caused by a lack of chloride movement in the nose, sinuses, lungs, intestines, pancreas and sweat glands. We are conducting this study to determine the safety of using a combination of two medicines, Phenylbutyrate and Genistein, to improve the ability of the cells lining the nose to regulate movement of salt (chloride) and water in people with CF. Phenylbutyrate has been extensively used to treat patients with rare metabolic diseases (which are very different from CF), Phenylbutyrate is an investigational drug for the purpose of this study. Genistein is a naturally occurring substance that is found in food products such as soy and tofu, but is also an investigational drug for this study. Both drugs may be able to restore normal chloride movements in body organs and glands. We will be studying salt and water in the nose movement by a technique called nasal transepithelial potential difference (NPD). Phase(s): Phase I Study Type: Interventional

8

These are listed at www.ClinicalTrials.gov.

178

Fibrosis

Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016744 •

Efficacy and safety of oral bosentan in patients with Idiopathic Pulmonary Fibrosis Condition(s): Idiopathic Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): Actelion Purpose - Excerpt: Endothelin-1 (ET-1) is expressed in a variety of pulmonary pathological conditions including pulmonary vascular disease and pulmonary fibrosis. Bosentan (an oral dual ET-1 receptor antagonist) could delay the progression of idiopathic pulmonary fibrosis (IPF), a condition for which no established treatment is available. The present trial investigates a possible use of bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH) WHO class III and IV, to a new category of patients suffering from IPF. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00071461

•

Evaluation of Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis Condition(s): Polycystic Kidney, Autosomal Recessive Study Status: This study is currently recruiting patients. Sponsor(s): National Human Genome Research Institute (NHGRI) Purpose - Excerpt: This study will evaluate patients with autosomal recessive polycystic kidney disease (ARPKD) and congenital hepatic fibrosis (CHF). People with ARPKD develop kidney cysts and eventually kidney failure. Hypertension (high blood pressure), poor growth, and urinary infections are common symptoms. CHF is a specific type of liver disease associated with ARPKD. It involves fibrosis, or scarring, of the liver, which can lead to life-threatening complications, including internal bleeding of enlarged blood vessels called varices in the esophagus (food pipe). The goal of the study is to better understand the medical complications of ARPKD and CHF and identify characteristics that can help in the design of new treatments. Patients 6 months of age and older with ARPKD may be eligible for this 5- to 10-year study, excluding those who require frequent hospitalizations due to complications of end-stage renal disease or liver disease. Participants will undergo some or all of the following tests and procedures every 12 months during a 4- to 5-day hospital admission at the NIH Clinical Center: Medical history and physical examination; 24-hour urine collection and blood tests to evaluate kidney and liver function; face and body photography to document growth and the effects of enlarged organs on posture; blood tests for basic research, including genetic studies related to ARPKD - Ultrasound of the abdomen to see changes in the kidneys, liver, spleen, and portal vein (vein leading to the liver); ultrasound of the heart in patients with hypertension. Ultrasound uses a probe held on the skin to send sound waves to organs. A computer converts the sound waves into images. - Magnetic resonance imaging (MRI) of the liver and kidneys. MRI uses a magnetic field and radio waves to scan organs while the patient lies still in a tunnel-like machine. -

Clinical Trials 179

Electroencephalogram (EEG) in patients with portal hypertension to look for signs of hepatic encephalopathy. Electrodes are placed on the head to measure electrical activity of the brain (brain waves). - Cognitive function testing in patients with portal hypertension. Brain function is assessed through paper and pencil exercises that involve answering questions or drawing pictures. - X-rays and other tests, such as placement of intravenous lines, as needed for medical management - Endoscopy, if needed, to help prevent bleeding of esophageal varices. For this procedure, the patient is given medication for relaxation and sleep. Then, a tube with a light on the tip is advanced through the mouth down the food pipe and stomach to examine the organs and stop any bleeding. Results of tests performed, including information on the genetic cause of the ARPKD, will be provided the patient (or parent) if requested. In addition, medical data gathered on participants will be submitted to the ARPKD registry in Birmingham, Alabama. Identifying information will not be attached to the information. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00068224 •

Identification of Genes Associated with Lung Disease in Patients with Rheumatoid Arthritis Condition(s): Healthy; Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Data gathered from previous research studies suggest that genetics may play a role in the development of PF in patients with rheumatoid arthritis. However, the actual genetic factors involved in the disease process have not been identified. The goal of this study is to identify the genetic markers in patients with pulmonary fibrosis and rheumatoid arthritis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001885

•

Idiopathic Pulmonary Fibrosis Condition(s): Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): Wyeth-Ayerst Research Purpose - Excerpt: The objective of the study is to evaluate the safety and efficacy of etanercept in comparison with placebo in a double-blind, parallel, randomized fashion in subjects with idiopathic pulmonary fibrosis (IPF) who failed previous therapy. The treatment period will be up to 1 year. The primary objective is evaluation of safety and efficacy. Secondary: The secondary objective is to evaluate quality of life (QoL) and pharmacokinetics (PK). Phase(s): Phase II

180

Fibrosis

Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00063869 •

Lung Disease Associated with Rheumatoid Arthritis Condition(s): Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Patients participating in this study will undergo a series of tests and examinations before and throughout the study. The tests include blood and urine tests, electrical measures of heart function (ECG), chest x-rays, CAT scans, nuclear medicine scans, breathing tests, exercise tests, and fiberoptic bronchoscopy. The goals of this study are to: 1. Estimate how common pulmonary fibrosis is in patients with rheumatoid arthritis, 2. Describe the natural course of pulmonary fibrosis in patients with rheumatoid arthritis, 3. Estimate the survival rate of patients with pulmonary fibrosis and rheumatoid arthritis, and 4. Learn more about the factors that contribute to the development or progression fibrotic lung disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001876

•

Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome Condition(s): Albinism; Inborn Errors of Metabolism; Oculocutaneous Albinism; Platelet Storage Pool Deficiency; Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Human Genome Research Institute (NHGRI) Purpose - Excerpt: Hermansky-Pudlak Syndrome (HPS) is an inherited disease which results in decreased pigmentation (oculocutaneous albinism), bleeding problems due to a platelet abnormality (platelet storage pool defect), and storage of an abnormal fatprotein compound (lysosomal accumulation of ceroid lipofuscin). The disease can cause poor functioning of the lungs, intestine, kidneys, or heart. The most serious complication of the disease is pulmonary fibrosis and typically causes death in patients ages 40 - 50 years old. The disorder is common in Puerto Rico, where many of the clinical research studies on the disease have been conducted. Neither the full extent of the disease nor the basic cause of the disease is known. There is no known treatment for HPS. The drug Pirfenidone blocks the biochemical process of inflammation and has been reported to slow or reverse pulmonary fibrosis in animal systems. In this study researchers will select 40 patients diagnosed with pulmonary fibrosis 20 who have not received steroid therapy in the last 3 months and 20 currently taking steroids. The patients will be randomly divided into 4 groups. The patients will not know if they are taking pirfenidone or a placebo "sugar pill". 1. Group one will be patients not taking steroids who will receive pirfenidone. 2. Group two will be patients not taking steroids who will receive a placebo "sugar pill" 3. Group three will be patients taking steroids

Clinical Trials 181

who will receive pirfenidone. 4. Group four will be patients taking steroids who will receive a placebo "sugar pill". The major outcome measurement of the therapy will be a change in the lung function (forced vital capacity). The study will be stopped if one therapy proves to be more effective than the others. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001596 •

Phase II Study of Growth Hormone in Children With Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): University of Utah Purpose - Excerpt: Objectives: I. Determine the effect of growth hormone on height, height velocity, body weight, and lean body mass in patients with cystic fibrosis. II. Determine the effect of growth hormone on pulmonary function in these patients. III. Determine the impact of this drug on the quality of life in these patients. IV. Determine if the clinical response from this drug is sustained in these patients. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016445

•

Randomized Study of Alendronate in Adult Patients With Cystic Fibrosis Related Osteoporosis Condition(s): Osteoporosis; Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; University of North Carolina Purpose - Excerpt: Objectives: I. Determine the bioavailability and biologic effect of alendronate on bone metabolism in patients with cystic fibrosis. II. Assess the safety and efficacy of this treatment regimen in improving osteoporosis in this patient population. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004489

•

Safety and Efficacy of Recombinant Adeno-Associated Virus containing CFTR in the treatment of Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): Targeted Genetics Coporation; Cystic Fibrosis Foundation Purpose - Excerpt: The purpose of this study is to confirm the improvement in pulmonary function and cytokine levels observed in the recently completed multidose aerosol study for the treatment of Cystic Fibrosis (CF).

182

Fibrosis

Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00073463 •

Safety and Tolerability Study of FG-3019 in Patients with Idiopathic Pulmonary Fibrosis Condition(s): Idiopathic Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): FibroGen, Inc. Purpose - Excerpt: The purpose of this study is to evaluate the safety and tolerability of FG-3019, a therapeutic antibody designed to block the pro-fibrotic activity of connective tissue growth factor (CTGF). CTGF triggers the production of collagen and fibronectin, which cause scarring and thickening of the lungs. Approximately 18 to 27 males and females, 21 to 80 years of age with a diagnosis of idiopathic pulmonary fibrosis (IPF) will be enrolled in this study. The duration of the study is approximately one month, during which patients will receive a single infusion of FG-3019. In addition, there will be two follow-up visits 6 and 12 months after receiving the study drug. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00074698

•

Specimen Collection for Individuals with Lung Disease Associated with Rheumatoid Arthritis Condition(s): Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Researchers hope to improve their understanding of the disease process involved in PF and RA by analyzing specimens collected by bronchoscopy, lung biopsy, lung transplantation, or autopsy from patients with these conditions. The purpose of this study is to collect specimens from rheumatoid arthritis patients with and without pulmonary fibrosis as well as patients with pulmonary fibrosis without associated diseases or cause (idiopathic pulmonary fibrosis). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001884

•

Study of Hepatic Glucose Production and De novo Lipogenesis in Patients With Cystic Fibrosis Condition(s): Cystic Fibrosis

Clinical Trials 183

Study Status: This study is currently recruiting patients. Sponsor(s): University of Utah Purpose - Excerpt: Objectives: I. Determine the amount of hepatic glucose production derived from gluconeogenesis and glycogenolysis in the post-absorptive state in patients with cystic fibrosis. II. Determine de novo lipogenesis in relationship to resting energy expenditure in this patient population. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014781 •

Study of Tauroursodeoxycholic Acid for Hepatobiliary Disease in Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; Children's Hospital Medical Center - Cincinnati Purpose - Excerpt: Objectives: I. Determine the optimum dose of tauroursodeoxycholic acid (TUDCA) required to achieve maximal bioavailability for patients with cystic fibrosis-associated liver disease. II. Compare optimized doses of TUDCA with ursodiol (ursodeoxycholic acid; UDCA) for effects on biliary bile acid composition and metabolism, serum biochemistries, fat absorption, and fat-soluble vitamin status in these patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004441

•

Study of Total Energy Expenditure in Infants and Children With Moderate to Severe Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Indiana University Purpose - Excerpt: Objectives: I. Compare the resting energy expenditure using respiratory calorimetry in infants and children with moderate to severe cystic fibrosis versus age matched healthy controls. II. Determine the total energy expenditure and energy spent on physical activity using the doubly labeled water method in these patient populations. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006273

•

Studying Patients with Cystic Fibrosis and Other Pulmonary and Pancreatic Disorders Condition(s): Bronchiectasis; Cystic Fibrosis; Pancreatic Insufficiency Study Status: This study is currently recruiting patients.

184

Fibrosis

Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: Cystic fibrosis is a disease that affects many parts of the body, particularly the lungs and pancreas. The main purpose of this study is to further understand the natural history, clinical presentation, and genetics of cystic fibrosis. Patients with cystic fibrosis will be asked to participate in this study by undergoing standard medical tests and procedures. Patients will have a history taken and have a physical examination as well as blood tests, and a sweat test (a test for cystic fibrosis of the pancreas in which electrolytes are measured in collected sweat). Patients may also be asked to provide samples of urine, stool, and sputum for additional tests. More complicated procedures such as bronchoscopy or bronchoalveolar lavage may be required for diagnosis, treatment, or research purposes. Patients will receive appropriate treatment with antibiotics, pancreatic enzymes, vitamins, physiotherapy, and other agents. Medications may be given by mouth or injected into a vein. This study will provide patients with information on the prognosis of the disease as well as recommendations for management of cystic fibrosis. In addition this study will provide information to researchers which may be useful in other studies of cystic fibrosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001223 •

The INSPIRE A Study of Interferon gamma-1b for Idiopathic Pulmonary Fibrosis (IPF) Condition(s): Idiopathic Pulmonary Fibrosis; Lung Disease; Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): InterMune Purpose - Excerpt: - Purpose: A phase 3, randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of 200 µg of recombinant Interferon gamma-1b administered by subcutaneous (SC) injection, compared with placebo, in patients with IPF * Enrollment: 600 patients will be enrolled from approximately 70 centers in North America and Europe * Randomization: 2:1 active-to-placebo ratio * Duration: 2 years active drug or placebo (rescue therapy will be permitted for patients who meet predefined criteria) Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00075998

•

Tissue Collection from People with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will examine the relationship between bacterial products in lung infections in cystic fibrosis and disease severity. It will examine plasma and lung tissue from cystic fibrosis patients. Patients with cystic fibrosis and having certain genetic characteristics, who are between 9 and 65 years of age and any cystic fibrosis

Clinical Trials 185

patient undergoing lung transplantation at INOVA Fairfax Hospital in Fairfax, Virginia, may be eligible for this study. Lung specimens of participating transplant patients will be collected at INOVA Fairfax Hospital. Patients who participate in the apheresis portion of the study will be admitted to the NIH Clinical Center for 2 to 3 days. Apheresis is a procedure for collecting large quantities of specific blood components. For this study, plasma-the liquid part of the blood-will be collected. For the procedure, whole blood is collected through a needle in an arm vein, similar to donating blood. The blood is separated into its components by centrifugation (spinning), the plasma and white cells are extracted and collected in a bag, and the red cells are returned to the body, either through the same needle or through another needle in the other arm. During the hospital stay, patients may also be asked to participate in other cystic fibrosis studies involving blood tests, an echocardiogram (ultrasound test of the heart), urine pregnancy test, and pulmonary function (breathing) tests. Patients who cannot undergo apheresis may be asked to provide up to an additional 100 cc (7 tablespoons) of blood for research to look at bacterial products. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00015756 •

An Open-label study of the safety and efficacy of subcutaneous recombinant interferon-gamma 1b (IFN-gamma 1b) in patients with Idiopathic Pulmonary Fibrosis (IPF) Condition(s): Lung Disease; Pulmonary Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): InterMune Purpose - Excerpt: Study GIPF-004 is an open-label, multicenter study that will enroll approximately 250 patients who complete Protocol GIPF-001. The purpose of this study is to assess the safety and efficacy of continued IFN-gamma 1b therapy in this welldefined cohort of patients for up to 48 weeks. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00052052

•

An Open-Label Study of the Safety of Interferon gamma-1b in Patients with IPF Condition(s): Idiopathic Pulmonary Fibrosis; Pulmonary Fibrosis; Lung Disease Study Status: This study is no longer recruiting patients. Sponsor(s): InterMune Purpose - Excerpt: Open-label therapy will be administered to up to 220 patients, following completion of either InterMune Protocol GIPF-002 Part B or Protocol GIPF004, to assess the long-term safety of subcutaneous Interferon gamma-1b. The study duration will be 5 years. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below

186

Fibrosis

Web Site: http://clinicaltrials.gov/ct/show/NCT00076635 •

Gene Modifiers in Cystic Fibrosis Lung Disease Condition(s): Cystic Fibrosis; Lung Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To examine genetic modifiers of the severity of cystic fibrosis lung disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037765

•

Linkage Study in Familial Pulmonary Fibrosis Condition(s): Pulmonary Fibrosis; Lung Diseases; Lung Diseases, Interstitial Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To map the gene (or genes) for familial pulmonary fibrosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016627

•

Phase I Pilot Study of Gene Therapy for Cystic Fibrosis Using Cationic Liposome Mediated Gene Transfer Condition(s): Cystic Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Alabama Purpose - Excerpt: Objectives: Determine whether copies of the cystic fibrosis gene (pGT-1) can be delivered to the cells lining the nose of cystic fibrosis patients using cationic liposome (DMRIE/DOPE) mediated gene transfer. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004471

•

Phase I Randomized Study of Adeno-Associated Virus-CFTR Vector in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Florida

Clinical Trials 187

Purpose - Excerpt: Objectives: I. Determine the maximum tolerated dose of recombinant adeno-associated virus-CFTR vector in patients with cystic fibrosis. II. Assess the safety of this gene therapy in these patients. III. Assess the in vivo gene transfer of this vector in these patients. IV. Assess the CFTR gene expression and physiologic activity following gene transfer in these patients. V. Assess the clinical impact of CFTR gene expression following gene transfer in these patients. VI. Monitor patient immune response directed against CFTR or vector components following vector administration. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004533 •

Phase II Pilot Study to Compare the Bioavailability of Buffered, Enteric-Coated Ursodiol with Unmodified Ursodiol for Chronic Cholestatic Liver Disease and Cystic Fibrosis-Associated Liver Disease Condition(s): Cystic Fibrosis; Gastrointestinal Diseases; Cholestasis Study Status: This study is no longer recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Children's Hospital Medical Center - Cincinnati Purpose - Excerpt: Objectives: I. Compare the bioavailability of polymer-coated and buffered ursodiol (ursodeoxycholic acid) to unmodified ursodiol in patients with cystic fibrosis-associated liver disease or chronic cholestatic liver disease. II. Compare the differences in pruritus, weight gain, and liver function for both treatments. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004315

•

Pirfenidone to Treat Radiation-Induced Fibrosis Condition(s): Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: This study will evaluate the safety and effectiveness of the experimental anti-fibrotic drug pirfenidone in treating fibrosis (scar tissue) resulting from cancer radiation treatment. Fibrosis in the radiation-treated area is probably the most significant long-term side effect of this therapy. Depending on the area involved, fibrosis can lead to ulceration with poor wound healing, impaired range of motion, swallowing problems and neuropathy. Pirfenidone may prevent or remove excessive scar tissue found in fibrosis associated with injured tissues or organs such as the lung, skin, joints, kidney, prostate and liver. Patients 18 years of age and older with radiationinduced fibrosis causing at least moderate disability in range of motion, strength, pain, swelling, or swallowing may be eligible for this 2-year study. Candidates must have received radiation therapy more than 6 months before entering the study, and must have no evidence of active cancer or history of collagen vascular disease. Participants will be evaluated in the Clinical Center's Rehabilitation Medicine Department, where

188

Fibrosis

one symptom due to fibrosis will be selected for monitoring. They will then start treatment with pirfenidone pills, taken by mouth three times a day. Patients will return to the Clinical Center every 3 months for a physical examination and blood tests, and to complete questionnaires assessing level of daily functioning, pain, and other health and quality of life measurements. Some patients with scar tissue involving the skin will be asked to undergo spectroscopy. This test involves shining a light on parts of the skin both with and without fibrosis and taking measures of how the light is reflected back. Patients who benefit from the treatment may continue to receive pirfenidone for up to 2 years. Those who do not improve after 1 year of treatment, or whose cancer recurs will stop pirfenidone and be taken off the study. Phase(s): Phase II; MedlinePlus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014924 •

Study of INS37217 Inhalation Solution in Mild to Moderate Cystic Fibrosis Lung Disease Condition(s): Cystic Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): Inspire Pharmaceuticals; Cystic Fibrosis Foundation Therapeutics Purpose - Excerpt: The purpose of this study is to assess the safety and effectiveness of multiple dosages of INS37217 compared to placebo over 28 days in subjects with mild to moderate cystic fibrosis (CF) lung disease. Study drug will be administered through a nebulizer (a device that delivers medication as a mist by breathing it in). Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00056147

•

A Study of the Safety and Clinical Effects of Interferon gamma-1b in Patients with Idiopathic Pulmonary Fibrosis (IPF) Condition(s): Idiopathic Pulmonary Fibrosis Study Status: This study is completed. Sponsor(s): InterMune Purpose - Excerpt: Study GIPF-002 is a phase 2 study designed to characterize the biologic and clinical effects of IFN-g 1b. The objective of the Study is to characterize the biologic and clinical effects of IFN-g 1b administered to patients with idiopathic pulmonary fibrosis (IPF). The Study will be conducted at multiple sites and enroll 30 patients with IPF who have failed treatment with corticosteroids. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00047658

Clinical Trials 189

•

A study of the safety and efficacy Interferon-gamma 1b in patients with Idiopathic Pulmonary Fibrosis (IPF) Condition(s): Idiopathic Pulmonary Fibrosis Study Status: This study is completed. Sponsor(s): InterMune Purpose - Excerpt: Study GIPF-001 is phase 3 study designed to determine the safety and efficacy of IFN-g 1b administered by subcutaneous injection; compared to placebo in patients with IPF who are unresponsive to steroids. 330 patients have been enrolled and were assigned to either a IFN-g 1b group or a placebo group. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00047645

•

A Study of the Safety and Efficacy of Tobramycin for Inhalation in Young Children with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR) Purpose - Excerpt: This study's primary goals are to test the safety and effectiveness of Tobramycin for Inhalation (TOBIr) in cystic fibrosis (CF) patients who are between 6 months and 6 years of age. This drug is an antibiotic that is inhaled into the lungs by the patient. It has already been studied and approved by the FDA for treatment of CF patients 6 years and older. Lung fluid will be examined for bacteria before and after the 28-day treatment. The amount of bacteria before and after treatment will be compared. This will indicate whether the antibiotic was effective in killing bacteria in the lungs. Once treatment begins, patients will be monitored every 2 weeks throughout the study (5 exams in 56 days). Half of the patients will receive TOBIr, half will receive a placebo (a substance that looks like TOBIr but contains no medication). Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006280

•

Benefits and Risks of Newborn Screening for Cystic Fibrosis Condition(s): Cystic Fibrosis; Lung Disease; Pseudomonas Infections Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR) Purpose - Excerpt: Although cystic fibrosis (CF) is the most common, life-threatening autosomal recessive genetic disorder of the white population, there are often delays in diagnosis and hence start of treatment. Advances of the past two decades have made CF screening feasible using routinely collected neonatal blood specimens and measuring an

190

Fibrosis

enzyme level followed by CF mutation DNA analysis. Our overall goal of the study is to see if early diagnosis of CF through neonatal screening will be medically beneficial without major risks. ''Medically beneficial'' refers to better nutrition and/or pulmonary status, whereas '' risks'' include laboratory errors, miscommunication or misunderstanding, and adverse psychosocial consequences. Specific aims include assessment of the benefits, risks, costs, quality of life, and cognitive function associated with CF neonatal screening and a better understanding of the epidemiology of CF. A comprehensive, randomized clinical trial emphasizing early diagnosis as the key variable has been underway since 1985. Nutritional status has been assessed using height and weight measurements and biochemical methods. The results have demonstrated significant benefits in the screened (early diagnosis) group. We are now focusing on the effect of early diagnosis of CF on pulmonary outcome. Pulmonary status is measured using chest radiographs, chest scans using high resolution computerized tomography, and pulmonary function tests. Other factors that we are looking at include risk factors for the acquisition of respiratory pathogens such as Pseudomonas aeruginosa, quality of life and cognitive function of children with CF who underwent early versus delayed diagnosis, as well as the cost effectiveness of screening and the costs of diagnosis and treatment of CF throughout childhood. If the questions underlying this study are answered favorably, it is likely that neonatal screening using a combination of enzyme level (immunoreactive trypsinogen) and DNA test will become the routine method for identifying new cases of CF not only in the State of Wisconsin, but throughout the country. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014950 •

Bone Health of People with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Cystic Fibrosis Foundation Purpose - Excerpt: People with cystic fibrosis (CF) now frequently live into adulthood and with this extended life expectancy has come new clinical problems. Poor bone health, including osteoporosis and bone fractures, is one of these increasingly important conditions. Preventing the negative outcomes of poor bone health in later life is primarily related to ensuring optimal growth (weight and height) and obtaining maximal amount of bone mass during growth and development. This study will identify factors that influence bone health in a sample of children, adolescents and young adults as measured by dual energy x-ray absorptiometry and new bone densitometry methods (peripheral quantitative computerized tomography [p-QCT] and bone sonometer). We will also identify factors which influence changes in bone status over a 12-month follow-up period in a subsample of people with CF. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00008762

•

Growth Hormone Use in Cystic Fibrosis - a Multicenter Study Condition(s): Cystic Fibrosis

Clinical Trials 191

Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Genentech Purpose - Excerpt: Cystic Fibrosis (CF) is the most common lethal genetic disorder in America. Previous studies by our group and others have shown that human recombinant growth hormone (GH) improves height velocity, weight velocity, lean body mass (LBM) and pulmonary function. These positive results have prompted us to ask further questions regarding GH use in CF including: a) Do patients with better baseline body weight and pulmonary function derive more benefit from treatment than those with worse weight and pulmonary function?, b) Does GH use improve the patient's quality of life?, c) Once GH is discontinued, are the positive effects sustained? We hypothesize that GH treatment in CF patients will improve their clinical status and their quality of life. We further hypothesize that these effects will be present regardless of baseline body weight or pulmonary function, and that positive outcome will be sustained for at least one year after GH treatment is discontinued. To test our hypothesis, we will recruit 40 prepubertal children from five CF centers across the United States (8 per center). Patients will be randomly assigned to receive treatment with GH (0.3mg/kg/wk) during either the first or the second year. All subjects will be seen every three months. We will evaluate the following parameters every three months: 1) height, height velocity and Z-score, 2) body weight and weight velocity. Every six months we will measure: 1) lean body mass utilizing DEXA, 2) pulmonary function, including measurement of respiratory muscle strength (peak inspiratory and peak expiratory pressure), 3) quality of life (QOL), quantitated from QOL forms specific for CF ("The Cystic Fibrosis Questionnaire"). After one year of study, subjects will "crossover" to the other treatment arm. This 24 month study will allow us to statistically compare outcome measures in 20 treated and 20 nontreated subjects from multiple centers, and will allow us to assess sustained effect in the 20 subjects who receive GH during the first year, by comparing their results to results obtained during the year post treatment. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005112 •

Idiopathic Pulmonary Fibrosis: a Case-control Study Condition(s): Lung Diseases; Pulmonary Fibrosis; Lung Diseases, Interstitial Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine risk factors for idiopathic pulmonary fibrosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005295

•

Idiopathic Pulmonary Fibrosis--Pathogenesis and Staging - SCOR in Occupational and Immunological Lung Diseases Condition(s): Lung Diseases; Scleroderma, Systemic

Pulmonary

Fibrosis;

Lung

Diseases,

Interstitial;

192

Fibrosis

Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct cross-sectional and longitudinal studies of patients with idiopathic pulmonary fibrosis (IPF) and patients with progressive systemic sclerosis (PSS), with and without associated lung disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005317 •

Interferon gamma-1b by inhalation for the treatment of patients with cystic fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): InterMune Purpose - Excerpt: The purpose of this research study is to evaluate the safety and effectiveness of Interferon gamma-1b (IFN-g 1b) on lung function when given to patients with cystic fibrosis by inhalation (breathed into the lungs) three times a week for 12 weeks. The FDA has not approved Interferon gamma-1b for use with cystic fibrosis patients, which is the condition being examined in this study. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043316

•

Multicenter Study of Nontuberculous Mycobacteria in Cystic Fibrosis Patients Condition(s): Cystic Fibrosis; Atypical Mycobacterium Infection Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of North Carolina Purpose - Excerpt: Objectives: I. Determine the prevalence of nontuberculous mycobacteria in sputum cultures from patients with cystic fibrosis. II. Compare the clinical course of patients with negative versus positive cultures. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004296

•

Phase I Pilot Study of Ad5-CB-CFTR, an Adenovirus Vector Containing the Cystic Fibrosis Transmembrane Conductance Regulator Gene, in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of North Carolina

Clinical Trials 193

Purpose - Excerpt: Objectives: I. Assess the safety and efficacy of gene transfer into the nasal epithelium using Ad5-CB-CFTR, an E1-deleted adenovirus vector containing the cystic fibrosis transmembrane conductance regulator gene, in patients with cystic fibrosis (CF). II. Determine whether ion transport abnormalities in CF airway cells can be corrected. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004779 •

Phase I Randomized Study of CPX for the Treatment of Adult Patients with Mild Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; SciClone Pharmaceuticals Purpose - Excerpt: Objectives: I. Evaluate the safety of ascending doses of CPX administered to adult patients with mild cystic fibrosis. II. Evaluate the pharmacokinetics of ascending doses of CPX in this patient population. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004428

•

Phase I Study of Liposome-Mediated Gene Transfer in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Alabama Purpose - Excerpt: Objectives: Evaluate the efficacy and safety of lipid-mediated transfer of the cystic fibrosis transmembrane conductance regulator gene to nasal epithelium in patients with cystic fibrosis. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004806

•

Phase I Study of the Third Generation Adenovirus H5.001CBCFTR in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of Pennsylvania

194

Fibrosis

Purpose - Excerpt: Objectives: I. Assess the safety and feasibility of gene transfer with the third generation adenovirus H5.001CBCFTR in patients with cystic fibrosis. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004287 •

Phase II Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Mucoid Exopolysaccharide Pseudomonas Aeruginosa Immune Globulin for Cystic Fibrosis Condition(s): Cystic Fibrosis; Bacterial Infections Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Vanderbilt University Medical Center Purpose - Excerpt: Objectives: I. Assess the efficacy of monthly intravenous mucoid exopolysaccharide Pseudomonas aeruginosa immune globulin (MEP IGIV) given over 1 year in reducing the frequency of acute pulmonary exacerbation in patients with cystic fibrosis, mild to moderate pulmonary disease, and mucoid P. aeruginosa colonization. II. Assess the effect of MEP IGIV on FEV1, sputum density of mucoid P. aeruginosa, and the quality of life in these patients. III. Assess the safety of monthly MEP IGIV. IV. Assess population-based MEP IGIV pharmacokinetics during chronic therapy. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004747

•

Phase III Randomized Study of the Inhalation of Tobramycin in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis; Bacterial Infection Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development Purpose - Excerpt: Objectives: I. Determine the safety and efficacy of tobramycin in patients with cystic fibrosis who are chronically colonized with Pseudomonas aeruginosa. II. Determine whether this treatment produces tobramycin-resistant bacteria at a frequency different from the placebo group and whether the emergence of resistance is associated with a lack of clinical response. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004829

Clinical Trials 195

•

Randomized Study of Pancrelipase With Bicarbonate (PANCRECARB) Capsules in Reducing Steatorrhea in Patients With Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Indiana University School of Medicine Purpose - Excerpt: Objectives: I. Compare the efficacy of enteric coated pancrelipase with bicarbonate (PANCRECARB) capsules versus the patient's usual enteric coated pancreatic enzyme without bicarbonate in decreasing fecal fat and nitrogen losses in patients with cystic fibrosis. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006063

•

Safety and efficacy study of Interferon gamma-1b in hepatitis C patients with liver fibrosis or cirrhosis Condition(s): Liver Fibrosis; Cirrhosis Study Status: This study is completed. Sponsor(s): InterMune Purpose - Excerpt: The purpose of this research study is to test the safety and effectiveness of Interferon gamma-1b (IFN-g 1b) injected subcutaneously (under the skin) for the treatment of advanced liver fibrosis and cirrhosis in patients with chronic hepatitis C infections. IFN-g 1b is not currently approved for the treatment of liver fibrosis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043303

•

Study of Ibuprofen to Preserve Lung Function in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; Case Western Reserve University Purpose - Excerpt: Objectives: I. Determine the effect of different doses of ibuprofen on neutrophil (polymorphonuclear leukocyte; PMN) delivery to a mucosal surface (the oral mucosa) in patients with cystic fibrosis and healthy controls. II. Determine the duration of effect (and possible rebound effect) of ibuprofen on PMN delivery to a mucosal surface in these patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004440

196

•

Fibrosis

Study of Interferon gamma-1b by injection for the treatment of patients with cystic fibrosis Condition(s): Cystic Fibrosis Study Status: This study is terminated. Sponsor(s): InterMune Purpose - Excerpt: The purpose of this research study is to evaluate the safety, tolerability, and efficacy of Interferon gamma-1b (IFN-gamma 1b) when administered by subcutaneous injection over a period of 4 weeks to patients with mild-to-moderate cystic fibrosis. Additionally, preliminary assessments on the effects of IFN-gamma 1b on lung function and other indicators of health will be made. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043342

•

Study of Metabolic Effects of Pregnancy in Women With Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is terminated. Sponsor(s): National Center for Research Resources (NCRR); University of Utah Purpose - Excerpt: Objectives: I. Compare the clinical status of pregnant vs nonpregnant women with cystic fibrosis. II. Determine glucose tolerance during each trimester of pregnancy in these women. III. Evaluate peripheral insulin sensitivity in these women. IV. Evaluate whole body protein turnover and hepatic glucose production in these women. V. Determine resting energy expenditure in these women. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014768

•

Study of Uridine Triphosphate (UTP) as an Aerosol Spray for Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; University of North Carolina Purpose - Excerpt: Objectives: I. Determine the stability of uridine triphosphate (UTP) and examine the metabolism of exogenous nucleotides on airway epithelial surfaces in patients with cystic fibrosis. II. Determine the acute safety and efficacy of aerosolized UTP in children with cystic fibrosis. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004705

•

Trial of Pentoxifylline in Patients with Functional Disability Caused by RadiationInduced Advanced Regional Fibrosis Condition(s): Fibrosis; Radiation Injuries

Clinical Trials 197

Study Status: This study is completed. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: After initial assessment of their condition by specified clinical and laboratory parameters, each of the patients will be treated for 8 weeks at the standard pentoxifylline dose (400 mg po TID). Objective and subjective response parameters will be re-assessed at the end of the treatment and 8 weeks later for possible decay of response. Phase(s): Phase II; MedlinePlus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001437

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 “fibrosis” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

•

For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

•

For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

•

For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

•

For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

•

For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

•

For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

•

For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

198

Fibrosis

•

For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

•

For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

•

For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

•

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

•

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

•

For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

•

For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

199

CHAPTER 5. PATENTS ON FIBROSIS 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 “fibrosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on fibrosis, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Fibrosis By performing a patent search focusing on fibrosis, 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

9Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

200

Fibrosis

will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on fibrosis: •

1, 3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders Inventor(s): Hoong; Lee K. (Suwanee, GA), Meng; Charles Q. (Alpharetta, GA), Ni; Liming (Duluth, GA), Sikorski; James A. (Alpharetta, GA) Assignee(s): Atherogenics, Inc. (alpharetta, Ga) Patent Number: 6,608,101 Date filed: June 20, 2001 Abstract: It has been discovered certain 1,3-bis-(substituted-phenyl)-2-propen-1-ones, including compounds of formula (I) inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1. Examples of inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, postangioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease. Excerpt(s): The present invention includes novel heteroaryl or heterocyclic 1,3-bis(substituted-phenyl)-2-propen-1-ones as well as methods and compositions for the treatment of disorders mediated by VCAM-1 or MCP-1 and for the treatment of inflammatory disorders generally that include the administration of a 1,3-bis(substituted-phenyl)-2-propen-1-one that has at least one phenyl substituent that is an aryl, heteroaryl or heterocyclic moiety. Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, autoimmune disorders and bacterial and viral infections. Leukocyte recruitment to endothelium is mediated in part by the inducible expression of adhesion molecules on the surface of endothelial cells that interact with counterreceptors on immune cells. Endothelial cells determine which types of leukocytes are recruited by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 binds to the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages, eosinophils, and basophils but not neutrophils. This interaction facilitates the firm adhesion of these leukocytes to the endothelium. VCAM-1 is an inducible gene that is not expressed, or expressed at very low levels, in normal tissues. VCAM-1 is upregulated in a number of inflammatory diseases, including arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease. Coronary heart disease (CHD), primarily as a result of atherosclerosis, remains the leading cause of death in industrialized countries. Atherosclerosis is a disease characterized by vascular inflammation, deposition of lipids in the arterial vessel wall and smooth muscle cell proliferation resulting in a narrowing of the vessel passages. In advanced stages of the disease atherosclerotic lesions can become unstable resulting in plaque rupture, thrombosis, myocardial infarction and

Patents 201

ischemic heart disease. It is now well accepted that the initiating events in atherosclerosis are local injury to the arterial endothelium that results in the induction of VCAM-1 and recruitment of mononuclear leukocytes that express the integrin counterreceptor, VLA-4, (O'Brien, et al., J. Clin. Invest., 92: 945-951, 1993). Subsequent conversion of leukocytes to foamy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors, and chemoattractants that help propagate formation of the mature atheromatous plaque by further inducing endothelial activation, leukocyte recruitment, smooth muscle cell proliferation, and extracellular matrix deposition. Pharmacological inhibition of VCAM-1 expression has been shown to inhibit atherosclerosis in several animal models (Sundell et al., Circulation, 100: 42, 1999). A monoclonal antibody against VCAM-1 has also been shown to inhibit neointimal formation in a mouse model of arterial wall injury (Oguchi, S., et al., Arterioscler. Thromb. Vasc. Biol., 20: 1729-1736, 2000). Web site: http://www.delphion.com/details?pn=US06608101__ •

Antagonists of MCP-1 function and methods of use thereof Inventor(s): Anuskiewicz; Steven E. (San Bruno, CA), Inagaki; Hideaki (Anjoh, JP), Ishiwata; Yoshiro (Aichi-gun, JP), Jomori; Takahito (Nagoya, JP), Kakigami; Takuji (Inabe-gun, JP), Laborde; Edgardo (Foster City, CA), Matsumoto; Yukiharu (Gifu, JP), Matsushima; Kouji (Matsudo, JP), Meng; Fanying (San Francisco, CA), Peterson; Brian T. (San Francisco, CA), Robinson; Louise (San Carlos, CA), Villar; Hugo O. (La Jolla, CA), Yokochi; Shoji (Inabe-gun, JP) Assignee(s): Sanwa Kagaku Kenkyusho Co., Ltd. (jp), Telik, Inc. (palo Alto, Ca) Patent Number: 6,677,365 Date filed: March 25, 2002 Abstract: Chemical compounds which are antagonists of Monocyte Chemoattractant Protein-1 (MCP-1) function, pharmaceutical compositions comprising these compounds, methods of treatment employing these compounds and compositions, and processes for preparing these compounds. The compounds are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection. Excerpt(s): The present invention relates to chemical compounds, pharmaceutical compositions comprising said compounds, uses of said compounds and compositions, methods of treatment employing said compounds and compositions, and processes for preparing said compounds. Specifically, this invention relates to novel compounds which are antagonists of Monocyte Chemoattractant Protein-1 (MCP-1) function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection. More specifically, the invention is related to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases. The migration of leukocytes from blood vessels into diseased tissues is an important process in the initiation of normal inflammatory responses to certain stimuli

202

Fibrosis

or insults to the immune system. However, this process is also involved in the onset and progression of life-threatening inflammatory and autoimmune diseases; blocking leukocyte recruitment in these disease states, therefore, can be an effective therapeutic strategy. The mechanism by which leukocytes leave the bloodstream and accumulate at inflammatory sites involves three distinct steps: (1) rolling, (2) arrest and firm adhesion, and (3) transendothelial migration [Springer, Nature 346:425-433 (1990); Lawrence and Springer, Cell 65:859-873 (1991); Butcher, Cell 67:1033-1036 (1991)]. The second step is mediated at the molecular level by chemoattractant receptors on the surface of leukocytes which bind chemoattractant cytokines secreted by proinflammatory cells at the site of damage or infection. Receptor binding activates leukocytes, increases their adhesiveness to the endothelium, and promotes their transmigration into the affected tissue, where they can secrete inflammatory and chemoattractant cytokines and degradative proteases that act on the subendothelial matrix, facilitating the migration of additional leukocytes to the site of injury. Web site: http://www.delphion.com/details?pn=US06677365__ •

Bis(benzimidazole) derivatives serving as potassium blocking agents Inventor(s): Jensen; Bo Skaaning (Copenhagen S, DK), Olesen; S.o slashed.ren Peter (Klampenborg, DK), Peters; Dan (Arlov, SE), Str.o slashed.b.ae butted.k; Dorte (Farum, DK), Teuber; Lene (V.ae butted.rl.o slashed.se, DK) Assignee(s): Neurosearch A/s (ballerup, Dk) Patent Number: 6,569,880 Date filed: February 28, 2002 Abstract: This invention relates to novel potassium channel blocking agents, and their use in the preparation of pharmaceutical compositions.Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labor, baldness, cancer, and immune suppression. Excerpt(s): This invention relates to novel potassium channel blocking agents, and their use in the preparation of pharmaceutical compositions. Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent

Patents 203

claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labor, baldness, cancer, and immune suppression. Ion channels are transmembrane proteins, which catalyze the transport of inorganic ions across cell membranes. The ion channels participate in processes as diverse as the generation and timing of action potentials, synaptic transmissions, secretion of hormones, contraction of muscles, etc. Web site: http://www.delphion.com/details?pn=US06569880__ •

Crystalline form of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4methoxyphenyl)benzo [b]thiophene hydrochloride Inventor(s): Bush; Julie Kay (Fishers, IN), Conrad; Preston Charles (Indianapolis, IN), Flom; Merlyn Gerard (Noblesville, IN) Assignee(s): Eli Lilly and Company (indianapolis, In) Patent Number: 6,610,706 Date filed: January 10, 2002 Abstract: The present invention is directed to a novel crystalline hydrate of 6-hydroxy-3(4-[2-(piperidin-1-yl)ethoxy]-phenoxy)-2-(4-methoxyphenyl)benz o[b]thiophene hydrochloride and uses for same, including inhibition of disease states associated with estrogen deprivation including cardiovascular disease, hyperlipidemia, and osteoporosis; and inhibition of other pathological conditions such as endometriosis, uterine fibrosis, estrogen-dependent cancer (including breast and uterine cancer), prostate cancer, benign prostatic hyperplasia, CNS disorders including Alzheimer's disease, prevention of breast cancer, and up-regulating ChAT. Excerpt(s): 6-Hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4methoxyphenyl)benzo[ b]thiophene hydrochloride (arzoxifene) was first described generically in U.S. Pat. No. 5,510,357 and was specifically disclosed in U.S. Pat. No. 5,723,474 ('474) and European Patent Application 0729956. Arzoxifene is a nonsteroidal mixed estrogen antagonist/agonist, useful for, inter alia, lowering serum cholesterol and for inhibiting hyperlipidemia, osteoporosis, estrogen dependent cancers including breast and uterine cancer, endometriosis, CNS disorders including Alzheimer's disease, aortal smooth muscle cell proliferation, and restenosis. Specifically, arzoxifene is useful for, and is being clinically evaluated for the treatment of receptor positive metastatic breast cancer; the adjuvent treatment of receptor positive patients following appropriate systemic or local therapy; the reduction of recurrence of invasive and noninvasive breast cancer; and the reduction of the incidence of invasive breast cancer and ductal carcinoma in situ (DCIS). Arzoxifene is also useful in combination with radiotherapy, aromatase inhibitors, LHRH analogues, and acetyl choline esterase (AChE) inhibitors. Xray powder diffraction (XRD), thermogravimetric (TGA), proton nuclear magnetic resonance (.sup.1 H NMR) and Karl Fischer (KF) analyses of bulk arzoxifene isolated by the procedures taught in '474 later indicated that said material was hydrated, poorly crystalline, and contained variable amounts of an organic volatile (ethyl acetate) in its lattice. Web site: http://www.delphion.com/details?pn=US06610706__

204

•

Fibrosis

Cyclic tetrapeptide compound and use thereof Inventor(s): Hino; Motohiro (Tsuchiura, JP), Mori; Hiroaki (Suita, JP), Sakamoto; Kazutoshi (Tsuchiura, JP), Takase; Shigehiro (Ishioka, JP), Tsurumi; Yasuhisa (Tsukuba, JP) Assignee(s): Fujisawa Pharmaceutical Co., Ltd. (osaka, Jp) Patent Number: 6,656,905 Date filed: May 4, 2001 Abstract: A cyclic tetrapeptide compound and use thereof. Especially, a compound WF27082, a process for production of the compound by culturing, in a nutrient medium, a WF27082-producing strain belonging to Acremonium and recovering the compound from a culture broth, a pharmaceutical composition containing the compound as an active ingredient, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient, the compound for use as a medicament, a use of the compound for manufacture of a medicament for inhibiting histone deacetylase, a use of the compound for manufacture of a medicament for treating or preventing inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), protozoal infections, organ transplant rejections, autoimmune diseases, or tumors, a use of histone deacetylase inhibitors as an immunosuppressant or an antitumor agent, and a use of histone deacetylase inhibitors for manufacture of a medicament for treating or preventing organ transplant rejections, autoimmune diseases or tumors are described. Excerpt(s): The present invention relates to a cyclic tetrapeptide compound which is useful as a medicament, to a process for producing the same and to a pharmaceutical composition comprising the same. Histone deacetylases are known to play an essential role in the transcriptional machinery for regulating gene expression, and histone deacetylase inhibitors induce histone hyperacetylation and affect the gene expression. Therefore, a histone deacetylase inhibitor is useful as a therapeutical or prophylactic agent for several diseases caused by abnormal gene expression, such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), protozoal infection, or the like. In this connection, a cyclic tetrapeptide compound that can be used as an anti-tumor agent is disclosed in JP-A-7-196686 but this publication is silent on the action against histone deacetylases and the effect against the above-mentioned various diseases. Web site: http://www.delphion.com/details?pn=US06656905__

•

Deoxyribonuclease, gene encoding same and use thereof Inventor(s): Shiokawa; Daisuke (Tokyo, JP), Tanuma; Sei-ichi (2-21-8-707, Bessho, Hachioji-shi, Tokyo 192-0363, JP) Assignee(s): Tanuma; Sei-ichi (hachioji, Jp) Patent Number: 6,653,118 Date filed: July 3, 2001 Abstract: This invention provides a novel acid DNase (DLAD) which is an endonuclease capable of cleaving DNA independently from divalent cations, under acidic conditions, which retains its activity in acidic to even neutral pH range, and which is not inhibited by G-actin. This invention also provides a DNA encoding the enzyme, an expression

Patents 205

vector containing the DNA, and a host cell transformed with the expression vector. Furthermore, a pharmaceutical composition containing DLAD, DLAD expression vector or a host cell transformed with the expression vector as an active ingredient is provided. The pharmaceutical composition is useful as a therapeutic agent replacing DNase I for cystic fibrosis, and can provide a new approach for the prophylaxis and treatment of infectious diseases. Excerpt(s): This invention relates to a novel deoxyribonuclease capable of cleaving DNA independently from divalent cations under acidic conditions, a DNA encoding same and use of these for the prophylaxis and treatment of infectious diseases as well as for the treatment of cystic fibrosis. The presence of various deoxyribonucleases (hereinafter referred to as DNase) in mammalian cells has been known. DNase II is one of the DNases studied most and catalyzes DNA hydrolysis reaction in the absence of divalent cations at acidic pH [in The Enzymes (Boyer, P. D., ed) 3rd Ed., Vol. 4, pp. 271-287 (1971), Academic Press, New York; Arch. Biochem. Biophys., 300: 440-450 (1993)]. While the acid DNase activities are widely found in various animal tissues [Biochim. Biophys. Acta, 1119: 185-193 (1992); J. Biol. Chem., 273: 2610-2616 (1998)], DNase II has been considered to be the sole enzyme responsible for the acid DNase activities. Because DNase II shows low organ specificity and is distributed ubiquitously, a possibility of DNase II playing an important biological role in the fundamental biological phenomena, such as DNA catabolism and apoptosis, has been suggested [The Enzymes (1971), supra; Arch. Biochem. Biophys., 300: 440-450 (1993)]. Even though the enzymological properties of the DNase II isolated from different organisms are very similar, their physicochemical properties and molecular structures are strikingly different. For example, it is known that porcine DNase II is a complex protein consisting of unidentical subunits derived from its precursor protein, but DNase II derived from other animals are mostly single polypeptides [J. Biol. Chem., 260: 10708-10713 (1985); Biochem. Biophys. Res. Commun., 247: 864-869 (1998); J. Biol. Chem., 251: 116-123 (1976); Gene, 215: 281-289 (1998)]. Furthermore, the apparent molecular weights of DNase II vary from 26.5 kDa to 45 kDa [J. Biol. Chem. (1976), supra; Gene, (1998), supra; J. Biol. Chem., 247: 1424-1432 (1972); Eur. J. Biochem., 202: 479-484 (1991)]. Web site: http://www.delphion.com/details?pn=US06653118__ •

Dinucleoside polyphosphate compositions and their therapuetic use as purinergic receptor agonists Inventor(s): Douglass, III; James G. (Apex, NC), Rideout; Janet (Raleigh, NC), Shaver; Sammy Ray (Chapel Hill, NC), Yerxa; Benjamin R. (Raleigh, NC) Assignee(s): Inspire Pharmaceuticals, Inc. (durham, Nc) Patent Number: 6,555,675 Date filed: March 23, 2001 Abstract: The present invention relates to certain novel dinucleotide polyphosphates of general Formulae I, II and III, and formulations thereof which are selective agonists of the P2Y purinergic receptors. They are useful in the prevention, management or treatment of diseases and disorders associated with abnormalities of tissue fluid secretion, hydration and clearance, including chronic obstructive pulmonary diseases (chronic bronchitis, PCD, cystic fibrosis, immobility-associated pneumonia), sinusitis, otitis media, nasolacrimal duct obstruction, dry eye disease, glaucoma, retinal degeneration, and edematous retinal disorders, including retinal detachment, vaginal dryness, and gastrointestinal tract disease. Finally, these novel dinucleotides may be

206

Fibrosis

useful for diagnostic purposes, such as the facilitation of sputum induction and expectoration for the analysis of respiratory tract secretions. Excerpt(s): The present invention relates to novel compositions of dinucleoside polyphosphates with purinergic receptor agonist activity, which facilitate secretory mechanisms, such as increasing the hydration of mucus secretions, stimulating the production of mucins and increasing ciliary beat frequency to facilitate clearance of retained secretions. Chronic obstructive pulmonary disease (COPD) affects 15 million patients in the U.S. and is the sixth leading cause of death. It is characterized by the retention of mucus secretions in the lungs. Many patients diagnosed with COPD have a disorder called chronic bronchitis (CB), and 600,000 patients are hospitalized each year due to an acute exacerbation of CB. Cystic fibrosis and Primary Ciliary Dyskinesia (PCD) are other examples of lung disorders which assume a clinical profile similar to COPD. Ciliary dyskinesia, whether primary or secondary, results in retained secretions that can only be cleared by coughing. Another disease state characterized by the accumulation of retained mucous secretions is sinusitis, an inflammation of the paranasal sinuses typically associated with an upper respiratory infection. Sinusitis is this country's most common health-care complaint, affecting an estimated 31 million people. (A. Moss and V. Parsons, National Center for Health Statistics, 1986: 66-7, DHHS Publication No. (PHS)86-1588 (1985)). Web site: http://www.delphion.com/details?pn=US06555675__ •

Human aggrecanase and nucleic acid compositions encoding the same Inventor(s): Allard; John David (Cupertino, CA), Ileller; Renu Anand (Stanford, CA), Klonowski; Paul (Cambridge, MA), VanWart; Harold Edgar (Los Altos, CA) Assignee(s): Syntex (u.s.a.) Llc (palo Alto, Ca) Patent Number: 6,649,377 Date filed: May 9, 2000 Abstract: Human aggrecanase and polypeptides related thereto, as well as nucleic acid compositions encoding the same, are provided. The subject polypeptides and nucleic acid compositions find use in a variety of applications, including research, diagnostic, and therapeutic agent screening applications. Also provided are methods of inhibiting aggrecanase activity in a host and methods of treating disease conditions associated with aggrecanase activity, e.g. rheumatoid arthritis, osteo-arthritis, infectious arthritis, gouty arthritis, psoriatic arthritis, spondolysis, sports injury, joint trauma, pulmonary disease, fibrosis, and the like. Excerpt(s): The field of the invention is proteases, particularly proteases that cleave aggrecan. Cartilage matrix structure as dry weight of the tissue is made up of 70% collagen and 20-30% proteoglycans. The proteoglycan component confers mechanical flexibility to load bearing tissues and imparts viscoelastic properties to cartilage. Its loss leads to rapid structural damage as is seen most frequently in arthritic joint diseases and joint injury. The G1 domain of the core protein forms a stable ternary complex by binding to hyaluronic acid and link proteins in the matrix. Any enzymatic cleavage in this region destabilizes the cartilage matrix structure, leads to the loss of the major proteoglycan aggrecan and exposes type II collagen to collagenases, causing cartilage loss and the consequent development of joint disease. Since a variety of anti-arthritic drugs do not target aggrecanase and are incapable of blocking cleavage of aggrecan, the aggrecanase site plays a key role in the proteolytic degradation of aggrecan.

Patents 207

Web site: http://www.delphion.com/details?pn=US06649377__ •

Matrix metalloprotease Inventor(s): Atsushi; Nishimura (Tsukuba, JP), Koji; Yoshimura (Tsukuba, JP), Yuichi; Hikichi (Tsukuba, JP) Assignee(s): Takeda Chemical Industries, Ltd. (osaka, Jp) Patent Number: 6,566,116 Date filed: July 26, 1999 Abstract: This invention relates to a novel metalloprotease having a proteolytic activity, its partial peptide or a salt either of them, a DNA coding for the protein, a recombinant vector comprising the DNA, a transformant carrying the recombinant vector, a process for producing the protein, a pharmaceutical composition comprising the DNA, an antibody against the protein, a method for screening for a compound which activates or inhibits a proteolytic activity of the protein, a kit for screening for the compound, and a compound which activates or inhibits a proteolytic activity of the protein which is identified by the screening method or the kit. The DNA coding for the protein of the present invention can be used as a therapeutic and prophylactic composition for a variety of diseases including diabetic nephropathy, glomerulonephritis, pulmonary fibrosis, hepatolienal fibrosis, hepatocirrhosis, osteopetrosis and herniated disk. Furthermore, the protein of the present invention is useful as a screening reagent for any compounds which activate or inhibit the function of the protein of the present invention. In addition, the antibody against the protein of the present invention specifically recognizes the protein of the present invention and can be used in the quantitative determination of the protein of the present invention in a test fluid. Excerpt(s): This application is based on PCT/JP97/01433, having an International filing date of Apr. 24, 1997, which claims the priority date of Apr. 24, 1996 of Japanese application number 8-104902. The extracellular matrix, which is a cell-supporting tissue composed mainly of collagens and proteoglycans, is profoundly involved in such events as cell development, inflammation, and tissue repair. The enzymes known to be associated with the degradation of extracellular matrix are (1) cathepsin D, etc. which belongs to the aspartic proteaseas, (2) cathepsin B, H, L, etc. which belong to the cysteine proteases, (3) plasmin, kallikrein, neutrophil elastase, tryptase, chymase, cathepsin G, etc. which belong to the serine proteases, and (4) metalloproteases are known. Also called matrix metalloproteases, these metalloproteases are known to be playing central roles in the degradation of extracellular matrix. So far, in humans, 13 kinds of matrix metalloproteases such as collagenases, gelatinases stromelysins, and membrane-type matrix metalloproteases have been cloned and their nucleotide sequences and amino acid sequences have been reported (T. Takino et al., Journal of Biological Chemistry, 270, 23013, 1995; J. M. P. Freije et al., Journal of Biological Chemistry, 269, 16766, 1994; H. Wills et al., European Journal of Biochemistry, 231, 602, 1995). All of these enzymes are zinc-dependent metalloproteases, in which the amino acid sequence of the zinc-binding domain: His-Glu-X-Gly-His-Ser-Leu-Gly-Leu-X-His-Ser is well conserved, and their activities are inhibited by o-phenanthroline. Each of these enzymes is secreted in the latent form which is inactive with a propeptide at the N-terminus of the active enzyme. A conserved domain consisting in the amino acid sequence of Met-Arg-Lys-Pro-ArgCys-Gly-Val-Pro-Asp is located near the C-terminal region of the propeptide. This domain is called "cysteine switch", and it controls a protease activity by coordinating the zinc atom at active center with cysteine in the domain. While the latent enzymes are

208

Fibrosis

activated upon cleavage of the propeptide, three kinds of inhibitor proteins, named TIMP, have been reported and known to performing strict control of activity. It is also known that, in vitro, the latent enzymes are activated by treatment with trypsin or aminophenyl-mercuric acetate. Web site: http://www.delphion.com/details?pn=US06566116__ •

Method and device for enhancing vessel occlusion Inventor(s): Palermo; Thomas (San Jose, CA) Assignee(s): Radio Therapeutics Corporation (mountain View, Ca) Patent Number: 6,656,173 Date filed: April 30, 2001 Abstract: Body lumens such as blood vessels are selectively occluded by applying radiofrequency voltage to a vaso-occlusive coil (100) at the target site (TS) and generating a thermal reaction to induce fibrogenic occlusion of the blood vessel (BV) around the vaso-occlusive coil. The radiofrequency current is usually sufficient to induce thermal damage to the luminal wall and to coagulate the surrounding blood, thereby initiating clotting and subsequent fibrosis to permanently occlude the lumen. The invention also includes a method for endoluminally deploying the vaso-occlusive coil and preventing migration of the coil from of the target site. Excerpt(s): The present invention relates generally to methods and devices for the selective occlusion of body lumens. More particularly, the present invention relates to methods and devices for applying high frequency electrical energy to vaso-occlusion elements within the body lumen to enhance fibrogenic occlusion of the body lumen. The selective occlusion of blood vessels in a patient is a part of many modem therapeutic treatments, including the control of internal bleeding, the occlusion of blood supply to tumors, the isolation of diseased body organs prior to removal, the relief of blood pressure in a region of aneurism, and the like. While such procedures rely generally on the blockage of arteries, the selective occlusion of veins is also useful in procedures such as veiniotomy. The selective occlusion of blood vessels can be achieved by a variety of specific techniques. One such technique involves mechanically clamping or occluding the target site within the blood vessel. For example, in open surgical and endoscopic procedures, the body vessel can be externally clamped and radiofrequency energy applied. While the external procedures can be very effective, it requires external access to the lumen and is unsuitable for endoluminal techniques. Web site: http://www.delphion.com/details?pn=US06656173__

•

N-arylsulfonyl aryl aza-bicyclic derivatives as potent cell adhesion inhibitors Inventor(s): Chang; Linda L. (Wayne, NJ), Hagmann; William K. (Westfield, NJ), Lin; Linus S. (Westfield, NJ), Mumford; Richard A. (Red Bank, NJ), Shah; Shrenik K. (Metuchen, NJ) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 6,559,174 Date filed: March 13, 2002

Patents 209

Abstract: Compounds of Formula I are antagonists of VLA-4 and/or alpha4/beta7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, multiple myeloma, myocarditis, organ transplantation, psoriasis, pulmonary fibrosis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, uveititis, and type I diabetes. Excerpt(s): The compounds of the present invention are antagonists of the VLA-4 integrin ("very late antigen-4"; CD49d/CD29; or.alpha.sub.4.beta.sub.1), the.alpha.sub.4.beta.sub.7 integrin (LPAM-1 and.alpha.sub.4.beta.sub.p), and/or the.alpha.sub.9.beta.sub.1 integrin, and are useful in the treatment, prevention and suppression of diseases mediated by VLA-4-,.alpha.sub.4.beta.sub.7 -, and/or.alpha.sub.9.beta.sub.1 -binding and cell adhesion and activation. The present invention relates to potent substituted N-arylsulfonylated-proline derivatives which are useful for the inhibition and prevention of leukocyte adhesion and leukocyte adhesionmediated pathologies. This invention also relates to compositions containing such compounds and methods of treatment using such compounds. Many physiological processes require that cells come into close contact with other cells and/or extracellular matrix. Such adhesion events may be required for cell activation, migration, proliferation and differentiation. Cell-cell and cell-matrix interactions are mediated through several families of cell adhesion molecules (CAMs) including the selectins, integrins, cadherins and immunoglobulins. CAMs play an essential role in both normal and pathophysiological processes. Therefore, the targeting of specific and relevant CAMs in certain disease conditions without interfering with normal cellular functions is essential for an effective and safe therapeutic agent that inhibits cell--cell and cell-matrix interactions. Web site: http://www.delphion.com/details?pn=US06559174__ •

Polynucleotide molecules encoding proteins having proteinase inhibitor activity Inventor(s): Chen; Dadong (Alameda, CA), Davies; Christopher (Walnut Creek, CA), Roczniak; Steve (Lafayette, CA) Assignee(s): Bayer Pharmaceuticals Corporation (west Haven, Ct) Patent Number: 6,689,582 Date filed: May 12, 2000 Abstract: BTL.010 is a novel human serine proteinase inhibitor of the Kunitz family that exhibits greater potency towards neutral serine proteinases, particularly leukocyte elastase and proteinase 3 than towards trypsin-like proteinases. BTL.010, or variants thereof, may be employed as therapeutics in diseases such as emphysema, idiopathic pulmonary fibrosis, adult respiratory distress syndrome, cystic fibrosis, rheumatoid arthritis, organ failure, and glomerulonephritis in which uncontrolled proteolysis due to neutral serine proteinase activity results in tissue damage. Excerpt(s): Field This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and

210

Fibrosis

polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention has been identified as a member of the Kunitz serine proteinase inhibitor family and is hereinafter referred to as BTL.010. The inflammatory response after surgeries, trauma and infection involves neutrophil activation and infiltration into the injured tissue. The activated neutrophils release the neutral serine proteinases leukocyte elastase, cathepsin G and proteinase 3, which, if not properly controlled, cause abnormal connective tissue turnover and result in severe damage to healthy tissue (1-3, 81). The uncontrolled proteolysis can lead to a myriad of diseases including emphysema, idiopathic pulmonary fibrosis, adult respiratory distress syndrome, cystic fibrosis, rheumatoid arthritis, organ failure, and glomerulonephritis. Proteins capable of inhibiting the neutral serine proteinases released by neutrophils can have therapeutic efficacy in treating inflammatory diseases. In patients suffering from hyperdynamic septic shock, plasma levels of the serine proteinase inhibitors antithrombin III, alpha 2-macroglobulin and inter-alpha-trypsin inhibitor, as well as those of various clotting, complement and other plasma factors, are significantly decreased (5). In an experimental endotoxemia model, the reduction in the plasma levels of these factors was considerably diminished by the intravenous injection of a soybean-derived leukocyte elastase and cathepsin G inhibitor, indicating that these neutral proteinases are at least partially responsible for the proteolysis of the plasma factors. In addition, the survival rate in the rat lethal peritonitis model (cecal ligation and puncture-induced septic shock model) was improved by treatment with the second domain of human urinary trypsin inhibitor (2), which has been shown to inhibit leukocyte elastase and cathepsin G (6, 7). Web site: http://www.delphion.com/details?pn=US06689582__ •

Preventing desensitization of receptors Inventor(s): Koch; Walter J. (Durham, NC), Lefkowitz; Robert J. (Durham, NC), Piantadosi; Claude A. (Durham, NC), Stamler; Jonathan S. (Chapel Hill, NC), Whalen; Erin J. (Durham, NC) Assignee(s): Duke University (durham, Nc) Patent Number: 6,627,602 Date filed: October 25, 2002 Abstract: Desensitization of receptors that control disease is prevented by inhibiting Gprotein receptor kinases. This has applicability, e.g., for patients with heart failure or on a left ventricular heart device or a heart pump after surgery or about to undergo surgery and at high risk for a cardiac event or on an opiate or addicted to opiate or with cystic fibrosis or rheumatoid arthritis. Excerpt(s): Many receptors which are involved in controlling pathologic conditions are coupled to G-proteins (Pierce, K. L., et al, Nature Review (Molecular Cell Biology) 3, 639-650 (2002)). These are called G-protein coupled receptors (GPCRs). The GPCRs include.alpha.-adrenergic receptors,.beta.-adrenergic receptors, opioid receptors and prostaglandin receptors. Over time, when agonists are administered to activate the receptors, the receptors become desensitized, i.e., agonist administration no longer results in therapeutic activation of receptors and the receptors regardless of agonist administration are unable to control the pathologic condition. It is known that when agonist binds to a GPCR to activate it, the sequence of events is that the receptor is phosphorylated, the phosphorylated receptor moves to the interior of the cell it is associated with, i.e., it is internalized, with the internalization often involving

Patents 211

recruitment of.beta.-arrestin and then the receptor is recycled and moves to the surface of the cell housing it where it is available to control a disease event and to bind to agonist for activation for control of the disease event. The GPCRs have G-protein receptor kinases (GRKs) associated with them. The GRKs phosphorylate agonistoccupied receptors thereby promoting binding of.beta.-arrestin molecules which inhibit interactions between the receptors and G-proteins while also promoting internalization of the receptors. GRKs thus dampen signaling by the GPCRs. The typical response is decreased level of GPCRs and desensitization thereof (i.e., inability of agonist to activate the receptor and inability of the GPCRs to control the disease event). It has been discovered herein that nitric oxide donors (NO donors) that donate nitric oxide or a related redox species and provide bioactivity that is identified with nitric oxide, preferably S-nitrosoglutathione (GSNO), inhibit the GRKs dramatically thereby allowing GPCRs to signal and to be recycled to the cell surface, i.e., thus preventing desensitization of the GPCRs and allowing GPCRs to be available in sufficient amount to control the disease event. It has also been discovered herein that administration of GSNO results in growth of heart muscle (hypertrophy) in vivo (which can be both dependent and independent of expression of receptors) and prevents cardiac.beta.adrenergic receptor down regulation after chronic administration of a.beta.-adrenergic agonist. The above discoveries support the invention herein which is directed to a method for treating a patient with a disease or pathologic condition associated with Gprotein receptor kinase activity where the G-protein receptor kinase activity would otherwise cause desensitization of a receptor controlling said disease or condition, said method comprising the step of administering NO donor that donates nitric oxide or a related redox species and provides bioactivity that is identified with nitric oxide to inhibit the G-protein receptor kinase activity, thereby sensitizing or preventing desensitization of said receptor. Web site: http://www.delphion.com/details?pn=US06627602__ •

Protein and DNA thereof Inventor(s): Hikichi; Yuichi (Tsukuba, JP), Nishimura; Atsushi (Tsukuba, JP), Yoshimura; Koji (Tsukuba, JP) Assignee(s): Takeda Chemical Industries, Ltd. (osaka, Jp) Patent Number: 6,680,189 Date filed: May 10, 2001 Abstract: The present invention relates to a novel protein belonging to an ADAM family, a partial peptide thereof or a salt thereof, a DNA encoding the protein, a recombinant vector comprising the DNA, a transformant, a method for producing the protein, a medicine comprising the protein or the DNA, an antibody against the protein, a method/kit for screening for a compound or a salt thereof which promotes or inhibits the protease activity or the extracellular metric degrading enzyme activity (preferably, the peptidoglycan degrading enzyme activity) of the protein, a compound obtained by the screening, and a medicine comprising the compound. The present protein and a DNA encoding it can be used, for example, as an agent for treating or preventing various diseases such as disc herniation, ischialgia, glomerular nephritis, diabetic nephropathy, hepatic fibrosis, pulmonary fibrosis or osteopetrosis. In addition, the present antibody can be used for quantitating the present protein in a test solution. Further, the present protein is useful as a reagent for screening for a compound which promotes or inhibits the protease activity of the present protein.

212

Fibrosis

Excerpt(s): This Application is the National Stage of International Application Serial No. PCT/JP99/04766, filed Sep. 2, 1999. The present invention relates to a novel ADAM protein. An extracellular matrix is a cell-supporting tissue surrounding cells of the tissue and is composed of a fibrous protein such as collagen and elastin, a complex carbohydrate such as proteoglycan, a glycoprotein such as fibronectin and laminin, which relate to cell-adhesion, and a sugar such as hyaluronic acid. The exracellular matrix is known to have the important influence of activities of cells such as shape, metabolism, migration, proliferation and differentiation. Therefore, the extracellular matrix is known to be associated with many living body phenomena such as development, aging, inflammation, wound healing, immunity and tumor of the living body. It is known that the abnormal degradation of the extracellular matrix occurs in a variety of diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, cancer metastasis and infiltration, arteriosclerosis and corneae ulcer. There is a possibility that regulation of the enzyme activities involved in degradation of the extracellular matrix produces a therapeutic agent for these diseases. Web site: http://www.delphion.com/details?pn=US06680189__ •

Regulated angiogenesis genes and polypeptides Inventor(s): Jay; Gilbert (North Bethesda, MD), Li; Xuan (Silver Spring, MD), Sun; Zairen (Rockville, MD) Assignee(s): Origene Technologies, Inc. (rockville, Md) Patent Number: 6,657,054 Date filed: June 10, 2002 Excerpt(s): The present invention relates to all facets of novel polynucleotides, the polypeptides they encode, antibodies and specific binding partners thereto, and their applications to research, diagnosis, drug discovery, therapy, clinical medicine, forensic science and medicine, etc. The polynucleotides are expressed in angiogenesis and are therefore useful in variety of ways, including, but not limited to, as molecular markers for blood vessels and blood vessel formation, as drug targets, and for detecting, diagnosing, staging, monitoring, prognosticating, preventing, treating, and/or determining predisposition to diseases and conditions of the vascular system. The identification of specific genes, and groups of genes, expressed in pathways physiologically relevant to angiogenesis permits the definition of functional and disease pathways, and the delineation of targets in these pathways which are useful in diagnostic, therapeutic, and clinical applications. The present invention also relates to methods of using the polynucleotides and related products (proteins, antibodies, etc.) in business and computer-related methods, e.g., advertising, displaying, offering, selling, etc., such products for sale, commercial use, licensing, etc. Angiogenesis, the process of blood vessel formation, is a key event in many physiological processes that underlie normal and diseased tissue function. During ontogeny, angiogenesis is necessary to establish to the network of blood vessels required for normal cell, tissue and organ development and maintenance. In the adult organism, the production of new blood vessels is needed for organ homeostasis, e.g., in the cycling of the female endometrium, for blood vessel maturation during wound healing, and other processes involved in the maintenance of organism integrity. It also is important in regenerative medicine, including, e.g., in promoting tissue repair, tissue engineering, and the growth of new tissues, inside and outside the body. Not all angiogenesis is beneficial. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of

Patents 213

pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Web site: http://www.delphion.com/details?pn=US06657054__ •

Treatment of acute lung injury and fibrosis with antagonists of.beta.6-specific antibodies Inventor(s): Huang; Xiaozhu (Daly City, CA), Sheppard; Dean (Oakland, CA) Assignee(s): The Regents of the University of California (oakland, Ca) Patent Number: 6,692,741 Date filed: March 27, 2001 Abstract: Methods and compositions comprising antagonists of.alpha.v.beta.6 are provided for the treatment of acute lung injury fibrosis. Excerpt(s): Integrins are heterodimeric cell adhesion receptors composed of two subunits,.alpha. and.beta. The integrin.alpha.v.beta.6 is a fibronectin and tenascin receptor expressed predominantly by epithelial cells. In healthy adult primate tissues,.beta.6 mRNA and protein are rarely detected, although.beta.6 is expressed during fetal development, wound healing, and in some epithelial tumors. When the.beta.6 subunit is expressed in a colon carcinoma cell line, from which it is normally absent, expression of the subunit confers an enhanced ability to proliferate. An 11 amino acid COOH-terminal region, unique to the.beta.6 subunit, is required for the proliferation-enhancing activity of the.alpha.v.beta.6 integrin (Agrez et al. J. Cell. Biol. 127:547-556 (1994).beta.6 expression is induced in type II aveolar epithelial cells during injury caused by injection of live bacteria, and.beta.6 expression is observed at focal sites of subclinical inflammation, as well as in a variety of clinical specimens from patients with chronic or acute inflammation of the lungs or kidneys (Breuss et al. J. Cell Sci. 108:2241-2251 (1995). Huang et al. (J. Cell Biol. 133:921-928 (1996)) disclosed mice homozygous for a null mutation in the gene encoding the.beta.6 subunit had juvenile baldness associated with infiltration of macrophages into the skin, and accumulated activated lymphocytes around conducting airways in the lungs. Pulmonary fibrosis is a common disorder thought to be due to the destructive effects of products released from leukocytes (see, for example, Marshall et al., Int. J Biochem. Cell Bio., 29:107-120 (1997)). Bleomycin-induced lung injury and pulmonary fibrosis are associated with and may depend upon the recruitment and activation of lymphocytes (Schrier, D. J. et al., Am. J. Pathol, 116:270-278 (1984)). Among proposed therapies for parenchymal lung injury and pulmonary fibrosis is the use of "anticytokine" therapeutic approaches (Coker et al. Thorax 52 (2):294-296 (1997)). Web site: http://www.delphion.com/details?pn=US06692741__

214

•

Fibrosis

Treatment of hepatitis C virus infections with interleukin-10 Inventor(s): Davis; Gary L. (Gainesville, FL), Grint; Paul C. (San Diego, CA), Nelson; David R. (Gainesville, FL) Assignee(s): Schering Corporation (kenilworth, Nj) Patent Number: 6,685,931 Date filed: December 20, 1999 Abstract: The hepatoprotective effect of IL-10 is described, in particular, the use of interleukin-10 in the treatment of liver damage (e.g. fibrosis or cirrhosis) in a difficultto-treat patient afflicted with chronic hepatitis C virus infection who has failed to respond to, or achieve a sustained virologic response to an anti-HCV therapy(e.g., interferon-.alpha. in combination with ribavirin). Excerpt(s): The invention is directed to the use of interleukin-10 to improve liver histology in patients afflicted with chronic hepatitis C virus infections. In particular, the invention relates to the use of interleukin-10 to reduce hepatic fibrosis in difficult-totreat patients afflicted with chronic hepatitis C virus infections. Chronic hepatitis C is an insidious and slowly progressive disease having a significant impact on morbidity and mortality. While many patients who contract hepatitis C will have subclinical or mild disease, HCV infection causes progressive liver damage in the majority of those infected. At least 80% of the individuals who contract HCV will develop chronic infection and hepatitis, a disease state characterized by fluctuating serum transaminase abnormalities and inflammatory with or without fibrosis lesions on liver biopsy. Twenty to fifty percent of these will eventually progress to cirrhosis and 1-2% will develop liver cancer after a 10-20 year period. Multiple factors influence the hepatitis C virus-host interaction resulting in a unique individual disease pattern. In individuals chronically infected with HCV, there is persistent viremia and liver damage despite the presence of both humoral and cellular responses. The mechanisms responsible for hepatocellular injury are not fully understood. The role of IL-10 in inhibiting liver fibrogenesis has been evaluated in the mouse. Two studies (Louis et al., Heptatology, 1998;28:1607-1615; and Thompson et al., Heptatology, 1998;28:1597-1606) showed that IL-10 knock-out mice develop significantly more severe fibrosis than wild-type mice. Web site: http://www.delphion.com/details?pn=US06685931__

Patent Applications on Fibrosis 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 fibrosis:

10

This has been a common practice outside the United States prior to December 2000.

Patents 215

•

1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders Inventor(s): Hoong, Lee K.; (Suwanee, GA), Meng, Charles Q.; (Alpharetta, GA), Ni, Liming; (Duluth, GA), Sikorski, James A.; (Alpharetta, GA) Correspondence: King & Spalding; 191 Peachtree Street, N.E.; Atlanta; GA; 30303-1763; US Patent Application Number: 20030236298 Date filed: May 21, 2003 Abstract: It has been discovered certain 1,3-bis-(substituted-phenyl)-2-propen-1-one- s, including compounds of formula (I) inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1. Examples of inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, postangioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease. Excerpt(s): This application is a continuation U.S. Ser. No. 09/886,348, filed Jun. 20, 2001, which claims priority to U.S. S. No. 60/212,769, filed on Jun. 20, 2000, and U.S. S. No. 60/255,934 filed on Dec. 15, 2000, the disclosures of which are hereby incorporated by reference in their entirety. The present invention includes novel heteroaryl or heterocyclic 1,3-bis-(substituted-phenyl)-2-propen-1-ones as well as methods and compositions for the treatment of disorders mediated by VCAM-1 or MCP-1 and for the treatment of inflammatory disorders generally that include the administration of a 1,3bis-(substituted-phenyl)-2-propen-1-one that has at least one phenyl substituent that is an aryl, heteroaryl or heterocyclic moiety. Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, autoimmune disorders and bacterial and viral infections. Leukocyte recruitment to endothelium is mediated in part by the inducible expression of adhesion molecules on the surface of endothelial cells that interact with counterreceptors on immune cells. Endothelial cells determine which types of leukocytes are recruited by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 binds to the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages, eosinophils, and basophils but not neutrophils. This interaction facilitates the firm adhesion of these leukocytes to the endothelium. VCAM-1 is an inducible gene that is not expressed, or expressed at very low levels, in normal tissues. VCAM-1 is upregulated in a number of inflammatory diseases, including arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

216

•

Fibrosis

5-Arylsulfonyl-imidazo[1',2':1,6]pyrido[2,3-b]pyrazine-6-amines compounds

and

related

Inventor(s): Kleinman, Edward F.; (Pawcatuck, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030203911 Date filed: April 28, 2003 Abstract: A compound of the formula 1wherein a, X, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS. Excerpt(s): This non-provisional patent application is based upon and claims priority from U.S. patent application Ser. No. 09/918,099, filed Jul. 30, 2001, which claims priority from United States non-provisional application Ser. No. 09/489,689, filed Jan. 24, 2000, which claims priority from U.S. provisional patent application No. 60/117,875, filed Jan. 29, 1999. This invention relates to 5-arylsulfonyl-imidazo[1',2':1,6]pyrido[2- ,3b]pyrazine-6-amines and related compounds. The compounds are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosins factor (TNF), and as such are useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia, and AIDS. This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Accommodating intraocular lens having T-shaped haptics Inventor(s): Cumming, J. Stuart; (Anaheim, CA) Correspondence: Orrick, Herrington & Sutcliffe, Llp; 4 Park Plaza; Suite 1600; Irvine; CA; 92614-2558; US Patent Application Number: 20030199977 Date filed: June 3, 2003 Abstract: An accommodating intraocular lens having anteriorly and posteriorly movable extended portions, such as T-shaped haptics, extending from a central optic to be implanted within a natural capsular bag of a human eye with the extended portions positioned between an anterior capsular rim and a posterior capsule of the bag, whereby during a post-operative healing period, fibrosis occurs about the extended portions to fixate the lens in the bag in a manner such that subsequent natural contraction and

Patents 217

relaxation of the ciliary muscle moves the optic to provide vision accommodation of increased accommodation amplitude and diopters of accommodation. Excerpt(s): This invention relates generally to intraocular lenses to be implanted within a natural capsular bag in the human eye formed by evacuation of the crystalline matrix from the natural lens of the eye through a anterior capsulotomy in the lens. The invention relates more particularly to novel accommodating intraocular lenses of this kind having a number of improved features including, most importantly, increased amplitude or diopters of accommodation. The human eye has an anterior chamber between the cornea and iris, a posterior chamber behind the iris containing a crystalline lens, a vitreous chamber behind the lens containing vitreous humor, and a retina at the rear of the vitreous chamber. The crystalline lens of a normal human eye has a lens capsule attached about its periphery to the ciliary muscle of the eye by zonules and containing a crystalline lens matrix. This lens capsule has elastic optically clear anterior and posterior membrane-like walls commonly referred to by ophthalmologists as anterior and posterior capsules, respectively. Between the iris and the ciliary muscle is an annular crevice-like space called the ciliary sulcus. The human eye possesses natural accommodation capability. Natural accommodation capability involves relaxation and constraction of the ciliary muscle of the eye by the brain to provide the eye with near and distant vision. This ciliary muscle action is automatic and shapes the natural crystalline lens to the appropriate optical configuration for focusing on the retina the light rays entering the eye from the scene being viewed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Activation of the cystic fibrosis transmembrane conductance regulator chloride channel Inventor(s): Cai, Zhiwei; (Bristol, GB), Sheppard, David Noel; (Bristol, GB) Correspondence: Bozicevic, Field & Francis Llp; 200 Middlefield RD; Suite 200; Menlo Park; CA; 94025; US Patent Application Number: 20040006127 Date filed: June 9, 2003 Abstract: Fluorescein and derivatives have use in the treatment of a disease of condition of a living animal body, including human, which disease is responsive to the activation of the cystic fibrosis transmembrane conductance regulator chloride channels, for instance cystic fibrosis, disseminated brocheiectasis, pulmonary infections, chronic pancreatitis, male infertility and long QT syndrome. Excerpt(s): The present invention relates to the activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride (Cl.sup.-) channel. More particularly, t relates to members of a defined class of chemical compounds as activators of the CFTR Cl.sup.- channel and the use of these agents in the treatment of diseases caused by the dysfunction of the CFTR Cl.sup.- channel. CFTR (1) forms a Cl.sup.channel with complex regulation (2,3). It is predominantly expressed in the apical membrane of epithelia, where it provides a pathway for the movement of Cl.sup.- ions and a key point at which to regulate the rate of transepithelial salt and water movement (4). CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains' (NBDs), and a regulatory (R) domain (1). The MSDs contribute to the formation of the Cl.sup.--selective pore, while the NBDs and R domain control channel activity (2,3). The activation of the cAMP-dependent protein kinase

218

Fibrosis

(PKA) causes the phosphorylation of multiple serine residues within the R domain. Once the R domain is phosphorylated, channel gating is controlled by a cycle of ATP hydrolysis at the NBDs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Attenuation of fibroblast proliferation Inventor(s): Cauchon, Elizabeth; (Ile Perrot, CA), Denholm, Elizabeth M.; (Montreal, CA), Silver, Paul J.; (Spring City, PA) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20040018187 Date filed: July 18, 2003 Abstract: Highly purified and specific glycosaminoglycan degrading enzymes, chondroitinase B and chondroitinase AC, are used to treat fibroproliferative diseases. The enzymatic removal of chondroitin sulfate B(dermatan sulfate), and to a lesser extent, chondroitin sulfate A or C, from cell surfaces effectively decreases growth factor receptors on the cells and thereby decreases the cell proliferative response to such growth factors. In addition, removal of chondroitin sulfates reduces secretion of collagen, one of the major extracellular matrix components. Through the combined inhibition of fibroblast proliferation and collagen synthesis, treatment with chondroitinase B or chondroitinase AC decreases the size of fibrous tissue found in psoriasis, scleroderma, keloids, pulmonary fibrosis and surgical adhesions. Excerpt(s): This application claims priority to U.S. S. No. 60/168,518,filed Dec. 2,1999. The present invention is a method and composition using chondroitinase and chondroitinase AC, glycosaminoglycan degrading enzymes, to inhibit the formation of fibrotic tissue. Proteoglycans on the cell surface and in the extracellular matrix contain variable glycosaminoglycan chains, which include heparan sulfate and chondroitin sulfates A, B, or C. While some proteoglycans contain only one type of glycosaminoglycan; others contain a mixture of heparan and chondroitin sulfates (Jackson et. al., Physiol. Rev. 71:481-530,1991). Extracellular proteoglycans form a structural framework for cells and tissues, and together with cell-associated proteoglycans, have major functions in regulating cell adhesion, migration, and proliferation. The functions of proteoglycans and their component parts have been extensively studied, with much of the emphasis on the roles of heparin and heparan sulfate on cell metabolism (Kjellen, L., and Lindahl, U. (1991) Ann. Rev. Biochem. 60:443-475; Vlodavsky,et al. (1995) Thrombosis Haemostasis 74:534-540; Yayon, et al. (1991) Cell 64:841-848)). Much less is known about the biological activities of proteoglycans containing. chondroitin sulfate glycosaminoglycans, and in particular, their effects on cell proliferation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 219

•

Cardiac-specific 11beta hydroxysteroid dehydrogenase type 2 transgenic mice Inventor(s): Goellner, Joseph; (St. Charles, MO), McMahon, Ellen G.; (St. Louis, MO), Qin, Wenning; (Ballwin, MO), Rudolph, Amy E.; (St. Louis, MO) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20030221207 Date filed: February 11, 2003 Abstract: Five independent transgenic founder lines were created which have all developed cardiac hypertrophy and heart failure. The line with the most severe phenotype was analyzed in detail. Transgenic cardiac 11.beta.HSD2 mRNA expression is increased 4,000 fold over non-transgenic mice and the expressed enzyme was found to possess catalytic activity. At five months of age transgenic mice had developed severe myocardial hypertrophy in the absence of an increase in blood pressure. Interstitial fibrosis in the left ventricle of transgenic mice was revealed by picrosirius red staining. The hearts of the mice were severely dilated and cardiomyocyte size was increased. Excerpt(s): This application claims the benefit of provisional application Ser. No. 60/355,812 filed Feb. 13, 2002. The disclosure of the provisional application is expressly incorporated herein in its entirety. A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. The invention relates to the field of cardio therapeutics. In particular, it relates to a model system for identifying and developing new drugs for treating cardiac failure. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Compounds and methods Inventor(s): Bondinell, William E.; (Collegeville, PA), Neeb, Michael J.; (Collegeville, PA) Correspondence: Smithkline Beecham Corporation; Corporate Intellectual Property-us, Uw2220; P. O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20040038982 Date filed: February 5, 2003 Abstract: This invention relates to substituted heterocyclic compounds which are modulators, agonists or antagonists, of the CCR5 receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, by the use of substituted heterocyclic compounds which are CCR5 receptor antagonists. Furthermore, since CD8+ T cells have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic in the treatment of COPD. Also, since CCR5 is a coreceptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection.

220

Fibrosis

Excerpt(s): This invention relates to substituted heterocyclic compounds which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996, 2, 1174-8). In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5. T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or enhanced activation state of T cells, especially CD4+ T cells, have been demonstrated in the synovium of individuals with rheumatoid arthritis (M. J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C. J. Corrigan and A. B. Kay, Immunol. Today 13:501506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci. 32: 121-182, 1995), in psoriatic lesions (J. L. Jones, J. Berth-Jone, A. Fletcher and P. E. Hutchinson, J. Pathol. 174: 77-82, 1994) and in the fatty streaks of atherosclerosis (R. Ross, Annu. Rev. Physiol. 57: 791-804, 1995). T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. RANTES, which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; and J. J. Oppenheim, C. O. C. Zachariae, N. Mukaida, and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Copper lowering treatment of inflammatory and fibrotic diseases Inventor(s): Brewer, George J.; (Ann Arbor, MI) Correspondence: Thomas J. Bordner; Medlen & Carroll, Llp; Suite 350; 101 Howard Street; San Francisco; CA; 94105; US Patent Application Number: 20040009237 Date filed: May 23, 2003 Abstract: The present invention relates generally to the field of prophylaxis and therapy for inflammatory and/or fibrotic diseases which include responses to injuries. In particular, the present invention is related to agents that can bind or complex copper such as thiomolybdate, and to the use of these agents in the prevention and treatment of inflammatory and/or fibrotic diseases. Exemplary thiomolybdates include mono-, di-, tri- and tetrathiomolybdate; these agents are administered to patients to prevent and/or treat inflammatory and/or fibrotic diseases, such as pulmonary disease including pulmonary fibrosis and acute respiratory distress syndrome, liver disease including liver cirrhosis and hepatitis C, kidney disease including renal interstitial fibrosis, scleroderma, cystic fibrosis, pancreatic fibrosis, keloid, secondary fibrosis in the gastrointestinal tract, hypertrophic bum scars, myocardial fibrosis, Alzheimer's disease, retinal detachment inflammation and/or fibrosis resulting after surgery, and graft versus host and host versus graft rejections.

Patents 221

Excerpt(s): The present invention claims priority to U.S. No. 60/382,993 filed on May 24, 2002, the disclosure of which is herein incorporated by reference in its entirety. The present invention relates generally to the field of prophylaxis and therapy for inflammatory and fibrotic diseases. In particular, the present invention is related to agents that can bind or complex copper, and to the use of these agents in the prevention and treatment of inflammatory and fibrotic diseases. Many diseases begin with inflammation, which if excessive, may overwhelm and kill the patient, or if the patient survives, often leads to a disabling fibrosis, which ultimately may also kill the patient. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Histone deacetylase inhibitors based on alpha-chalcogenmethylcarbonyl compounds Inventor(s): Kaufman, Robert J.; (St. Louis, MO), Lan-Hargest, Hsuan-Yin; (Fallston, MD) Correspondence: Fish & Richardson P.C.; 1425 K Street, N.W.; 11th Floor; Washington; DC; 20005-3500; US Patent Application Number: 20040023944 Date filed: May 21, 2003 Abstract: Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, for example, an alphachalcogenmethylcarbonyl group, such as an alpha-ketothio group, can inhibit histone deacetylase. Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, autosomal dominant disorders, e.g. spinal muscular atrophy and Huntington's disease, genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy, or for stimulating hematopoietic cells ex vivo. Excerpt(s): This application claims priority under 35 USC.sctn. 119(e) to U.S. patent application Ser. No. 60/382,077, filed on May 22, 2002, the entire contents of which is hereby incorporated by reference. This invention relates to alphachalcogenmethylcarbonyl compounds, and more particularly to alphachalcogenmethylcarbonyl compounds that are histone deacetylase inhibitors. DNA in the nucleus of the cell exists as a hierarchy of compacted chromatin structures. The basic repeating unit in chromatin is the nucleosome. The nucleosome consists of a histone octamer of proteins in the nucleus of the cell around which DNA is wrapped twice. The orderly packaging of DNA in the nucleus plays an important role in the functional aspects of gene regulation. Covalent modifications of the histones have a key role in altering chromatin higher order structure and function and ultimately gene expression. The covalent modification of histones, such as acetylation, occurs by enzymatically mediated processes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

222

•

Fibrosis

Lectins as anti-fibrotic agents Inventor(s): Cantor, Jerome Owen; (Brooklyn, NY), Shteyngart, Bronislava; (Brooklyn, NY) Correspondence: Jerome O. Cantor, MD; 242 92nd Street; Brooklyn; NY; 11209; US Patent Application Number: 20030216300 Date filed: May 12, 2003 Abstract: The subject invention is directed to the treatment of tissue fibrosis by administration of an effective amount of lectin. Fibrosis herein refers to the accumulation of extracellular matrix constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia. Examples of tissue fibrosis include, but are not limited to, pulmonary fibrosis, cirrhosis of the liver, skin scars and keloids, adhesions, fibromatosis, atherosclerosis, and amyloidosis. The treatment is intended for a variety of mammals, including humans. Excerpt(s): Lectins bind to carbohydrate moieties, e.g. acetylglucosamine, that are ubiquitous in the mammalian extracellular matrix. This suggests the possibility that lectins may be used to coat the matrix and limit further binding of collagen, elastin, and other connective tissue components to carbohydrate groups. The aggregation of large amounts of matrix constituents, as occurs in fibrosis, may therefore be subject to limitation by the introduction of lectins. This hypothesis was tested in our laboratory. Elastic fiber matrix prepared from cultured rat lung mesothelial cells (1,2) was first treated with tomato lectin (lycopersicon esculentum), then covered with hyaluronan (HA), which normally protects the matrix from degradation by elastases. It was found that lectin treatment abolished the protective effect of HA and facilitated breakdown of the elastic fiber matrix by elastase. Since the binding of HA to the elastic fibers is analogous to fibrosis in that it involves deposition of new matrix material (HA) over existing matrix, the addition of lectin may provide a means of counteracting this process and preventing the formation of scar tissue. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

MUCIN SYNTHESIS INHIBITORS Inventor(s): Jones, Steve; (Plymouth Meeting, PA), Levitt, Roy C; (Plymouth Meeting, PA), McLane, Mike; (Plymouth Meeting, PA), Nicolaides, Nicholas C; (Boothwyn, PA), Zhou, Yuhong; (Dreshler, PA) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 2000 Patent Application Number: 20030236220 Date filed: November 8, 2002 Abstract: The claimed invention relates to methods of modulating mucin synthesis and the therapeutic application of compounds in controlling mucin over-production associated with diseases such as chronic obstructive pulmonary diseases (COPD) including asthma and chronic bronchitis, inflammatory lung diseases, cystic fibrosis and acute or chronic respiratory infectious diseases. Excerpt(s): This application is a continuation-in-part of U.S. Application 09/951,906, filed September 14, 2001, which is a continuation-in-part of U.S. Application 09/920,287,

Patents 223

filed August 2, 2001, and is a continuation-in-part of U.S. Application 09/918,711, filed August 1, 2001, both of which are continuations-in-part of U.S. Application 09/774,243, filed January 31, 2001 which claims the benefit of U.S. Provisional Application 60/179,127, filed on January 31, 2000, Provisional Application 60/193,111, filed on March 30, 2000, Provisional Application 60/230,783, filed September 7, 2000, Provisional Application 60/242,134, filed October 23, 2000 and Provisional Application 60/252,052 filed November 20, 2000 all of which are herein incorporated by reference in their entirety.This invention is also related to the subject matter of U.S. Patent Application 08/702,110, filed on August 23, 1996, issued on March 14, 2000, as U.S. Patent No. 6,037,149 and is related to U.S. Patent Application 09/325,571, filed on June 9, 1999 and U.S. Patent No. 5,908,839 issued June 1, 1999 all of which are all herein incorporated by reference in their entirety. In addition, this application is related to U.S. Patent Application 08/980,872, filed December 1, 1997, which is herein incorporated by reference in its entirety. This invention relates to methods of modulating mucin synthesis and the therapeutic application of compounds in controlling mucin overproduction associated with diseases such as asthma, chronic bronchitis, inflammatory lung diseases, cystic fibrosis and acute or chronic respiratory infectious diseases as well as chronic obstructive pulmonary diseases (COPD). The airway epithelium is known to play an integral role in the airway defense mechanism via the mucociliary system and mechanical barriers. Recent studies indicate that airway epithelial cells (AEC) can be activated to produce and release biological mediators important in the pathogenesis of multiple airway disorders (Polito and Proud, 1998; Takizawa, 1998). Evidence has shown that the epithelium is fundamentally disordered in chronic airway disorders such as asthma, chronic bronchitis, emphysema, and cystic fibrosis (Holgate et al., 1999; Jeffery PK, 1991; Salvato, 1968; Glynn and Michaels, 1960). One of the hallmarks of these airway disorders is the over-production of mucus by AEC. The major macromolecular components of mucus are the large glycoproteins known as mucins. Recently, the molecular structure of at least 7 human mucins was determined. The known mucin transcripts are heterogeneous with no sequence homology between the genes (Voynow and Rose, 1994), yet they are similar in their overall repetitive structure. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Mutant plasminogen activator-inhibitor type 1 (PAI-1) and uses thereof Inventor(s): Lawrence, Daniel A.; (Derwood, MD), Stefansson, Steingrimor P.; (Gaithersburg, MD) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20030216321 Date filed: September 30, 2002 Abstract: Mutants of the human PAI-1 protein are described which are inhibitors of neutrophil elastase or are inhibitors of vitronectin (Vn)-dependent cell migration. These mutants preferably comprise one or two amino acid substitutions in the reactive center loop of PAI-1, particularly at positions 331 and 346 of the mature protein. These mutants are notable in being resistant to inactivation by elastase, having high affinity for Vn, or both properties. These mutant proteins as pharmaceutical compositions are used to inhibit elastase in a subject, thereby treating a number of disorders associated with elastase activity, most notatably emphysema, ARDS, inflammatory lung injury and cystic fibrosis. The mutants which interact with Vn are used to inhibit cell migration in

224

Fibrosis

a subject, thereby treating diseases or conditions associated with undesired cell migration and proliferation, particularly of smooth muscle cells. Such conditions include atherosclerosis, post angioplasty restenosis, fibrosis associated with chronic inflammation or chemotherapy, tumor invasion and metastasis and conditions in which angiogenesis is pathogenic. Also disclosed are peptides of such mutant proteins, mutant-specific antibodies, nucleic acid molecules, particularly DNA, encoding the mutant protein and host cells transformed by such nucleic acids. Excerpt(s): The invention in the field of biochemistry and medicine relates to compositions comprising mutant proteins of plasminogen activator inhibitor-type 1 (PAI-1) which have the capacity to inhibit the enzyme elastase and to inhibit vitronectin (Vn)-dependent migration of cells. This invention also relates to uses of these proteins for the treatment of diseases and disorders associated with elastase activity or in which migration and migration-driven proliferation of cells have pathophysiologic consequences. Plasminogen activators (PAs) are specific serine proteinases that activate the proenzyme plasminogen, by cleavage of a single Arg-Val peptide bond, to the enzyme plasmin (Saksela O, Biochim Biophys Acta (1985) 823:35-65). Two plasminogen activators are found in mammals, tissue-type PA (tPA) and urokinase-type PA (uPA) (Saksela O et al, Annu Rev Cell Biol (1988) 4:93-126). These enzymes are thought to influence critically many biological processes, including vascular fibrinolysis (Bachmann E, Thromb Haemost (1987) 10:227-265), ovulation (Hsuch A J W et al, In: Haseltine F P et al, eds, Meiotic Inhibition: Molecular Control of Meiosis New York: Liss 1988:227-258), inflammation (Pollanen J et al., Adv Cancer Res (1991) 57:273-328), tumor metastasis (Dano K et al., Adv Cancer Res (1985) 44:139-266), angiogenesis (Moscatelli D et al., Biochim Biophys Acta (1988) 948:67-85), and tissue remodeling (Saksela, supra). The regulation of PAs is a complex process controlled on many levels. The synthesis and release of PAs are governed by various hormones, growth factors, and cytokines (Saksela, supra; Dano et al., supra). Following secretion, PA activity can be regulated both positively and negatively by a number of specific protein-protein interactions. Activity can be enhanced or concentrated by interactions with fibrin (Hoylaerts M et al., J Biol Chem (1982) 257:2912-2919), the uPA receptor (uPAR) (Ellis V et al., Semin Thromb Hemost (1991) 17:194-200), the tPA receptor (tPAR) (Hajjar K A et al., J Biol Chem (1990) 265:2908-2916), or the plasminogen receptor (Plow E F et al., Thromb Haemost (1991) 66:32-36). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel crystalline form of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy- )-2-(4methoxyphenyl)benzo[b]thiophene hydrochloride Inventor(s): Luke, Wayne Douglas; (West Lafayette, IN) Correspondence: Eli Lilly And Company; Patent Division; P.O. Box 6288; Indianapolis; IN; 46206-6288; US Patent Application Number: 20040014672 Date filed: April 16, 2003 Abstract: The present invention is directed to a novel, non-solvated, anhydrous crystal form of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]-phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride and uses for same, including inhibition of disease states associated with estrogen deprivation including cardiovascular disease, hyperlipidemia, and osteoporosis; and inhibition of other pathological conditions such as endometriosis, uterine fibrosis, estrogen-dependent cancer (including breast and

Patents 225

uterine cancer), prostate cancer, benign prostatic hyperplasia, CNS disorders including Alzheimer's disease, prevention of breast cancer, and up-regulating ChAT. Excerpt(s): 6-Hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride (arzoxifene) was first described generically in U.S. Pat. No. 5,510,357 and was specifically disclosed in U.S. Pat. No. 5,723,474 ('474) and European Patent Application 0729956. Arzoxifene is a nonsteroidal mixed estrogen antagonist/agonist, useful for, inter alia, lowering serum cholesterol and for inhibiting hyperlipidemia, osteoporosis, estrogen dependent cancers including breast and uterine cancer, endometriosis, CNS disorders including Alzheimer's disease, aortal smooth muscle cell proliferation, and restenosis. Specifically, arzoxifene is useful for, and is being clinically evaluated for the treatment of receptor positive metastatic breast cancer; the adjuvent treatment of receptor positive patients following appropriate systemic or local therapy; the reduction of recurrence of invasive and noninvasive breast cancer; and the reduction of the incidence of invasive breast cancer and ductal carcinoma in situ (DCIS). Arzoxifene is also useful in combination with radiotherapy, aromatase inhibitors, LHRH analogues, and acetyl choline esterase (AChE) inhibitors. X-ray powder diffraction (XRD), thermogravimetric analysis (TGA), proton nuclear magnetic resonance (.sup.1H NMR) and Karl Fischer (KF) analyses of bulk arzoxifene isolated by the procedures taught in '474 later indicated that said material was hydrated, poorly crystalline, and contained variable amounts of an organic volatile (ethyl acetate) in its lattice. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Prevention or treatment of abnormal lipoprotein, atherosclerosis and cholestasis Inventor(s): Braun-Egles, Anne; (Strasbourg, FR), Krieger, Monty; (Needham, MA), Miettinen, Helena E.; (Helsinki, FI) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20040006129 Date filed: May 5, 2003 Abstract: Using an animal model, transgenic animals that do not express functional SRBI and apoE which develop severe atherosclerosis, by age four weeks in transgenic mice, a class of drugs, PROBUCOL (4,4'-(isopropylidenedithio) bis(2,6-di-tert-butylphenol)) and monoesters of PROBUCOL, and BO 653, 2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-ditert-butyl-benzofuran, has been discovered which is useful in normalizing abnormal lipoprotein levels and/or characteristics, such as those found in lipoprotein X-associated disease. These animals are good models for screening of drugs useful in the treatment and/or prevention of cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, and stroke, as well as for lipoprotein disorders such as cholestasis and lipoprotein X associated disorders. Studies demonstrate normalization of lipoprotein levels and structure, as well as significant decreases in atherosclerosis and prevention of heart attack, even when administered after disease onset. Excerpt(s): This application claims priority to U.S. Ser. No. 10/147,651 filed May 16, 2002, entitled "Screening of Compounds for Treatment of Atherosclerosis and Heart Attack" by Monty Krieger, Anne Braun-Egles and Helena Miettinen. The present invention is generally in the area of methods of prevention or treatment of abnormal

226

Fibrosis

lipoprotein disorders, atherosclerosis, and heart attack. Atherosclerosis is the leading cause of death in western industrialized countries. Atherosclerosis is the process in which deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances build up in the inner lining of an artery. This buildup is called plaque. It usually affects large and medium-sized arteries. Some hardening of arteries often occurs when people grow older. Plaques can grow large enough to significantly reduce the blood's flow through an artery, and it is thought that much damage occurs when they become fragile and rupture. Plaques that rupture cause blood clots to form that can block blood flow or break off and travel to another part of the body. If either happens (occlusive plaques with or without occlusive blood clots) and blocks a blood vessel that feeds the heart, it causes a heart attack. If it blocks a blood vessel that feeds the brain, it causes a stroke. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Prophylactic and therapeutic use of oltipraz as an antifibrotic and anticirrhotic agent in the liver and pharmaceutical composition containing oltipraz Inventor(s): Kang, Keon-Wok; (Seoul, KR), Kim, Sang-Geon; (Seoul, KR) Correspondence: Cantor Colburn, Llp; 55 Griffin Road South; Bloomfield; CT; 06002 Patent Application Number: 20030191137 Date filed: October 2, 2002 Abstract: The present invention provides a prophylactic and therapeutic use of 5-(2pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) as an antifibrotic and anticirrhotic agent in the liver and a pharmaceutical composition containing oltipraz for treating and preventing hepatic fibrosis and cirrhosis.Oltipraz of the invention can be used as a medicine optionally with other drugs for treating and preventing hepatic fibrosis and cirrhosis and shows an inhibiting effect of hepatic fibrosis at a relatively low dosage. Formulations using an optimal dose of oltipraz, which is provided by the invention, have a surprisingly good effect on the treatment and prevention of hepatic fibrosis and cirrhosis and are safe drugs that have a low toxicity on the human body. Excerpt(s): The present invention relates to a prophylactic and therapeutic use of 5-(2pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) as an antifibrotic and anticirrhotic agent in the liver and to a pharmaceutical composition comprising oltipraz as an active ingredient. The liver plays a key role in the metabolism of xenobiotics and in the metabolism of endogenous substances and is an important organ with consistent enzymatic reactions and energy metabolism. Among the many chronic diseases in Korea, hepatitis, cirrhosis, and liver cancer are the most widespread and life threatening next to cardiovascular diseases. As Korea has a relatively large population of drinkers of alcoholic beverages when compared to developed countries, and as liver damage due to binge drinking is fairly high, a lot of attention has been given to the treatment of liver diseases. Often chronic liver damage resulting from viral infection or alcohol consumption causes cirrhosis or liver cancer. In consideration of the physiological characteristics and importance of the liver, and in view of the importance of treating and preventing liver disease, demand is high for the ultimate development of therapeutic and preventive drugs against liver damage. Various substances, including several synthetic compounds and galenical preparations, show hepatoprotective functions both in vitro and in vivo. Although it has been known that silymarin and betaine have liver protective effects as a result of the action mechanism of cytokine inhibition and an increase in the level of glutathione, a curative effect would be hard to expect because of

Patents 227

its low effectiveness. Because no appropriate curative agents against liver disease are currently available, said agents are frequently used for clinical trials. Malotilate and its derivatives, the indication of which is the treatment of liver fibrosis, protect the liver from toxic chemicals and the possible action mechanism includes the induction of phase II conjugating enzymes and the inhibition of cytochrome P450s. However, the compounds non-selectively inhibit several cytochrome P450s and show only preventive effects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Respiratory delivery for gene therapy and lentiviral delivery particle Inventor(s): Anson, Don; (Thebarton, AU), Fuller, Maria; (Prospect, AU), Limberis, Maria; (Rostrevor, AU), Parsons, David; (Marino, AU) Correspondence: Henry D. Coleman; Coleman Sudol Sapone, P.C.; 714 Colorado Avenue; Bridgeport; CT; 06605-1601; US Patent Application Number: 20040037780 Date filed: August 23, 2002 Abstract: Delivery of an exogenous gene to the respiratory epithelium in a lentiviral expression vector. Includes the preconditioning of the respiratory tract with a penetrating agent such as a detergent to cause tolerable transient damage to the superficial epithelial cell layer. The effective amount of the penetrating agent may be determined by measuring a drop of TPD. Utilising LPC the present inventors have found persistence of expression of an exogenous gene for periods exceed the turnover time of epithelial cells. Additionally amelioration of the pulmonary manifestation of Cystic Fibrosis has been monitored in a mouse modely using th epresent invention. Additionally a safe lentiviral particle packaging system is described where the Gag protei and the GagPol proteins are separately expressed with mutation of the frameshift site in nucleic acid encoding the GagPol protein ensuring that both proteins cannot expressed. Excerpt(s): This invention relates to a method for respiratory delivery for gene therapy purposes and the treatment of a condition that has respiratory or pulmonary manifestations and a vector and method for treatment or prevention of the condition. Specific aspects of the invention relate to treatment of cystic fibrosis by gene therapy using a lentiviral particle to introduce the CTFR gene into cells of the lung with expression of CTFR that is persistent. Further specific aspects relate to a lentiviral based delivery system useful for gene therapy and therapeutic agent delivery applications. At present, a primary limitation in the use of gene therapy to treat human disease is the ineffectiveness of gene delivery methods. Respiratory delivery encounters a more complex defence system than that confronted by other delivery mechanisms. The highly evolved effective defences protecting the mammalian airway epithelium against allergens, irritants, dust, viruses and microbial pathogens (Bevans, 1999) also apply to gene transfer vectors. In particular, the superficial airway mucus layer, produced by submucosal glands and goblet cells continually captures inhaled or introduced particles for constant removal by mucociliary clearance. Closer to the cell surface the glycocalyx (Pickles et al., 2000) can bind some vector types, further preventing vector particle entry via the apical cell membrane. Finally, the tight-junctions between epithelial cells form yet another major delivery barrier to those gene transfer vectors that can bind to their specific receptors only abundant on basolateral cell membranes (Bergelson et al, 1997).

228

Fibrosis

Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Surfactant prevention of vaginitis and lung complications from cancer chemotherapy Inventor(s): Floros, Joanna; (Hershey, PA), Lin, Zhenwu; (Hershey, PA), MacNeill, Colin; (Hershey, PA), Phelps, David S.; (Hershey, PA), Umstead, Todd M.; (Etters, PA), Weisz, Judith; (Bainbridge, PA) Correspondence: Mckee, Voorhees & Sease, P.L.C.; 801 Grand Avenue; Suite 3200; Des Moines; IA; 50309-2721; US Patent Application Number: 20030225034 Date filed: May 2, 2003 Abstract: A means and method for treating pulmonary fibrosis and vaginitis in animals is described. The compositions include surfactant lipids in a pharmaceutically acceptable carrier. Surfactant lipids have been found to suppress the synergistic effect of bleomycin and SP-A in enhancing proinflammatory cytokine production. Surfactant lipids are also effective in the prevention and treatment of pulmonary fibrosis resulting from exposure to inflammatory agents affecting cytokine production. Furthermore, surfactant lipids are effective in treating attenuating the effect of proinflammatory cytokine production in vaginitis. Excerpt(s): This application is a continuation-in-part (CIP) of application Ser. No. 10/317,787 filed Dec. 12, 2002. This invention relates to the use of surfactant lipids for a variety of therapeutic uses, including the treatment of pulmonary inflammation and fibrosis, vaginitis, and inflammatory conditions relating to the same. Pulmonary fibrosis (PF) is a complicated, chronic illness characterized by abnormal formation of fiberlike scar tissue in the lungs. Most patients with PF first have alveolitis, or inflammation of the lung, which drives the scarring process. If the disease progresses, the lungs eventually thicken and become stiff, which prevents oxygen from getting from the air sacs into nearby blood vessels that deliver oxygen to the body, thus making it more difficult for the person to breathe. 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 fibrosis, 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 “fibrosis” (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 fibrosis. You can also use this procedure to view pending patent applications concerning fibrosis. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

229

CHAPTER 6. BOOKS ON FIBROSIS Overview This chapter provides bibliographic book references relating to fibrosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on fibrosis 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 “fibrosis” (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 fibrosis: •

Gallbladder and Biliary Tract Diseases Source: New York, NY: Marcel Dekker, Inc. 2000. 928 p. Contact: Available from Marcel Dekker, Inc. Cimarron Road, P.O. Box 5005, Monticello, NY 12701. (800) 228-1160 or (845) 796-1919. Fax (845) 796-1772. E-mail: [email protected]. International E-mail: [email protected]. Website: www.dekker.com. PRICE: $250.00 plus shipping and handling. ISBN: 0824703111. Summary: The gallbladder and biliary tract are the 'orphan' organs of the digestive system, falling between the realms of the solid organ liver specialist and the hollow organ intestinal expert. This comprehensive text covers the gallbladder and biliary tract disease, noting that the management of gallbladder and biliary disease is truly multidisciplinary, involving gastroenterologists, surgeons, endoscopists, and radiologists. The text attempts to translate advances in basic science into clinically relevant treatment and to bridge the gap between clinical disciplines. Parts I and II focus

230

Fibrosis

on important physiological and pathophysiological principles, with a special emphasis on gallstones. In Parts III to V, the authors focus on clinical disorders of the gallbladder and biliary tree, with input on management from surgeons, endoscopists, and radiologists. New imaging techniques, such as magnetic resonance cholangiography and endoscopic ultrasound, are discussed from both the radiologist's and endoscopist's perspective, and their role in disease management is defined. The 37 chapters cover the neurobiology of the gallbladder, gallbladder mucosal function, gallbladder smooth muscle function and dysfunction, canalicular lipid secretion, bile ductal secretion and its regulation, the pathogenesis of gallstones, pigment gallstones, cholesterol crystallization in bile, normal gallbladder motor functions, gallbladder motility and gallstones, the role of intestinal transit, prevention of gallstones, the gallbladder and biliary tree in cystic fibrosis, the silent gallstone, biliary crystals and sludge, biliary colic and acute cholecystitis (gallbladder infection), laparoscopic cholecystectomy (removal of the gallbladder), nonsurgical therapy of gallstones, biliary lithotripsy, topical contact dissolution of gallbladder stones, common bile duct stones, acalculous cholecystitis, gallbladder cancer, primary sclerosing cholangitis, vanishing bile duct syndrome, cholangiocarcinoma (bile duct cancer), ampullary tumors, infections of the bile ducts, and bile duct injuries. Each chapter includes extensive references and the text concludes with a detailed subject index. •

Gastroenterology and Hepatology: The Comprehensive Visual Reference. Volume 8: Pancreas Source: Philadelphia, PA: Current Medicine. 1998. [200 p.]. Contact: Available from Current Medicine. 400 Market Street, Suite 700, Philadelphia, PA 19106. (800) 427-1796 or (215) 574-2266. Fax (215) 574-2270. E-mail: [email protected]. Website: current-medicine.com. PRICE: $125.00 plus shipping and handling. ISBN: 0443078629. Summary: This atlas is one in an 8-volume collection of images that pictorially displays the gastrointestinal tract, liver, biliary tree, and pancreas in health and disease, both in children and adults. This volume includes 10 chapters on the pancreas. Topics covered include neurohormonal control of the pancreas, pathogenesis of pancreatic diseases, acute pancreatitis, chronic pancreatitis, surgery for chronic pancreatitis, developmental anomalies of the pancreas, pancreatic cancer, the rationale and application of radioligand imaging in gastroenterology, cystic fibrosis, and hereditary pancreatitis. The format of the atlas is visual images supported by relatively brief text. Tables, charts, diagrams, and photomicrographs are used extensively. A subject index concludes the volume.

•

Diseases of the Oral Mucosa and the Lips Source: Orlando, FL: W.B. Saunders Company. 1993. 389 p. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522 (individuals) or (800) 782-4479 (schools); Fax (800) 874-6418 or (407) 352-3445; http://www.wbsaunders.com. PRICE: $99.00 plus shipping and handling. ISBN: 0721640397. Summary: This book is a clinically oriented atlas and text covering the symptoms and diseases of the oral mucosa and perioral skin. The authors focus on the essential aspects of each illness, concentrating on the clinical features that are important in the differential diagnosis. The authors include not only diseases confined to the oral mucosa but also those oral problems that may be signs of accompanying cutaneous (skin) or systemic

Books 231

diseases. Sixty-seven chapters are presented in three sections: the normal oral mucosa, general aspects of oral pathology, and diseases of the oral mucosa and the lips. Specific topics are inflammation of the lips, acquired diseases of the tongue, gingival hyperplasia, enlargement of the parotid gland, aphthous ulcers (stomatitis), pyostomatitis vegetans, disorders of pigmentation, urticaria and angioedema, psoriasis, Reiter's syndrome, lichen planus, graft-versus-host disease, rosacea, perioral dermatitis, erythema multiforme, acute febrile neutrophilic dermatosis (Sweet's syndrome), vesicular and bullous autoimmune diseases, desquamative gingivitis, necrotizing sialometaplasia, oral mucosal hemorrhage, viral diseases, bacterial diseases, fungal diseases, protozoal and parasitic diseases, mechanical damage, trauma, allergic and toxic contact stomatitis, occupational diseases of the oral mucosa, drug reactions and side effects, morphea and scleroderma, lichen sclerosus et atrophicus, dermatomyositis, lupus erythematosus, Sjogren's syndrome, polyarteritis nodosa, giant cell arteritis, plasma cell gingivitis, oral submucous fibrosis, halitosis, xerostomia, sialorrhea, selfinduced mucosal injuries, benign granulomatous processes, malignant granulomatoses, heterotopias and congenital malformations, genodermatoses and congenital syndromes, benign and malignant tumors, actinic keratosis, leukoplakia, paraneoplastic disorders, and oral signs of hematologic, nutritional, metabolic, and endocrine disorders. Each chapter includes full-color photographs and references are provided in individual sections. A subject index concludes the volume. (AA-M). •

Chronic and disabling disorders Source: Philadelphia, PA: Hanley and Belfus. 1994. 169 pp. Contact: Available from Hanley and Belfus, 210 South 13th Street, Philadelphia, PA 19107. Telephone: (215) 546-4995. $66.00 for yearly subscription to three issues in the series; single issues available. Summary: This edition addresses both general issues of importance in health care for adolescents with special health needs and specific chronic conditions. The first set of articles focuses on the epidemiology of chronic illness in adolescence and developmental, educational, and health care delivery issues. The second set discusses specific chronic conditions that are prevalent in the adolescent population (i.e., deafness, cancer, traumatic brain injury, and sickle cell disease) or that have had recent advances in management (i.e., cystic fibrosis, organ transplants, and spinal cord injuries).

•

Clinical Practice of Gastroenterology. Volume Two Source: Philadelphia, PA: Current Medicine. 1999. 861 p. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. Website: www.wbsaunders.com. PRICE: $235.00 plus shipping and handling. ISBN: 0443065209 (two volume set); 0443065217 (volume 1); 0443065225 (volume 2). Summary: This lengthy textbook brings practitioners up to date on the complexities of gastroenterology practice, focusing on the essentials of patient care. This second volume includes 113 chapters in five sections: liver, gallbladder and biliary tract, pancreas, pediatric gastroenterology, and special topics. Specific topics include hepatic (liver) structure and function, jaundice, viral hepatitis, alcoholic liver injury, liver tumors, parasitic diseases of the liver, Wilson's disease, hemochromatosis, the pregnancy patient with liver disease, portal hypertension, hepatic encephalopathy, fulminant hepatic failure, liver transplantation, the anatomy of the gallbladder and biliary tract, gallstones, laparoscopic cholecystectomy (gallbladder removal), cholecystitis (gallbladder

232

Fibrosis

infection), primary sclerosing cholangitis, biliary obstruction, pancreatic anatomy and physiology, acute pancreatitis, pancreatic fistulas and ascites (fluid accumulation), chronic pancreatitis, cancer of the pancreas, endoscopic retrograde cholangiopancreatography, esophageal atresia, gastroesophageal reflux in infants and children, achalasia and esophageal motility disorders, caustic and foreign body ingestion, vomiting, chronic abdominal pain, gastritis and peptic ulcer disease in children, malabsorption syndromes in children, inflammatory bowel disease in children and adolescents, acute appendicitis, cystic fibrosis, constipation and fecal soiling (incontinence), hepatitis in children, liver transplantation in children, failure to thrive, pediatric AIDS, the gastrointestinal manifestations of AIDS, the evaluation and management of acute upper gastrointestinal bleeding, principles of endoscopy, eating disorders, nutritional assessment, enteral and parenteral nutrition, gastrointestinal diseases in the elderly and in pregnancy, nosocomial infections, and the psychosocial aspects of gastroenterology (doctor patient interactions). The chapters include figures, algorithms, charts, graphs, radiographs, endoscopic pictures, intraoperative photographs, photomicrographs, tables, and extensive references. The volume concludes with a detailed subject index and a section of color plates. •

Pediatric Gastrointestinal Disease. 2nd ed Source: Philadelphia, PA: W.B. Saunders Company. 1999. 823 p. Contact: Available from W.B. Saunders Company. Book Order Fulfillment Department, 11830 Westline Industrial Drive, Saint Louis, MO 63146-9988. (800) 545-2522 or (314) 4537010. Fax (800) 568-5136 or (314) 453-7095. E-mail: [email protected]. Website: customerservice.wbsaunders.com. PRICE: $155.00 plus shipping and handling. ISBN: 0721674615. Summary: This medical textbook covers all facets of clinical pediatric gastrointestinal disease. The text emphasizes a clinical focus and incorporates anatomy and physiology considerations into each chapter rather than a separate section. The book is organized into distinct sections, starting with the common clinical problems and followed by organ specific diseases. General chapters on clinical problems cover chronic abdominal pain of childhood and adolescence, vomiting, diarrhea, constipation and encopresis (fecal soiling), failure to thrive, gastrointestinal hemorrhage, eating disorders and obesity, jaundice, ascites, caustic ingestion and foreign bodies, abdominal masses in pediatric patients, and abdominal surgical emergencies. Sections on diseases of the esophagus, stomach, and the small and large bowel (intestine) are followed by chapters reviewing the clinical facets of pediatric liver disease. Specific chapters include gastrointestinal reflux, achalasia and other motor disorders, congenital anomalies, gastric motility disorders, bezoars (a mass of food, hair or other components found in the stomach or intestine), maldigestion and malabsorption, celiac disease, short bowel syndrome, enteric parasites, Crohn's disease, ulcerative colitis, polyps, appendicitis, hernia, Hirschsprung's disease, neoplasms (cancerous and noncancerous), hepatitis, gallbladder diseases, and liver transplantation. The last two sections review diseases of the pancreas and basic nutrition in children, including pancreatitis, cystic fibrosis, nutritional assessment, parenteral (outside the digestive system, for example, intravenous nutrition) and enteral nutrition, and the management of diarrhea. Each chapter offers black and white photographs and figures and concludes with extensive references. A detailed subject index concludes the text.

•

Primary Biliary Cirrhosis: From Pathogenesis to Clinical Treatment Source: Boston, MA: Kluwer Academic Publishers. 1998. 176 p.

Books 233

Contact: Available from Kluwer Academic Publishers. Customer Service Deparment, P.O. Box 358, Accord Station, Hingham, MA 02018-0358. (781) 871-6600. Fax (781) 6819045. E-mail: [email protected]. Website: www.wkap.nl. Summary: This monograph reprints papers from a conference held in November 1997 in Chicago, Illinois, on the clinical features (symptoms), pathogenesis, and treatment of primary biliary cirrhosis (PBC). PBC is generally considered to be an autoimmune disease and one that occurs in patients who are genetically predisposed to the disease. The part played by mitochondrial antibodies (AMA) in pathogenesis of PBC remains controversial. Alternatively, the disease may have an infectious etiology (cause). Therapy can be directed against any of these injurious processes. Drug therapy, notably combinations of drugs, can be used. Fibrosis (scarring) of the bile ducts occurs in PBC and is responsible for the end picture of cirrhosis (liver scarring). Complications such as ascites (fluid accumulation) and portal hypertension (high blood pressure) need to be treated; other complications can include bone thinning and pruritus (itching). Liver (hepatic) transplantation performed before the terminal stages of PBC offers a five year survival exceeding 85 percent. There is evidence of recurrence in the graft. The monograph includes 20 chapters covering the natural history and demography of PBC, the immune basis for PBC, isolation and cloning of antimitochondrial antibodies, determining pathogenesis, molecular considerations of PBC, animal models of PBC, fibrogenesis in PBC, natural history models, portal hypertension in patients with PBC, osteoporosis, managing fatigue in the patients with PBC, pruritus associated with cholestasis (suppression of the flow of bile), immunosuppressant agents, methotrexate and colchicine in the treatment of PBC, corticosteroids in PBC, ursodeoxycholic acid treatment of PBC, ursodiol and combination therapy, transplantation, and new clinical trials in PBC. Each chapter concludes with references and a subject index concludes the monograph. •

Urologic Prostheses: The Complete Practical Guide to Devices, Their Implantation, and Patient Follow up Source: Totowa, NJ: The Humana Press, Inc. 2002. 328 p. Contact: Humana Press, Inc. 999 Riverview Dr., Suite 208 Totowa, NJ 07512. (973) 2561699. Fax (973) 256-8341. E-mail: [email protected] PRICE: $125.00, plus shipping and handling. ISBN: 0896038947. Summary: This text was compiled to provide a broad view of prosthetic devices used in urologic surgery. In keeping with recent advances in urologic prosthetic surgery, contributors of recognized authority have been assembled to write expert articles for the book. The book offers 18 chapters, on the history of urologic prostheses; tissue engineering for the replacement of urologic organs; injectable agents for urinary incontinence; injectable materials for use in urology; Teflon injection for incontinence after radical prostatectomy; urethral stents for neurogenic bladder dysfunction; Urolume stents in the management of benign prostatic hyperplasia (BPH); testicular prostheses; current status and future of penile prosthesis surgery; semirigid, malleable, and mechanical penile prostheses; inflatable penile prostheses; experience with the Mentor Alpha-1; Peyronie disease and penile implants; current approach to penile prosthesis infection; reoperation for penile prosthesis implantation; corporeal fibrosis, penile prosthesis implantation and corporeal reconstruction; artificial urinary sphincter for treatment of male urinary incontinence; and female incontinence and the artificial urinary sphincter. Each chapter includes black and white photographs and charts, and concludes with a list of references. The text concludes with a subject index.

234

•

Fibrosis

Pediatric Clinical Gastroenterology. 4th ed Source: St. Louis, MO: Mosby-Year Book, Inc. 1995. 1065 p. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive. St. Louis, MO 63146. (800) 426-4545 or (800) 325-4177 or (314) 872-8370. Fax (314) 432-1380. PRICE: $100 (as of 1995). ISBN: 0815174063. Summary: This textbook of pediatric clinical gastroenterology presents 37 chapters in 5 sections: symptoms and signs; diseases of the gastrointestinal tract; diseases of the liver; diseases of the pancreas; and nutritional support. Specific topics include gastrointestinal (GI) emergencies of the neonate; intestinal obstruction; sucking and swallowing disorders; diseases of the esophagus; disorders of the stomach and duodenum; diarrheal disorders; carbohydrate intolerance; malabsorption syndrome; protein losing gastroenteropathy; immune homeostasis and the gut; inflammatory bowel diseases; constipation, fecal incontinence, and proctologic conditions; functional recurrent abdominal pain; parasitic and fungal disease of the GI tract; neonatal unconjugated hyperbilirubinemias; neonatal hepatitis; prolonged obstructive jaundice; acute and chronic viral hepatitis; bacterial, rickettsial, and parasitic infections and infestations; fulminant hepatic failure and hepatic coma; cirrhosis; portal hypertension; inborn errors of metabolism; hepatic tumors; liver transplantation; congenital anomalies and heredity disorders; cystic fibrosis; pancreatitis and pancreatic tumors; energy and nutrient requirements; infant feeding; and enteral and parenteral alimentation. Each chapter includes numerous references and a subject index concludes the volume.

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: When following the link below, you may discover non-medical books that use the generic term “fibrosis” (or a synonym) in their titles. •

Amazon.com: http://www.amazon.com/exec/obidos/externalsearch?tag=icongroupinterna&keyword=fibrosis&mode=books

Chapters on Fibrosis In order to find chapters that specifically relate to fibrosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and fibrosis 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 “fibrosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on fibrosis:

Books 235

•

Pathogenesis of Hepatic Fibrosis Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 605-620. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-6423. Fax: (301) 223-2400. Website: www.lww.com. PRICE: $289.00. ISBN: 781728614. Summary: This chapter reviews the current understanding of the pathogenesis of hepatic (liver) fibrosis and highlights those elements of the process for which intervention has been attempted. This chapter on the development of liver fibrosis and cirrhosis (scarring) is from a lengthy, two-volume textbook that integrates the various demands of science, technology, expanding information, good judgment, and common sense into the diagnosis and management of gastrointestinal patients. Topics include hepatic connective tissue, collagen synthesis, cellular sources of extracellular matrix proteins, matrix-degrading enzymes, the extracellular matrix in cirrhosis, activation and proliferation of fibrogenic cells, monitoring the progression of fibrosis, and antifibrotic therapies. 6 figures. 1 table. 174 references.

•

Toxigenic Diarrheas, Congenital Diarrheas, and Cystic Fibrosis: Disorders of Intestinal Ion Transport Source: in Hoffman, J.F. and De Weer, P., eds. Annual Review of Physiology. Palo Alto, CA: Annual Reviews Inc. 1993. Volume 55: 631-655. Contact: Available from Annual Reviews Inc. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (800) 523-8635. Fax (415) 424-0910. E-mail: [email protected]. PRICE: $46.00. ISBN: 0824303555. ISSN: 00664278. Individual chapter reprints available from Annual Reviews Preprints and Reprints. (800) 347-8007 or (415) 259-5017. Base price $13.50 per article. Summary: This entry from the Annual Review of Physiology discusses the pathophysiology of enterotoxic diarrheas, congenital diarrheas, and cystic fibrosis (CF). The authors begin with a brief summary of the ion transport properties of the intestine as they relate to the active secretion of electrolytes. Other topics include Vibrio Cholerae enterotoxins, including the cholera toxin and the enteric nervous system; heat-stable Escherichia Coli enterotoxin and guanylin; congenital defects of intestinal electrolyte transport; and directions for future research. 3 figures. 128 references.

•

Hereditary and Childhood Disorders of the Pancreas, Including Cystic Fibrosis Source: in Feldman, M.; Friedman, L.S.; Sleisenger, M.H. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. [2-volume set]. St. Louis, MO: Saunders. 2002. p. 881-912. Contact: Available from Elsevier. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 545-2522. Fax (800) 568-5136. Website: www.us.elsevierhealth.com. PRICE: $229.00 plus shipping and handling. ISBN: 0721689736. Summary: Understanding the role of developmental genes in human disease remains in its infancy, but emerging evidence suggests that altered function plays a role in developmental malformations and rare congenital disorders. This chapter focuses on recent advances in the understanding of pancreatic disorders associated with mutations in key pancreatic genes and on common acquired pancreatic diseases in children, including cystic fibrosis. The chapter is from a comprehensive and authoritative

236

Fibrosis

textbook that covers disorders of the gastrointestinal tract, biliary tree, pancreas, and liver, as well as the related topics of nutrition and peritoneal disorders. Topics include the genetic basis of congenital disorders of morphogenesis, including an overview of embryology, pancreatic agenesis and hypoplasia, agenesis of the dorsal pancreas, agenesis of the ventral pancreas, annular pancreas, and heterotopic pancreatic tissue; ductal abnormalities; inherited syndromes with major pancreatic manifestations, including cystic fibrosis, Shwachman-Diamond syndrome, Johanson-Blizzard syndrome, Pearson's Marrow-Pancreas syndrome, and other rare syndromes affecting the pancreas; gene mutations predisposing to acute and chronic pancreatitis; inherited disorders of metabolism causing pancreatitis; pancreatic insufficiency syndromes; and acquired pancreatic disease in children, including etiology, clinical features, complications, and treatment. The chapter includes a mini-outline with page citations, full-color illustrations, and extensive references. 8 figures. 10 tables. 363 references.

Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to fibrosis 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:11 •

1998-1999 Complete Directory for People with Rare Disorders Source: Lakeville, CT: Grey House Publishing, Inc. 1998. 726 p. Contact: Available from Grey House Publishing, Inc. Pocket Knife Square, Lakeville, CT 06039. (860) 435-0868. Fax (860) 435-0867. PRICE: $190.00. ISBN: 0939300982. Summary: This directory, from the National Organization for Rare Disorders (NORD) provides a wealth of information on diseases and organizations. The directory offers four sections: disease descriptions, disease specific organizations, umbrella organizations, and government agencies. In the first section, the directory includes descriptions of 1,102 rare diseases in alphabetical order. Each entry defines the disorder, then refers readers to the organizations that might be of interest. Diseases related to digestive diseases include achalasia, Addison's disease, Alagille syndrome, Barrett's esophagus, Budd Chiari syndrome, Caroli disease, celiac sprue, cholangitis, cholecystitis, cirrhosis, colitis, Crohn's disease, Cushing syndrome, cystic fibrosis, diverticulitis, Dubin Johnson syndrome, fructose intolerance, galactosemia, gastritis, gastroesophageal reflux, hepatitis, Hirschprung's disease, Hurler syndrome, imperforate anus, irritable bowel syndrome, jejunal atresia, Korsakoff's syndrome, lipodystrophy, maple syrup urine disease, Morquio syndrome, polyposis, porphyria, proctitis, prune belly syndrome, sarcoidosis, Stevens Johnson syndrome, Tropical sprue, tyrosinemia, valinemia, vitamin E deficiency, Whipple's disease, Wilson's disease, and Zollinger Ellison syndrome. Each of the 445 organizations listed in the second section is associated with a specific disease or group of diseases. In addition to contact information, there is a descriptive paragraph about the organization and its primary goals and program activities. Entries include materials published by the organization as well as the diseases

11

You will need to limit your search to “Directory” and “fibrosis” 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 “fibrosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.

Books 237

the organizations cover, which refer readers to Section I. The third section lists 444 organizations that are more general in nature, serving a wide range of diseases (for example, the American Liver Foundation). The final section describes 74 agencies that are important federal government contacts that serve the diverse needs of individuals with rare disorders. A name and key word index concludes the volume.

239

CHAPTER 7. MULTIMEDIA ON FIBROSIS Overview In this chapter, we show you how to keep current on multimedia sources of information on fibrosis. 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 fibrosis is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “fibrosis” 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 “fibrosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on fibrosis: •

What You Should Know About Xerostomia (Dry Mouth) Source: Fairburn, GA: National Oral Cancer Awareness (NOCAP). 199x. (videocassette). Contact: Available from American Dental Hygienists' Association (ADHA). 444 North Michigan Avenue, Suite 3400, Chicago, IL 60611. (800) 243-2342 (press 2) or (312) 4408900. Fax (312) 467-1806. Website: www.adha.org. PRICE: $18.00. Item Number 3917 COM. Summary: This videocassette program describes the problem of xerostomia (dry mouth). The introduction stresses that the health impact of saliva goes far beyond the mouth and includes eating, talking, tooth maintenance, and tasting. The program then features a person with xerostomia describing how it feels to have problems with dry mouth. A brief description of the chemical makeup of salivary and the anatomy of the salivary glands follow. The next section discusses the potential causes of xerostomia, including radiation therapy, especially for cancer of the head and neck; drug effects, particularly from antihistamines, tranquilizers, and some blood pressure medications;

240

Fibrosis

anxiety or depression, even without drug therapy; dehydration; and systemic diseases, including Sjogren's syndrome, lupus, cystic fibrosis, rheumatoid arthritis, and scleroderma. The narrator stresses that aging itself is not necessarily the cause of xerostomia. Complications of xerostomia include dry lips, burning mouth or tongue, constant thirst, difficulty talking or swallowing, impaired taste, dental caries (cavities), candidiasis (a fungal infection), and problems related to dehydration. Viewers are encouraged to work closely with health care providers to obtain an accurate diagnosis and employ strategies to cope with xerostomia. Treatment encompasses three options: eliminating the cause of the xerostomia, if possible; stimulating the salivary glands with sugar-free chewing gum, oral moisturizers, or the prescription drug pilocarpine; and using other measures to get relief, including saliva substitutes, frequent sips of water, room humidifiers (especially during winter), and lip balm. The program concludes with a reminder that xerostomia results in the need for increased attention to dental hygiene, including increased dental visits, limiting sugar intake, the use of fluoride, and the prevention of candidiasis. The program encourages viewers to learn about xerostomia, seek help, and improve the quality of their lives. •

Health Care Professionals' Guide to Xerostomia Source: Bethesda, MD: Sjogren's Syndrome Foundation, Inc. 1997. (videocassette). Contact: Available from Sjogren's Syndrome Foundation, Inc. 8120 Woodmont Avenue, Suite 530, Bethesda MD 20814-1437. (301) 718-0300 or (800) 475-6473. Fax (301) 718-0322. Website: www.sjogrens.org. PRICE: $29.00. Summary: This videotape program reviews xerostomia (dry mouth). The program begins with an overview of the anatomy and physiology of the salivary glands, followed by a discussion of the three functional roles of saliva: digestion (and taste facilitation), lubrication, and protection (including antimicrobial and pH mechanisms). The narrator notes that saliva is also being used more and more as a diagnostic tool to measure systemic health. The program begins with a physician narrating, then includes interviews with two middle age women who have xerostomia; the interviews focus on the impact xerostomia has on quality of life and on the difficulties of obtaining an accurate diagnosis. The program then details the three causes of xerostomia: medical therapies (including drug side effects, radiation therapy, and surgery or trauma of the salivary glands), systemic disorders (including Sjogren's syndrome, HIV, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, graft versus host disease, sarcoidosis, amyloidosis, cystic fibrosis, and neural disease affecting the salivary glands), and dehydration. The program emphasizes that xerostomia is not a natural consequence of the aging process. The program then reviews the clinical signs and oral complications of xerostomia; each is illustrated with a color photograph. Other topics include problems associated with xerostomia, the need for a multidisciplinary team approach to patients with salivary gland dysfunction, diagnostic tests used, treatment options (including chewing activity, oral moisturizing agents, and oral pilocarpine hydrochloride), determining residual salivary gland function, and the behavioral and lifestyle changes that can help patients cope with xerostomia.

241

CHAPTER 8. 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 fibrosis. 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 fibrosis. 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

242

Fibrosis

following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to fibrosis: Aminobenzoate Potassium •

Systemic - U.S. Brands: Potaba http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202025.html

Beta-Carotene •

Systemic - U.S. Brands: Lumitene; Max-Caro http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202623.html

Dornase Alfa •

Inhalation - U.S. Brands: Pulmozyme http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202710.html

Fluoroquinolones •

Systemic - U.S. Brands: Avelox; Cipro; Cipro I.V.; Floxin; Floxin I.V.; Levaquin; Maxaquin; Noroxin; Penetrex; Tequin; Zagam http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202656.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/.

PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter,

Researching Medications

243

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 fibrosis 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 “fibrosis” (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 fibrosis: •

2-0-desulfated heparin (trade name: Aeropin) http://www.rarediseases.org/nord/search/nodd_full?code=1

•

recombinant human alpha 1-antitrypsin (rAAT) (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1196

•

Meropenem (trade name: Merrem IV) http://www.rarediseases.org/nord/search/nodd_full?code=1041

•

N-acetylcysteinate (trade name: Nacystelyn Dry Powder) http://www.rarediseases.org/nord/search/nodd_full?code=1078

•

N-acetycsteinate (trade name: Nacystelyn Dry Powder Inhaler) http://www.rarediseases.org/nord/search/nodd_full?code=1089

•

p1-(uridine 5')-p4-(2'-deoxycytidine 5'-) tetrapho http://www.rarediseases.org/nord/search/nodd_full?code=1100

•

p1-(uridine 5' -)-p4-(2' -deoxcytidine 5' -) tetra http://www.rarediseases.org/nord/search/nodd_full?code=1106

•

aztreonam (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1236

•

carbamic acid, ((4-((30((4-10(4-hydroxypheny1)-1-m http://www.rarediseases.org/nord/search/nodd_full?code=1238

244

Fibrosis

•

p1(uridine 5'-)-p4-(2'-deoxycytidine 5'-) tetrapho (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1190

•

recombinant human alpha-1-antitrypsin (rAAT) (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1230

•

Uridine 5'-triphosphate http://www.rarediseases.org/nord/search/nodd_full?code=229

•

aztreonam http://www.rarediseases.org/nord/search/nodd_full?code=1260

•

carbamic acid, ((4-((3-((4-((1-(4-hydroxypheny1)-1 http://www.rarediseases.org/nord/search/nodd_full?code=1262

•

octavalent Psuedomonas aeruginosa O-polsaccaharide (trade name: Aerugen) http://www.rarediseases.org/nord/search/nodd_full?code=1282

•

interferon Gamma-1B (trade name: Actimmune) http://www.rarediseases.org/nord/search/nodd_full?code=1304

•

Mucoid esopolysaccharide Pseudomonas hyperimmune g (trade name: MEPIG) http://www.rarediseases.org/nord/search/nodd_full?code=166

•

Mucoid exopolysaccharide Pseudomonas hyperimmune g (trade name: Mepig) http://www.rarediseases.org/nord/search/nodd_full?code=170

•

US http://www.rarediseases.org/nord/search/nodd_full?code=221

•

Adeno-associated viral-based vector cystic fibrosi http://www.rarediseases.org/nord/search/nodd_full?code=513

•

Lipid/DNA human cystic fibrosis gene http://www.rarediseases.org/nord/search/nodd_full?code=254

•

Dornase alfa (trade name: Pulmozyme) http://www.rarediseases.org/nord/search/nodd_full?code=285

•

Cystic fibrosis Tr gene therapy (recombinant adeno (trade name: AdGVCFTR.10) http://www.rarediseases.org/nord/search/nodd_full?code=384

•

Cystic fibrosis gene therapy http://www.rarediseases.org/nord/search/nodd_full?code=389

•

Recombinant secretory leucocyte protease inhibitor http://www.rarediseases.org/nord/search/nodd_full?code=392

•

Cystic fibrosis transmembrane conductance regulato http://www.rarediseases.org/nord/search/nodd_full?code=393

•

Cystic fibrosis transmembrane conductance regulato http://www.rarediseases.org/nord/search/nodd_full?code=415

•

DMP 777 http://www.rarediseases.org/nord/search/nodd_full?code=435

•

Recombinant human gelsolin http://www.rarediseases.org/nord/search/nodd_full?code=462

•

Dextran sulfate (inhaled, aerosolized) (trade name: Uendex) http://www.rarediseases.org/nord/search/nodd_full?code=480

Researching Medications

•

Amiloride HCL solution for inhalation http://www.rarediseases.org/nord/search/nodd_full?code=534

•

Tobramycin for inhalation (trade name: TOBI) http://www.rarediseases.org/nord/search/nodd_full?code=62

•

8 Cyclopentyl 1,3-dipropylxanthine http://www.rarediseases.org/nord/search/nodd_full?code=830

•

P1, P4-Di(uridine 5'-tetaphosphate), tetrasodium s http://www.rarediseases.org/nord/search/nodd_full?code=944

•

Duramycin http://www.rarediseases.org/nord/search/nodd_full?code=862

245

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.

247

APPENDICES

249

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute12: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

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/

12

These publications are typically written by one or more of the various NIH Institutes.

250

Fibrosis

•

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

Physician Resources

251

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.13 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:14 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

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

13

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 14 See http://www.nlm.nih.gov/databases/databases.html.

252

Fibrosis

•

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 “fibrosis” 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 “fibrosis” (or synonyms) into the “For these words:” box. The following is a sample result: •

Hepatitis C Update: Recommendations from the NIH and CDC Source: JAAPA. Journal of the American Academy of Physician Assistants. 11(12): 35-37. December 1998. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Fax (201) 573-4956. Summary: In March 1997, the National Institutes of Health (NIH) conducted a consensus development conference on the management of hepatitis C virus (HCV) infection. In July 1998, the Centers for Disease Control and Prevention (CDC) held a consultants meeting on HCV, from which it developed recommendations for the prevention and control of HCV infection and related chronic disease. This article reviews these two sets of recommendations, summarizing and comparing the guidelines in the areas of screening, counseling, monitoring, and treatment. The CDC recommends screening persons at low risk of HCV infection with the enzyme immunoassay (EIA) HCV antibody test, which has a sensitivity of greater than 97 percent. If indicated, the recombinant immunoblot assay is used as a confirmation test. The NIH, on the other hand, recommends measurement of HCV RNA with the polymerase chain reaction, if indicated, as a confirmatory test of a positive EIA. The CDC recommends that people who test positive for HCV should be counseled about being evaluated for their disease and possibly being treated. They should be instructed about reducing the risk of transmitting the virus to another person and refraining from donating blood or other body tissues. The CDC recommends vaccination against hepatitis A in a person who has chronic HCV infection; the NIH recommends vaccination against hepatitis A and B. Liver biopsy remains the gold standard for assessing disease activity, including progression to fibrosis and cirrhosis. Treatment is recommended when findings on liver biopsy include periportal or bridging fibrosis and a moderate degree of inflammation and necrosis. Patients who have had one or more episodes of decompensated cirrhosis (ascites, variceal bleedings, or encephalopathy) should be referred to a center that performs liver transplantation. 1 figure. 3 references.

•

Chronic Hepatitis B Virus Infection in Asian Countries Source: Journal of Gastroenterology and Hepatology. 15(12): 1356-1361. December 2000.

Physician Resources

253

Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: Of the estimated 50 million new cases of hepatitis B virus (HBV) infection diagnosed annually, 5 to 10 percent of adults and up to 90 percent of infants will become chronically infected. Of those who become chronically infected, 75 percent are in Asia where hepatitis B is the leading cause of chronic hepatitis (liver infection), cirrhosis (liver scarring), and hepatocellular carcinoma (liver cancer). This article offers detailed statistics on chronic HBV infection in Asian countries, including Indonesia, the Phillipines, Thailand, China, Taiwan, and Malaysia. In the highly endemic countries in Asia (places where HBV is found on a routine basis in the population), the majority of infections are contracted postnatally or perinatally (during birth). Three phases of chronic HBV infection are recognized: phase 1 patients are HBeAg positive with high levels of virus in the serum (blood) and minimal hepatic (liver) inflammation; phase 2 patients have intermittent or continuous hepatitis of varying degrees of severity; phase 3 is the inactive phase during which viral concentrations are low and there is minimal inflammatory activity in the liver. In general, patients who clear HBeAg have a better prognosis than patients who remain HBeAg positive for prolonged periods of time. The outcome after anti HBe seroconversion depends on the degree of preexisting liver damage and any subsequent HBV reactivation. Without preexisting cirrhosis, there may be only slight fibrosis or mild chronic hepatitis, but with preexisting cirrhosis, further complications may happen. The annual incidence of hepatic decompensation (reduction in liver function) in HBV related cirrhosis varies from 2 to 10 percent and in these patients, the 5 year survival rate drops dramatically to 14 to 35 percent. The annual risk of developing HCC (liver cancer) in patients with cirrhosis varies between 1 and 6 percent. Chronic hepatitis B is not a static disease and the natural history of the disease is affected by both viral and host factors. The prognosis is poor with decompensated cirrhosis and effective treatment options are limited. The authors conclude that prevention of HBV infection through vaccination is still therefore the best strategy for decreasing the incidence of hepatitis B associated cirrhosis and HCC. 1 table. 32 references. •

Hepatitis Report: A Critical Review of the Research and Treatment of Hepatitis C Virus (HCV) and Hepatitis and HIV Coinfection Source: New York, NY: Treatment Action Group. 2000. 134 p. Contact: Treatment Action Group. 350 Seventh Avenue, Suite 1603, New York, NY 10036. (212) 972-9022. Fax (212) 971-9019. Website: www.treatmentactiongroup.org. PRICE: Single copy free. Summary: This report is designed to bring clinicians, allied health care workers, and patients up to date on hepatitis C virus (HCV), including epidemiology, natural history, diagnosis, pathogenesis, and treatment. After an analysis of peer reviewed articles, over 40 researchers, clinicians, primary care physicians, government health administrators, industry representatives, and patients with viral hepatitis were interviewed for this report. Eleven chapters cover epidemiology, modes of transmission, and risk factors; pathogenesis, viral dynamics, and immunologic response; natural history, clinical manifestations, and prognostic indicators of disease progression and survival of HCV infection; diagnostic considerations; the use of interferon to treat HCV infection; the mechanism of HCV resistance to interferon; experimental treatments and new areas of research; hepatitis and HIV coinfection; current opinions and controversies in HCV infection; research and policy recommendations; and clinician's response. The natural

254

Fibrosis

history chapter reminds readers that not all patients with HCV inexorably deteriorate to end stage liver disease, liver transplantation, or death. The diagnosis of HCV is often complex with multiple tests and the confusion of liver biopsy evaluation. The role of HCV in response to HIV therapy is largely unknown. Approximately only half of HCV patients respond to current therapies, but the report considers whether perhaps only half may actually need therapy in the long term. Unfortunately, clinicians cannot determine which patients will progress to fibrosis and end stage liver disease and so most patients are treated, especially if they have some scarring without cirrhosis. Interferon remains the mainstay of therapy, with pegylated IFNs providing new advances. Each chapter includes illustrations and a list of references. •

Demonstrating cost-effectiveness of nutrition services for children with special health care needs: A national network Source: Arlington, VA: National Center for Education in Maternal and Child Health; Los Angeles, CA: Center for Child Development and Developmental Disabilities, University of Southern California. 1999. 67 pp. Contact: Available from National Maternal and Child Health Clearinghouse, 2070 Chain Bridge Road, Suite 450, Vienna, VA 22182-2536. Telephone: (703) 356-1964 or (888) 4344MCH / fax: (703) 821-2098 / e-mail: [email protected]. Available at no charge. Summary: This report summarizes a literature review and a field survey related to the cost-effectiveness of nutrition services for children with special health care needs (CSHCN). The literature review concentrates on cystic fibrosis, cerebral palsy, and failure to thrive. It includes an overview of each illness and the outcome indicators cited in the literature. The survey analysis results are presented by agency setting (i.e., clinical, public health, or university setting) and by federal region. A report on the expert panel convened to identify nutrition indicators for CSHCN, a description of workshop participant projects, and a list of workshop participants are included. The report was prepared for the Maternal and Child Health Interorganizational Nutrition Group (MCHING). [Funded by the Maternal and Child Health Bureau].

The NLM Gateway15 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “fibrosis” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category.

15 16

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH).

Physician Resources

255

Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 71638 577 727 190 804 73936

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.19 Simply search by “fibrosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists20 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.21 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.22 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

17

Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html.

18

The HSTAT URL is http://hstat.nlm.nih.gov/.

19 Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 20 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 21

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 22 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

256

Fibrosis

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/.

The Genome Project and Fibrosis In the following section, we will discuss databases and references which relate to the Genome Project and fibrosis. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).23 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “fibrosis” (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 fibrosis: •

Camptodactyly, Myopia, and Fibrosis of the Medial Rectus Muscle of Eye Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602612

•

Cystic Fibrosis Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=219700

•

Cystic Fibrosis Modifier 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603855

•

Cystic Fibrosis Transmembrane Conductance Regulator Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602421

•

Cystic Fibrosis with Helicobacter Pylori Gastritis, Megaloblastic Anemia, and Subnormal Mentality Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=219721

23 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

Physician Resources

•

Fibrosis of Extraocular Muscles, Congenital, 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=135700

•

Fibrosis of Extraocular Muscles, Congenital, 2 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602078

•

Fibrosis of Extraocular Muscles, Congenital, 3 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600638

•

Fibrosis of Extraocular Muscles, Congenital, 3a Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607034

•

Hepatic Fibrosis, Severe, Susceptibility To, due to Schistosoma Mansoni Infection Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604201

•

Myelofibrosis, Familial Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=254450

•

Pulmonary Fibrosis, Idiopathic Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=178500

257

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

•

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

•

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

•

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

258

Fibrosis

•

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

•

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

•

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

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

Physician Resources

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

259

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 “fibrosis” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database24 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database25 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “fibrosis” (or synonyms) into the search box, and

24

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 25 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

260

Fibrosis

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).

261

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 fibrosis 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 fibrosis. 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 fibrosis. 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 “fibrosis”:

262

•

Fibrosis

Other guides Acne http://www.nlm.nih.gov/medlineplus/acne.html Cystic Fibrosis http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html High Risk Pregnancy http://www.nlm.nih.gov/medlineplus/highriskpregnancy.html Pulmonary Fibrosis http://www.nlm.nih.gov/medlineplus/pulmonaryfibrosis.html Respiratory Diseases http://www.nlm.nih.gov/medlineplus/respiratorydiseases.html

Within the health topic page dedicated to fibrosis, the following was listed: •

General/Overviews Facts about Pulmonary Fibrosis and Interstitial Lung Disease Source: American Lung Association http://www.lungusa.org/diseases/pulmfibrosis.html Let's Talk about Idiopathic Pulmonary Fibrosis: Questions and Answers for Patients and Caregivers http://www.coalitionforpf.org/pdfs/patientbro.pdf

•

Diagnosis/Symptoms Blood Gas Tests Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/blood_gases/test.html Bronchoscopy: Pulmonary Branch Protocols Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/pepubs/bronchoscopy.pdf Radiography -- Chest (Chest X-ray) Source: American College of Radiology, Radiological Society of North America http://www.radiologyinfo.org/content/chest_radiography.htm Spirometry Testing Source: National Jewish Medical and Research Center http://www.nationaljewish.org/medfacts/spirometry.html Symptoms and Diagnosis: Idiopathic Pulmonary Fibrosis Source: Coalition for Pulmonary Fibrosis http://www.coalitionforpf.org/patient/symptoms.asp Understanding PFT's (Pulmonary Function Testing) Source: Alpha 1 Association http://www.alpha1.org/what/lunginfo_pfts.htm

Patient Resources 263

•

Treatment Treatment: Idiopathic Pulmonary Fibrosis Source: Coalition for Pulmonary Fibrosis http://www.coalitionforpf.org/patient/treatment.asp

•

From the National Institutes of Health Facts about Idiopathic Pulmonary Fibrosis Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/public/lung/other/idiopath.htm

•

Organizations American Lung Association http://www.lungusa.org/ National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/

•

Pictures/Diagrams Atlas of the Body: The Respiratory System -- Structure Detail Source: American Medical Association http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZ8PPLCGJC &sub_cat=285

•

Research IPF Research Source: Coalition for Pulmonary Fibrosis http://www.coalitionforpf.org/patient/ipfresearch.asp

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 fibrosis. 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: •

Questions and Facts About Cystic Fibrosis Source: Rockville, MD.: Cystic Fibrosis Foundation. 5 p.

264

Fibrosis

Contact: Available from Cystic Fibrosis Foundation. 6000 Executive Boulevard, Suite 309, Rockville, MD 20852. Summary: This brochure describes Cystic Fibrosis (CF), how it occurs and its genetic etiology, identifying CF carriers, symptoms, complications of the disease, age of onset, treatment, and the outlook for the CF patient. Also included is a description of the Cystic Fibrosis Foundation and the programs it supports. •

For adults with cystic fibrosis: Facts on reproduction Source: Madison, WI: Great Lakes Regional Genetics Group, University of Wisconsin Madison. 1993. 12 pp. Contact: Available from National Maternal and Child Health Clearinghouse, 2070 Chain Bridge Road, Suite 450, Vienna, VA 22182-2536. Telephone: (703) 356-1964 or (888) 4344MCH / fax: (703) 821-2098 / e-mail: [email protected] / Web site: http://www.nmchc.org. Available at no charge. Summary: This pamphlet, aimed at adults with cystic fibrosis who want to have a child, describes how the disease might have affected the male and female reproductive organs, how to overcome or circumvent these problems, and the genetics of the disease, so that the couple can make an informed choice. [Funded by the Maternal and Child Health Bureau]. 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: •

Check Your Cystic Fibrosis I.Q. Summary: Test your knowledge of cystic fibrosis. Answer true or false to the statements online and find out what you know or don't know about this respiratory disease. Source: American Association for Respiratory Care http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6169

•

Gene Therapy and Cystic Fibrosis Summary: A patient education brochure that discusses gene therapy as a potentially a life-saving treatment that tackles the root cause of cystic fibrosis (CF), rather than the symptoms. Source: Cystic Fibrosis Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5032

Patient Resources 265

•

Sweat Testing Procedure and Commonly Asked Questions Summary: This online fact sheet answers some of the commonly asked questions about the sweat test, a diagnostic procedure for Cystic Fibrosis. Source: Cystic Fibrosis Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5014 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 fibrosis. 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. 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

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMD®Health: http://my.webmd.com/health_topics

News Services and Press Releases One of the simplest ways of tracking press releases on fibrosis 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 “fibrosis” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days.

266

Fibrosis

Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to fibrosis. 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 “fibrosis” (or synonyms). 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 “fibrosis” (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 “fibrosis” (or synonyms). If you know the name of a company that is relevant to fibrosis, 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/.

Patient Resources 267

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 “fibrosis” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “fibrosis” (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 fibrosis: •

ARPKD: A Quick Review Source: PKD Progress. 16(3): 7. Summer 2001. Contact: Available from PKD (Polycystic Kidney Disease) Foundation. 9221 Ward Parkway, Suite 400 Kansas City, MO 64114.(800) PKD-CURE. Fax (816) 931-8655. Email:[email protected]. Website: www.pkdcure.org. Summary: ARPKD (autosomal recessive polycystic kidney disease) primarily affects, the kidneys (always both) with progressive cysts and the liver with congenital hepatic fibrosis (CHF), which is malformation and progressive scarring of the bile duct system. This brief article reviews ARPKD, its diagnosis and treatment. The author notes that because of continually improved mechanical ventilation, neonate support, control of systemic and portal hypertension, management of ESRD, and transplantation, the ARPKD population is living longer into adulthood. Unfortunately, 30 to 50 percent of infants with ARPKD die at birthor shortly thereafter, usually as a result of underdeveloped lungs and pulmonary complications. Almost everyone with ARPKD is diagnosed during infancy or childhood; however, the first signs of the disease vary greatly. Approximately 30 percent of the infants experience failure-to-thrive, although the exact cause is unknown. Hypertension (high blood pressure) is thought to be a factor in progression of renal deterioration, and without aggressive treatment, severe hypertension can be life threatening. The same inherited defect that affects the kidneys occurs in the liver, but the two organs react differently with great variability of onset and severity of clinical symptoms. Even for symptomatic individuals, synthetic liver function generally is preserved, as it usually continues to excrete, produce, and regulate hormones and chemicals normally.

•

Secondary Diabetes in Children Source: On the Cutting Edge. 22(6): 9-10. Winter 2001. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: Secondary diabetes is diagnosed when glucose levels are elevated as the result of another disorder or medications; this article discusses secondary diabetes in

268

Fibrosis

children. The author notes that children diagnosed with secondary diabetes may find it hard to adjust to the daily self care routines needed for good blood glucose (sugar) control while dealing with the reality of not one but two disease states. Individualizing educational plans to allow for flexibility while still promoting good metabolic control is important for these patients. Identifying key dietary changes and sick-day nutritional guidelines for the child can also foster better choices by patients when they are independently making decisions. A meal plan containing 10 to 20 percent of daily calorie intake from protein is encourages and the remainder of calories should be distributed between carbohydrates and fats. The benefits of consistency in meal times as well as portions should be stressed for a child with secondary diabetes. The design of the meal plan may be influenced by the primary diagnosis (e.g., AIDS or cystic fibrosis). 6 references. •

Therapy-Treatment of Systemic Sclerosis Source: Scleroderma Voice. p. 12-14. Winter 2000-2001. Contact: Available from Scleroderma Foundation. 12 Kent Way, Suite 101, Byfield, MA 01922. (800) 722-HOPE or (978) 463-5843. Fax (978) 463-5809. E-mail: [email protected]. Website: www.scleroderma.org. Summary: This newsletter article provides health professionals and people who have scleroderma with information on approaches to treating systemic sclerosis (SSc). Interrupting the pathogenetic cycle is a reasonable approach to the treatment of SSc. Treatment might be aimed at addressing the vascular damage, preventing fibrosis, or suppressing the immune response. The article highlights the results of recent clinical trials of a prostacyclin derivative, iloprost, interferon gamma, D-penicillamine, chlorambucil, cyclosporine A, methotrexate, and cyclophosphamide. In general, these trials support the use of prostacyclin derivatives, antifibrotic regimens, and immunosuppressive agents to treat SSc. A more definitive test of the usefulness of immunosuppression for SSc is a trial of stem cell transplantation (SCT). Although SCT results have been encouraging, there has been almost a 25 percent mortality rate among SCT treated patients.

•

Pulmonary Manifestations of SLE Source: Lupus News. 20(2): 18-19. Spring 2000. Contact: Available from Lupus Foundation of America. 1300 Piccard Drive, Suite 200, Rockville, MD 20850-4303. (800) 558-0121 or (301) 670-9292. Fax (301) 670-9486. Website: www.lupus.org/lupus. Summary: This newsletter article provides people who have lupus with information on its pulmonary manifestations. The prevalence of lung involvement in people with lupus is very high. Lupus manifestations within the lung parenchyma include infections, pneumonitis, interstitial lung disease (ILD), diffuse alveolar hemorrhage, and acute reversible hypoxia syndrome. Infection is the most common cause of an abnormal chest x ray involving the lung parenchyma. People who have lupus are susceptible to infections because their immune system functions abnormally and because the medications they use decrease the ability to resist infection. Infections are caused by bacteria, viruses, fungi, and parasites. Pneumonitis, noninfectious pneumonia, is a form of inflammation within the alveoli that is not associated with infection. ILD is inflammation within the interstitium, which leads to fibrosis in the area if the inflammation persists. Diffuse alveolar hemorrhage is a severe and life threatening complication of lupus and probably reflects vasculitis of the pulmonary blood vessels.

Patient Resources 269

Acute reversible hypoxia causes shortness of breath from low oxygen within the blood. Fifty to eighty percent of people who have lupus develop inflammation of the lining around the lungs and the heart, causing fluid to accumulate around these organs. Blood clot formation or elevation of the blood pressure within the pulmonary arteries may also occur in people who have lupus. In rare cases, pulmonary neuromuscular system involvement in lupus can cause shrinking lung syndrome. Drugs used to treat lupus may also have pulmonary side effects. 1 figure.

Associations and Fibrosis The following is a list of associations that provide information on and resources relating to fibrosis: •

Canadian Cystic Fibrosis Foundation Telephone: (416) 485-9149 Toll-free: (800) 378-2233 Fax: (416) 485-0960 Email: [email protected] Web Site: www.cysticfibrosis.ca Background: The Canadian Cystic Fibrosis Foundation (CCFF) is a national not-forprofit organization dedicated to helping individuals with cystic fibrosis (CF) and their family members. Cystic fibrosis is a rare inherited disorder that affects many exocrine ('outward-secreting') glands of the body including the sweat glands, salivary glands, and those within the pancreas and respiratory system. Due to unusually thick secretions of mucus that clog and obstruct air passages of the lungs, affected individuals experience chronic coughing and an increased susceptibility to repeated lung infections. Individuals with CF also exhibit an inability to break down food and absorb fats and nutrients properly; have abnormally salty sweat containing elevated levels of chloride and sodium; and/or may demonstrate other abnormalities. Established in 1960, the Canadian Cystic Fibrosis Foundation is committed to conducting research into improved care and treatment for CF, seeking a cure or control for the disorder, and promoting public awareness. In addition, the Foundation offers support groups, engages in patient advocacy, provides referrals, and promotes patient, professional, and general education.

•

Coalition for Pulmonary Fibrosis Telephone: (888) 266-3289 Toll-free: (888) 226-8541 Fax: (408) 266-3289 Email: [email protected] Web Site: www.coalitionforpf.org Background: The Coalition for Pulmonary Fibrosis (CPF) is a 501 (c) (3) nonprofit organization founded in 2001 to further education, patient support and research efforts for pulmonary fibrosis, specifically idiopathic pulmonary fibrosis (IPF). The CPF is governed by pulmonologists, individuals affected by pulmonary fibrosis, medical research professionals and advocacy organizations.

270

•

Fibrosis

Cochrane Cystic Fibrosis and Genetic Disorders Review Group Telephone: +44 (0) 1512525696 Fax: +44 (0) 1512525456 Email: [email protected] Web Site: www.liv.ac.uk/cfgd_home.htm Background: Cochrane Cystic Fibrosis and Genetic Disorders Review Group is an international network of health care professionals, researchers and consumers preparing, maintaining, and disseminating systematic reviews of randomized control trials in the treatment of cystic fibrosis and other genetic disorders. The group's aim is to help people make well-informed decisions about healthcare with the aid of these reviews. Abstracts (summaries) of these reviews are available free of charge on the group's website. The Cochrane Collaboration is a non-profit organization, established as a company, limited by guarantee, and registered as a charity in the UK.

•

Cystic Fibrosis Foundation Telephone: (301) 951-4422 Toll-free: (800) 344-4823 Fax: (301) 951-6378 Email: [email protected] Web Site: http://www.cff.org Background: The Cystic Fibrosis Foundation (CFF) is a voluntary, not-for-profit organization dedicated to raising funds for research to find a cure for cystic fibrosis (CF) and improving the quality of life for individuals with the disease. Cystic fibrosis is a rare inherited disorder that affects many exocrine ('outward-secreting') glands of the body including the sweat glands, salivary glands, and those within the pancreas and respiratory system. Established in 1955 and currently consisting of more than 70 chapters and branch offices across the country, the Cystic Fibrosis Foundation funds its own network of CF research centers at leading universities and medical schools throughout North America. It provides a variety of grants to scientists to fund CF research and finances over 100 CF care centers nationwide. The organization supports clinical trials at its care centers to test new drug therapies for CF and works closely with Congress, the Food and Drug Administration, and pharmaceutical companies to speed the development of new drugs to treat CF. The Foundation offers affected individuals, family members, health care professionals, and the public a variety of informational materials including research updates, regular newsletters, and brochures on several topics such as health insurance and financial assistance programs.

•

Cystic Fibrosis Research, Inc Telephone: (650) 404-9975 Fax: (650) 404-9981 Email: [email protected] Web Site: http://www.cfri.org Background: Cystic Fibrosis Research, Inc. (CFRI) is an independent, not-for-profit, voluntary health organization dedicated to offering emotional and educational support to families living with cystic fibrosis (CF). Cystic fibrosis is a genetic disorder that affects many exocrine glands of the body including the sweat glands, salivary glands, and glands within the pancreas and respiratory system. Associated characteristics

Patient Resources 271

include susceptibility to repeated lung infections, an impaired ability to absorb fats and other nutrients from food, abnormally salty sweat containing elevated levels of chloride and sodium, and/or other abnormalities. Cystic fibrosis is inherited as an autosomal recessive genetic trait. Established in 1975 and currently consisting of approximately 14,000 members, Cystic Fibrosis Research, Inc. is committed to providing a variety of educational and support programs for affected families including mail and telephone referrals and support services, regular membership meetings, parent support groups, CF support groups for ages 13 to adult, an annual conference, and a family retreat. The organization also funds cystic fibrosis research at major research centers in the U.S., supports ongoing gene therapy research, and offers community educational programs. Cystic Fibrosis Research, Inc. also provides a variety of educational materials, brochures, such as a teacher's guide to CF; a children's newsletter entitled 'Aspirations'; and a regular newsletter for affected families and professionals entitled 'CFRI News.'. •

Cystic Fibrosis Trust Telephone: 020 8646 7 Fax: 020 8313 0462 Email: [email protected] Background: The Cystic Fibrosis Trust is a voluntary organization in the United Kingdom dedicated to raising funds for hospital and medical research into improved treatment and prevention of cystic fibrosis (CF), a rare inherited disorder that affects many exocrine ('outwardly-secreting') glands of the body including the sweat glands, salivary glands, and those within the pancreas and respiratory system. Established in 1964, the Cystic Fibrosis Trust has approximately 16,000 members in 300 chapters throughout the United Kingdom. The CF Trust provides a network of support groups for affected individuals and family members and offers several materials including brochures, pamphlets, fact sheets, and videos.

•

Cystic Fibrosis Worldwide Telephone: +31 492 520241 Fax: +31 492 599068 Email: [email protected], [email protected] Web Site: www.cfww.org Background: Cystic Fibrosis Worldwide works to promote access to appropriate care and education for those people living with the disease in developing countries and to improve the knowledge of cystic fibrosis among medical professionals and governments worldwide. Cystic fibrosis is an inherited disorder that affects several 'outwardly secreting' glands, including respiratory, pancreatic, salivary, and sweat glands. CFW supports the search for a cure and promotes international linkage in the sharing of information. The current organization was created in January 2003 after the merger of International Cystic Fibrosis Adults (IACFA) and International Cystic Fibrosis (Mucoviscidosis) Association (ICFMA). Its philosophy is that people whose lives are affected by cystic fibrosis must have equal opportunities to participate in their society no matter where they live.

•

International Association of Cystic Fibrosis Adults Telephone: (978) 456-8387

272

Fibrosis

Fax: (978) 456-8387 Email: [email protected] Web Site: http://www.ourworld.compuserve.com/homepages/fantognini/iacfa.htm Background: The International Association of Cystic Fibrosis Adults (IACFA) is a nonprofit organization that provides information and support to individuals over the age of 18 who are diagnosed with cystic fibrosis, their families, allied health workers, and medical professionals. Cystic fibrosis (CF) is a rare inherited disorder that affects many exocrine ('outward-secreting') glands of the body including the sweat glands, salivary glands, and those within the pancreas and respiratory system. Due to unusually thick secretions of mucus that clog and obstruct air passages of the lungs, affected individuals experience chronic coughing and an increased susceptibility to repeated lung infections. Individuals with CF also exhibit an inability to break down food and absorb fats and nutrients properly; have abnormally salty sweat containing elevated levels of chloride and sodium; and/or may demonstrate other abnormalities. IACFA was established in 1982 and its mission is to assist in improving the quality of life by identifying common problems, attempting to define possible solutions, and enhancing the exchange of information in the world community of CF. The Association also endeavors to cooperate with the CF community in defining the new needs arising in the treatment of adults with CF and in raising the awareness of the medical profession to adults with CF as having specific requirements. IACFA publishes a quarterly self-titled newsletter and, every two years, sponsors an international conference open to adults with cystic fibrosis and their partners and siblings.

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to fibrosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with fibrosis. 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 fibrosis. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine.

Patient Resources 273

To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “fibrosis” (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 “fibrosis”. 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 “fibrosis” (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 “fibrosis” (or a synonym) into the search box, and click “Submit Query.”

275

APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.26

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

26

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

276

Fibrosis

libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)27: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

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

•

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

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

27

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries

277

•

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

•

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/

278

Fibrosis

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries

279

•

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/

280

Fibrosis

•

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

281

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).

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

283

FIBROSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Abducens: A striated, extrinsic muscle of the eyeball that originates from the annulus of Zinn. [NIH] Abducens Nerve: The 6th cranial nerve. The abducens nerve originates in the abducens nucleus of the pons and sends motor fibers to the lateral rectus muscles of the eye. Damage to the nerve or its nucleus disrupts horizontal eye movement control. [NIH] Abduction: Forcible pulling of a limb away from its natural position, a risk in road accidents and disasters; move outwards away from middle line. [NIH] Abductor: A muscle that draws a part away from the median line. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [NIH] Aborigines: Native inhabitants or indigenous individuals of a country. [NIH] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Abscess: A localized, circumscribed collection of pus. [NIH] Absenteeism: Chronic absence from work or other duty. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] 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] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the

284

Fibrosis

alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Actin: Essential component of the cell skeleton. [NIH] Actinic keratosis: A precancerous condition of thick, scaly patches of skin. Also called solar or senile keratosis. [NIH] Action Potentials: The electric response of a nerve or muscle to its stimulation. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [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] 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] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adjunctive Therapy: Another treatment used together with the primary treatment. Its purpose is to assist the primary treatment. [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] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenoleukodystrophy: A chromosome X-linked disease. [NIH]

Dictionary 285

Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agenesis: Lack of complete or normal development; congenital absence of an organ or part. [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] Air Sacs: Thin-walled sacs or spaces which function as a part of the respiratory system in birds, fishes, insects, and mammals. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] AK: Enzyme of the biosynthetic pathway. [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] Albinism: General term for a number of inherited defects of amino acid metabolism in which there is a deficiency or absence of pigment in the eyes, skin, or hair. [NIH] Alcohol Drinking: Behaviors associated with the ingesting of alcoholic beverages, including social drinking. [NIH] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Alendronate: A nonhormonal medication for the treatment of postmenopausal osteoporosis

286

Fibrosis

in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis. [NIH] Alfalfa: A deep-rooted European leguminous plant (Medicago sativa) widely grown for hay and forage. [NIH] Alginates: Salts of alginic acid that are extracted from marine kelp and used to make dental impressions and as absorbent material for surgical dressings. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha 1-Antitrypsin: Plasma glycoprotein member of the serpin superfamily which inhibits trypsin, neutrophil elastase, and other proteolytic enzymes. Commonly referred to as alpha 1-proteinase inhibitor (A1PI), it exists in over 30 different biochemical variant forms known collectively as the PI (protease inhibitor) system. Hereditary A1PI deficiency is associated with pulmonary emphysema. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [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] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH]

Dictionary 287

Alveolitis: Inflammation of an alveolus. Called also odontobothritis. [EU] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [NIH]

Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] 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-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Amiodarone: An antianginal and antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting Na,K-activated myocardial adenosine triphosphatase. There is a resulting decrease in heart rate and in vascular resistance. [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] Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaerobic Threshold: The oxygen consumption level above which aerobic energy production is supplemented by anaerobic mechanisms during exercise, resulting in a sustained increase in lactate concentration and metabolic acidosis. The anaerobic threshold is affected by factors that modify oxygen delivery to the tissues; it is low in patients with heart disease. Methods of measurement include direct measure of lactate concentration, direct measurement of bicarbonate concentration, and gas exchange measurements. [NIH]

288

Fibrosis

Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [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] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

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] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] 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] Aneurism: A localized abnormal dilatation of a blood vessel filled with fluid or clotted blood, forming a pulsating tumor, and resulting from disease of the vessel wall. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Angioedema: A vascular reaction involving the deep dermis or subcutaneous or submucal tissues, representing localized edema caused by dilatation and increased permeability of the capillaries, and characterized by development of giant wheals. [EU] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] 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

Dictionary 289

surgically, it is called endarterectomy. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Anhydrous: Deprived or destitute of water. [EU] 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] 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] Anterior Cruciate Ligament: A strong ligament of the knee that originates from the posteromedial portion of the lateral condyle of the femur, passes anteriorly and inferiorly between the condyles, and attaches to the depression in front of the intercondylar eminence of the tibia. [NIH] Antianginal: Counteracting angina or anginal conditions. [EU] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] 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] 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]

290

Fibrosis

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] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Aneurysm: Aneurysm of the aorta. [NIH] Aphakia: Absence of crystalline lens totally or partially from field of vision, from any cause except after cataract extraction. Aphakia is mainly congenital or as result of lens dislocation and subluxation. [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] Appendicitis: Acute inflammation of the vermiform appendix. [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] Aqueous fluid: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2)

Dictionary 291

the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatase: An enzyme which converts androgens to estrogens by desaturating ring A of the steroid. This enzyme complex is located in the endoplasmic reticulum of estrogenproducing cells including ovaries, placenta, testicular Sertoli and Leydig cells, adipose, and brain tissues. The enzyme complex has two components, one of which is the CYP19 gene product, the aromatase cytochrome P-450. The other component is NADPH-cytochrome P450 reductase which transfers reducing equivalents to P-450(arom). EC 1.14.13.-. [NIH] Arrestin: A 48-Kd protein of the outer segment of the retinal rods and a component of the phototransduction cascade. Arrestin quenches G-protein activation by binding to phosphorylated photolyzed rhodopsin. Arrestin causes experimental autoimmune uveitis when injected into laboratory animals. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteritis: Inflammation of an artery. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthritis, Gouty: Arthritis, especially of the great toe, as a result of gout. Acute gouty arthritis often is precipitated by trauma, infection, surgery, etc. The initial attacks are usually monoarticular but later attacks are often polyarticular. [NIH] Arthritis, Infectious: Arthritis caused by bacteria, rickettsiae, mycoplasmas, viruses, fungi, or parasites. Bacterial arthritis is frequently caused by Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae. Viral arthritis is less common than bacterial arthritis and may be a manifestation of such viral diseases as mumps, rubella, hepatitis, etc. [NIH] Arthritis, Psoriatic: Syndrome in which psoriasis is associated with arthritis, often involving inflammation in terminal interphalangeal joints. A rheumatoid factor is not usually present in the sera of affected individuals. [NIH]

292

Fibrosis

Articular: Of or pertaining to a joint. [EU] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Asbestosis: A lung disorder caused by constant inhalation of asbestos particles. [NIH] Ascending Colon: The part of the colon on the right side of the abdomen. [NIH] 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] Aspergillosis: Infections with fungi of the genus Aspergillus. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] 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] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atresia: Lack of a normal opening from the esophagus, intestines, or anus. [NIH] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] 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] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Auditory: Pertaining to the sense of hearing. [EU] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [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] Autologous bone marrow transplantation: A procedure in which bone marrow is removed

Dictionary 293

from a person, stored, and then given back to the person after intensive treatment. [NIH] Autopsy: Postmortem examination of the body. [NIH] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Aztreonam: A monocyclic beta-lactam antibiotic originally isolated from Chromobacterium violaceum. It is resistant to beta-lactamases and is used in gram-negative infections, especially of the meninges, bladder, and kidneys. It may cause a superinfection with grampositive organisms. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [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] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth

294

Fibrosis

of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH] Beta-Lactamases: Enzymes found in many bacteria which catalyze the hydrolysis of the amide bond in the beta-lactam ring. Well known antibiotics destroyed by these enzymes are penicillins and cephalosporins. EC 3.5.2.6. [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] Bezoars: Concretions of swallowed hair, fruit or vegetable fibers, or similar substances found in the alimentary canal. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Atresia: Atresia of the biliary tract, most commonly of the extrahepatic bile ducts. [NIH]

Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioassays: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical Phenomena: Biochemical functions, activities, and processes at organic and molecular levels in humans, animals, microorganisms, and plants. [NIH] Biofilms: Films of bacteria or other microbial organisms, usually embedded in extracellular polymers such as implanted medical devices, which adhere to surfaces submerged in, or subjected to, aquatic environments (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). Biofilms consist of multilayers of microbial cells glued together to form microbial communities which are highly resistant to both phagocytes and antibiotics. [NIH] Biological Phenomena: Biological functions and activities at the organic and molecular

Dictionary 295

levels in humans, animals, microorganisms, and plants. For biochemical and metabolic processes, biochemical phenomena is available. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] 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] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [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] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [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 Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a

296

Fibrosis

network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [NIH] Body Regions: Anatomical areas of the body. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [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 Transplantation: The transference of bone marrow from one human or animal to another. [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 Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad Ligament: A broad fold of peritoneum that extends from the side of the uterus to the wall of the pelvis. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the

Dictionary 297

trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiectasis: Persistent abnormal dilatation of the bronchi. [NIH] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchiolitis Obliterans: Inflammation of the bronchioles with obstruction by fibrous granulation tissue or bronchial exudate. It may follow inhalation of irritating gases or foreign bodies and it complicates pneumonia. [NIH] Bronchiolitis Obliterans Organizing Pneumonia: Inflammation of the bronchioles. [NIH] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchoalveolar Lavage: Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. [NIH] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Bronchoscopy: Endoscopic examination, therapy or surgery of the bronchi. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bullous: Pertaining to or characterized by bullae. [EU] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Cadherins: A group of functionally related glycoproteins responsible for the calciumdependent cell-to-cell adhesion mechanism. They are divided into subclasses E-, P-, and Ncadherins, which are distinct in immunological specificity and tissue distribution. They promote cell adhesion via a homophilic mechanism. These compounds play a role in the construction of tissues and of the whole animal body. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcinosis: Pathologic deposition of calcium salts in tissues. [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] 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

298

Fibrosis

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] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]

Capsular: Cataract which is initiated by an opacification at the surface of the lens. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Carcinoma in Situ: A malignant tumor that has not yet invaded the basement membrane of the epithelial cell of origin and has not spread to other tissues. [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] Cardiopulmonary: Having to do with the heart and lungs. [NIH] 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] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH]

Dictionary 299

Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carpal Tunnel Syndrome: A median nerve injury inside the carpal tunnel that results in symptoms of pain, numbness, tingling, clumsiness, and a lack of sweating, which can be caused by work with certain hand and wrist postures. [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] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalyse: To speed up a chemical reaction. [EU] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [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] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caustic: An escharotic or corrosive agent. Called also cauterant. [EU] Ceftazidime: Semisynthetic, broad-spectrum antibacterial derived from cephaloridine and used especially for Pseudomonas and other gram-negative infections in debilitated patients. [NIH]

Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH]

300

Fibrosis

Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [NIH] Cell Cycle Proteins: Proteins that control the cell division cycle. This family of proteins includes a wide variety of classes, including cyclin-dependent kinases, mitogen-activated kinases, cyclins, and phosphoprotein phosphatases (phosphoprotein phosphatase) as well as their putative substrates such as chromatin-associated proteins, cytoskeletal proteins, and transcription factors. [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 Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] 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] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cephaloridine: A cephalosporin antibiotic. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU]

Dictionary 301

Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Ceroid: A naturally occurring lipid pigment with histochemical characteristics similar to lipofuscin. It accumulates in various tissues in certain experimental and pathological conditions. [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] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chenodeoxycholic Acid: A bile acid, usually conjugated with either glycine or taurine. It acts as a detergent to solubilize fats for intestinal absorption and is reabsorbed by the small intestine. It is used as cholagogue, a choleretic laxative, and to prevent or dissolve gallstones. [NIH]

Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorambucil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Chloride Channels: Cell membrane glycoproteins selective for chloride ions. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholangiography: Radiographic examination of the bile ducts. [NIH] Cholangitis: Inflammation of a bile duct. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [NIH] Cholecystitis: Inflammation of the gallbladder. [NIH]

302

Fibrosis

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] Cholera Toxin: The enterotoxin from Vibrio cholerae. It is a protein that consists of two major components, the heavy (H) or A peptide and the light (L) or B peptide or choleragenoid. The B peptide anchors the protein to intestinal epithelial cells, while the A peptide, enters the cytoplasm, and activates adenylate cyclase, and production of cAMP. Increased levels of cAMP are thought to modulate release of fluid and electrolytes from intestinal crypt cells. [NIH] Choleretic: A choleretic agent. [EU] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [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] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [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] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic leukemia: A slowly progressing cancer of the blood-forming tissues. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [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

Dictionary 303

the small intestines to the tissues. [NIH] Cicatrix: The formation of new tissue in the process of wound healing. [NIH] Cicatrix, Hypertrophic: An elevated scar, resembling a keloid, but which does not spread into surrounding tissues. It is formed by enlargement and overgrowth of cicatricial tissue and regresses spontaneously. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliated cells: Epithelial cells with fine hair-like strands on their free borders. [NIH] Ciprofloxacin: A carboxyfluoroquinoline antimicrobial agent that is effective against a wide range of microorganisms. It has been successfully and safely used in the treatment of resistant respiratory, skin, bone, joint, gastrointestinal, urinary, and genital infections. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [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] 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] Coal: A natural fuel formed by partial decomposition of vegetable matter under certain environmental conditions. [NIH] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule.

304

Fibrosis

[NIH]

Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Duct: Spiral tube in the bony canal of the cochlea, lying on its outer wall between the scala vestibuli and scala tympani. [NIH] Cochlear Implantation: Surgical insertion of an electronic device implanted beneath the skin with electrodes to the cochlear nerve to create sound sensation in persons with sensorineural deafness. [NIH] Cochlear Nerve: The cochlear part of the 8th cranial nerve (vestibulocochlear nerve). The cochlear nerve fibers originate from neurons of the spiral ganglion and project peripherally to cochlear hair cells and centrally to the cochlear nuclei (cochlear nucleus) of the brain stem. They mediate the sense of hearing. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colic: Paroxysms of pain. This condition usually occurs in the abdominal region but may occur in other body regions as well. [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] Collagenases: Enzymes that catalyze the degradation of collagen by acting on the peptide bonds. EC 3.4.24.-. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colonopathy: Any disease or disorder of the colon. [EU] 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] Common Bile Duct: The largest biliary duct. It is formed by the junction of the cystic duct and the hepatic duct. [NIH]

Dictionary 305

Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] 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] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine.

306

Fibrosis

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] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Conjunctivitis, Allergic: Conjunctivitis due to hypersensitivity to various allergens. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [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] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] 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] Contractility: Capacity for becoming short in response to a suitable stimulus. [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]

Dictionary 307

Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [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] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

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] Coronary Vessels: The veins and arteries of the heart. [NIH] Corpus: The body of the uterus. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic

308

Fibrosis

hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cost of Illness: The personal cost of acute or chronic disease. The cost to the patient may be an economic, social, or psychological cost or personal loss to self, family, or immediate community. The cost of illness may be reflected in absenteeism, productivity, response to treatment, peace of mind, quality of life, etc. It differs from health care costs, meaning the societal cost of providing services related to the delivery of health care, rather than personal impact on individuals. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Critical Care: Health care provided to a critically ill patient during a medical emergency or crisis. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [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] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystic Duct: The tube that carries bile from the gallbladder into the common bile duct and

Dictionary 309

the small intestine. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] 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 Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [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] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decompensation: Failure of compensation; cardiac decompensation is marked by dyspnea, venous engorgement, and edema. [EU] Decompression: Decompression external to the body, most often the slow lessening of external pressure on the whole body (especially in caisson workers, deep sea divers, and persons who ascend to great heights) to prevent decompression sickness. It includes also sudden accidental decompression, but not surgical (local) decompression or decompression applied through body openings. [NIH] Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delivery of Health Care: The concept concerned with all aspects of providing and

310

Fibrosis

distributing health services to a patient population. [NIH] Delusions: A false belief regarding the self or persons or objects outside the self that persists despite the facts, and is not considered tenable by one's associates. [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] Demography: Statistical interpretation and description of a population with reference to distribution, composition, or structure. [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 Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Deoxycytidine: A drug that protects healthy tissues from the toxic effects of anticancer drugs. [NIH] Deoxyribonucleases: Enzymes which catalyze the hydrolases of ester bonds within DNA. EC 3.1.-. [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] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Dermatitis: Any inflammation of the skin. [NIH] Dermatosis: Any skin disease, especially one not characterized by inflammation. [EU] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Desmosine: 4-(4-Amino-4-carboxybutyl)-1-(5-amino-5-carboxypentyl)-3,5-bis(3-amino-3carboxypropyl)pyridinium. A rare amino acid found in elastin, formed by condensation of four molecules of lysine into a pyridinium ring. [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] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH]

Dictionary 311

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] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] 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] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]

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] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, 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] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Dimethylnitrosamine: A nitrosamine derivative with alkylating, carcinogenic, and mutagenic properties. It causes serious liver damage and is a hepatocarcinogen in rodents. [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]

312

Fibrosis

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] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by 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] 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] Diverticula: Plural form of diverticulum. [NIH] Diverticulitis: Inflammation of a diverticulum or diverticula. [NIH] Diverticulum: A pathological condition manifested as a pouch or sac opening from a tubular or sacular organ. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH]

Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Doxycycline: A synthetic tetracycline derivative with a range of antimicrobial activity and mode of action similar to that of tetracycline, but more effective against many species. Animal studies suggest that it may cause less tooth staining than other tetracyclines. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH]

Dictionary 313

Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Duct: A tube through which body fluids pass. [NIH] Ductal carcinoma in situ: DCIS. Abnormal cells that involve only the lining of a duct. The cells have not spread outside the duct to other tissues in the breast. Also called intraductal carcinoma. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dynorphins: A class of opioid peptides including dynorphin A, dynorphin B, and smaller fragments of these peptides. Dynorphins prefer kappa-opioid receptors (receptors, opioid, kappa) and have been shown to play a role as central nervous system transmitters. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dysmenorrhea: Painful menstruation. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] 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] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH]

314

Fibrosis

Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Encopresis: Incontinence of feces not due to organic defect or illness. [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] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH]

Dictionary 315

Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endoscopic retrograde cholangiopancreatography: ERCP. A procedure to x-ray the pancreatic duct, hepatic duct, common bile duct, duodenal papilla, and gallbladder. In this procedure, a thin, lighted tube (endoscope) is passed through the mouth and down into the first part of the small intestine (duodenum). A smaller tube (catheter) is then inserted through the endoscope into the bile and pancreatic ducts. A dye is injected through the catheter into the ducts, and an x-ray is taken. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelins: 21-Amino-acid peptides produced by vascular endothelial cells and functioning as potent vasoconstrictors. The endothelin family consists of three members, endothelin-1, endothelin-2, and endothelin-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides. [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] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxemia: A condition characterized by the presence of endotoxins in the blood. If endotoxemia is the result of gram-negative rod-shaped bacteria, shock may occur. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with

316

Fibrosis

the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Enteral Nutrition: Nutritional support given via the alimentary canal or any route connected to the gastrointestinal system (i.e., the enteral route). This includes oral feeding, sip feeding, and tube feeding using nasogastric, gastrostomy, and jejunostomy tubes. [NIH] Enteric Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Enteric-coated: A term designating a special coating applied to tablets or capsules which prevents release and absorption of their contents until they reach the intestines. [EU] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [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]

Enterotoxins: Substances that are toxic to the intestinal tract causing vomiting, diarrhea, etc.; most common enterotoxins are produced by bacteria. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Activators: Compounds or factors that act on a specific enzyme to increase its activity. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilia: Abnormal increase in eosinophils in the blood, tissues or organs. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the

Dictionary 317

pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] 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]

Epoprostenol: A prostaglandin that is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. It is a potent inhibitor of platelet aggregation. The sodium salt has been also used to treat primary pulmonary hypertension. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythema Multiforme: A skin and mucous membrane disease characterized by an eruption of macules, papules, nodules, vesicles, and/or bullae with characteristic "bull's-eye" lesions usually occurring on the dorsal aspect of the hands and forearms. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophageal Motility Disorders: Disorders affecting the motor function of the upper or lower esophageal sphincters, the esophageal body, or a combination of these parts. The failure of the sphincters to maintain a tonic pressure may result in the impeding of the passage of food, regurgitation of food, or reflux of gastric acid into the esophagus. [NIH] Esophageal Varices: Stretched veins in the esophagus that occur when the liver is not working properly. If the veins burst, the bleeding can cause death. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estrogen: One of the two female sex hormones. [NIH]

318

Fibrosis

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] Ethmoid: An unpaired cranial bone which helps form the medial walls of the orbits and contains the themoidal air cells which drain into the nose. [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] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] Excrete: To get rid of waste from the body. [NIH] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exotoxin: Toxic substance excreted by living bacterial cells. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Expiratory: The volume of air which leaves the breathing organs in each expiration. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH]

Dictionary 319

Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extraocular: External to or outside of the eye. [NIH] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [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] 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] Faecal: Pertaining to or of the nature of feces. [EU] Failure to Thrive: A condition in which an infant or child's weight gain and growth are far below usual levels for age. [NIH] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Fecal Incontinence: Failure of voluntary control of the anal sphincters, with involuntary passage of feces and flatus. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fetal Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an

320

Fibrosis

important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibril: Most bacterial viruses have a hollow tail with specialized fibrils at its tip. The tail fibers attach to the cell wall of the host. [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] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectins: Glycoproteins found on the surfaces of cells, particularly in fibrillar structures. The proteins are lost or reduced when these cells undergo viral or chemical transformation. They are highly susceptible to proteolysis and are substrates for activated blood coagulation factor VIII. The forms present in plasma are called cold-insoluble globulins. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fibrotic tissue: Inflamed tissue that has become scarred. [NIH] Fish Oils: Oils high in unsaturated fats extracted from the bodies of fish or fish parts, especially the livers. Those from the liver are usually high in vitamin A. The oils are used as dietary supplements, in soaps and detergents, as protective coatings, and as a base for other food products such as vegetable shortenings. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Fleroxacin: A third-generation fluoroquinolone derivative with a broad antimicrobial spectrum. The drug strongly inhibits the DNA-supercoiling activity of DNA gyrase which

Dictionary 321

may account for its antibacterial activity. [NIH] Flexion: In gynaecology, a displacement of the uterus in which the organ is bent so far forward or backward that an acute angle forms between the fundus and the cervix. [EU] Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH] Foetoplacental: Pertaining to the fetus and placenta. [EU] Fold: A plication or doubling of various parts of the body. [NIH] Follicles: Shafts through which hair grows. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forced Expiratory Volume: Measure of the maximum amount of air during a forced vital capacity determination that can be expelled in a given number of seconds. It is usually given as FEV followed by a subscript indicating the number of seconds over which the measurement is made, although it is sometimes given as a percentage of forced vital capacity. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [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] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Fructose Intolerance: An autosomal recessive fructose metabolism disorder due to deficient fructose-1-phosphate aldolase (EC 2.1.2.13) activity, resulting in accumulation of fructose-1phosphate. The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia following ingestion of fructose. Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. Patients develop a strong distaste for sweet food, and avoid a chronic course of the disease by remaining on a fructose- and sucrose-free diet. [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] 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

322

Fibrosis

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] Gadolinium: An element of the rare earth family of metals. It has the atomic symbol Gd, atomic number 64, and atomic weight 157.25. Its oxide is used in the control rods of some nuclear reactors. [NIH] Galactosemia: Buildup of galactose in the blood. Caused by lack of one of the enzymes needed to break down galactose into glucose. [NIH] Galenical: 1. Usually cap: of or relating to Galen or his medical principles or method. 2. Constituting a galenical. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [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] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]

Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Dictionary 323

Gastritis: Inflammation of the stomach. [EU] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal Hemorrhage: Bleeding in the gastrointestinal tract. [NIH] Gastrointestinal Neoplasms: Tumors or cancer of the gastrointestinal system. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [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] Gelatinases: A class of enzymes that catalyzes the degradation of gelatin by acting on the peptide bonds. EC 3.4.24.-. [NIH] Gelsolin: A 90-kD protein produced by macrophages that severs actin filaments and forms a cap on the newly exposed filament end. Gelsolin is activated by calcium ions and participates in the assembly and disassembly of actin, thereby increasing the motility of some cells. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH]

324

Fibrosis

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] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] Genital: Pertaining to the genitalia. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Gingival Hyperplasia: A pathological increase in the depth of the gingival crevice surrounding a tooth at the gum margin. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Ginkgo biloba: Exclusive species of the genus Ginkgo, family Ginkgoacea. It produces extracts of medicinal interest. Ginkgo may refer to the genus or species. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic

Dictionary 325

(drugs). [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [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] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [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] 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]

Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] 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] Glycopeptides: Proteins which contain carbohydrate groups attached covalently to the polypeptide chain. The protein moiety is the predominant group with the carbohydrate making up only a small percentage of the total weight. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH]

326

Fibrosis

Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Glycyrrhetinic Acid: 3-beta-Hydroxy-11-oxoolean-12-en-30-oic acid. A product from Glycyrrhiza glabra L. Leguminosae with some antiallergic, antibacterial, and antiviral properties. It is used topically for allergic or infectious skin inflammation and orally for its aldosterone effects in electrolyte regulation. [NIH] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Gonadal: Pertaining to a gonad. [EU] Goniotomy: A surgical procedure for congenital glaucoma in which a sweeping incision is made in the neshwork at the filtration angle by means of a knife-needle inserted through the opposite limbus and carried across the anterior chamber parallel to the iris. [NIH] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Government Agencies: Administrative units of government responsible for policy making and management of governmental activities in the U.S. and abroad. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Grading: A system for classifying cancer cells in terms of how abnormal they appear when examined under a microscope. The objective of a grading system is to provide information about the probable growth rate of the tumor and its tendency to spread. The systems used to grade tumors vary with each type of cancer. Grading plays a role in treatment decisions. [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] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU]

Dictionary 327

Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granulation Tissue: A vascular connective tissue formed on the surface of a healing wound, ulcer, or inflamed tissue. It consists of new capillaries and an infiltrate containing lymphoid cells, macrophages, and plasma cells. [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] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Gyrase: An enzyme that causes negative supercoiling of E. coli DNA during replication. [NIH]

Hair Cells: Mechanoreceptors located in the organ of Corti that are sensitive to auditory stimuli and in the vestibular apparatus that are sensitive to movement of the head. In each case the accessory sensory structures are arranged so that appropriate stimuli cause movement of the hair-like projections (stereocilia and kinocilia) which relay the information centrally in the nervous system. [NIH] Hairy cell leukemia: A type of chronic leukemia in which the abnormal white blood cells appear to be covered with tiny hairs when viewed under a microscope. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Halitosis: An offensive, foul breath odor resulting from a variety of causes such as poor oral hygiene, dental or oral infections, or the ingestion of certain foods. [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] Hay Fever: A seasonal variety of allergic rhinitis, marked by acute conjunctivitis with lacrimation and itching, regarded as an allergic condition triggered by specific allergens. [NIH]

Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH]

328

Fibrosis

Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [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] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] 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] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hemoptysis: Bronchial hemorrhage manifested with spitting of blood. [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]

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] Hepatic Duct, Common: Predominantly extrahepatic bile duct which is formed by the junction of the right and left hepatic ducts, which are predominantly intrahepatic, and, in turn, joins the cystic duct to form the common bile duct. [NIH] Hepatic Encephalopathy: A condition that may cause loss of consciousness and coma. It is usually the result of advanced liver disease. Also called hepatic coma. [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

Dictionary 329

contamination of food or water. [NIH] 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] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Hernia: Protrusion of a loop or knuckle of an organ or tissue through an abnormal opening. [NIH]

Herniated: Protrusion of a degenerated or fragmented intervertebral disc into the intervertebral foramen compressing the nerve root. [NIH] 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]

Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [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] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an

330

Fibrosis

antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] 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] Hydration: Combining with water. [NIH] Hydrogel: A network of cross-linked hydrophilic macromolecules used in biomedical applications. [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 Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] 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] 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]

Dictionary 331

Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hypereosinophilic Syndrome: A heterogeneous group of disorders with the common feature of prolonged eosinophilia of unknown cause and associated organ system dysfunction, including the heart, central nervous system, kidneys, lungs, gastrointestinal tract, and skin. There is a massive increase in the number of eosinophils in the blood, mimicking leukemia, and extensive eosinophilic infiltration of the various organs. It is often referred to as idiopathic. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperkeratosis: 1. Hypertrophy of the corneous layer of the skin. 2a. Any of various conditions marked by hyperkeratosis. 2b. A disease of cattle marked by thickening and wringling of the hide and formation of papillary outgrowths on the buccal mucous membranes, often accompanied by watery discharge from eyes and nose, diarrhoea, loss of condition, and abortion of pregnant animals, and now believed to result from ingestion of the chlorinated naphthalene of various lubricating oils. [EU] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperoxia: An abnormal increase in the amount of oxygen in the tissues and organs. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypersensitivity, Immediate: Hypersensitivity reactions which occur within minutes of exposure to challenging antigen due to the release of histamine which follows the antigenantibody reaction and causes smooth muscle contraction and increased vascular permeability. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophic cardiomyopathy: Heart muscle disease that leads to thickening of the heart walls, interfering with the heart's ability to fill with and pump blood. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypobetalipoproteinemia: A disease in which the low density lipoprotein (betalipoprotein) concentrations are far below normal. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH]

332

Fibrosis

Idiopathic: Describes a disease of unknown cause. [NIH] Ileum: The lower end of the small intestine. [NIH] Ileus: Obstruction of the intestines. [EU] Iliac Artery: Either of two large arteries originating from the abdominal aorta; they supply blood to the pelvis, abdominal wall and legs. [NIH] Iloprost: An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of epoprostenol, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation. [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] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunochemistry: Field of chemistry that pertains to immunological phenomena and the study of chemical reactions related to antigen stimulation of tissues. It includes physicochemical interactions between antigens and antibodies. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction. [NIH]

Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [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]

Dictionary 333

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] 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] Imperforate Anus: A birth defect in which the anal canal fails to develop. The condition is treated with an operation. [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] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indolent: A type of cancer that grows slowly. [NIH] 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] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [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,

334

Fibrosis

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]

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] Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] 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]

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] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [NIH] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [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] 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,

Dictionary 335

genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Intercellular Adhesion Molecule-1: A cell-surface ligand with a role in leukocyte adhesion and inflammation. Its production is induced by gamma-interferon and it is required for neutrophil migration into inflamed tissue. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are 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] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [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] Intermittent Claudication: A symptom complex characterized by leg pain and weakness brought on by walking, with the disappearance of the symptoms following a brief rest. [NIH]

336

Fibrosis

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] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] Intervertebral: Situated between two contiguous vertebrae. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestinal Obstruction: Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anus. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intraductal carcinoma: Abnormal cells that involve only the lining of a duct. The cells have not spread outside the duct to other tissues in the breast. Also called ductal carcinoma in situ. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [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]

Intussusception: A rare disorder. A part of the intestines folds into another part of the intestines, causing blockage. Most common in infants. Can be treated with an operation. [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]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients

Dictionary 337

produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [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] Irritants: Drugs that act locally on cutaneous or mucosal surfaces to produce inflammation; those that cause redness due to hyperemia are rubefacients; those that raise blisters are vesicants and those that penetrate sebaceous glands and cause abscesses are pustulants; tear gases and mustard gases are also irritants. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Jejunostomy: Surgical formation of an opening through the abdominal wall into the jejunum, usually for enteral hyperalimentation. [NIH] Jejunum: That portion of the small intestine which extends from the duodenum to the ileum; called also intestinum jejunum. [EU] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [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] Keloid: A sharply elevated, irregularly shaped, progressively enlarging scar resulting from formation of excessive amounts of collagen in the dermis during connective tissue repair. It is differentiated from a hypertrophic scar (cicatrix, hypertrophic) in that the former does not spread to surrounding tissues. [NIH] Keratolytic: An agent that promotes keratolysis. [EU] Keratosis: Any horny growth such as a wart or callus. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH]

338

Fibrosis

Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kidney Pelvis: The flattened, funnel-shaped expansion connecting the ureter to the kidney calices. [NIH] Kinesin: A microtubule-associated mechanical adenosine triphosphatase, that uses the energy of ATP hydrolysis to move organelles along microtubules toward the plus end of the microtubule. The protein is found in squid axoplasm, optic lobes, and in bovine brain. Bovine kinesin is a heterotetramer composed of two heavy (120 kDa) and two light (62 kDa) chains. EC 3.6.1.-. [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] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Labyrinthine: A vestibular nystagmus resulting from stimulation, injury, or disease of the labyrinth. [NIH] Labyrinthitis: Inflammation of the inner ear. [NIH] Lacrimal: Pertaining to the tears. [EU] Lacrimal Apparatus: The tear-forming and tear-conducting system which includes the lacrimal glands, eyelid margins, conjunctival sac, and the tear drainage system. [NIH] Lactation: The period of the secretion of milk. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH]

Dictionary 339

Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Latent period: A seemingly inactive period, as that between exposure of tissue to an injurious agent and the manifestation of response, or that between the instant of stimulation and the beginning of response. [EU] Lavage: A cleaning of the stomach and colon. Uses a special drink and enemas. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lethal: Deadly, fatal. [EU] 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]

Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] 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] Leukocyte Elastase: An enzyme that catalyzes the hydrolysis of proteins, including elastin. It cleaves preferentially bonds at the carboxyl side of Ala and Val, with greater specificity for Ala. EC 3.4.21.37. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukoplakia: A white patch that may develop on mucous membranes such as the cheek, gums, or tongue and may become cancerous. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to

340

Fibrosis

which any person of a given age may reasonably expect to live. [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] Ligation: Application of a ligature to tie a vessel or strangulate a part. [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] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipodystrophy: A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat. They include total, congenital or acquired, partial, abdominal infantile, and localized lipodystrophy. [NIH] Lipofuscin: A naturally occurring lipid pigment with histochemical characteristics similar to ceroid. It accumulates in various normal tissues and apparently increases in quantity with age. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lithotripsy: The destruction of a calculus of the kidney, ureter, bladder, or gallbladder by physical forces, including crushing with a lithotriptor through a catheter. Focused percutaneous ultrasound and focused hydraulic shock waves may be used without surgery. Lithotripsy does not include the dissolving of stones by acids or litholysis. Lithotripsy by laser is laser lithotripsy. [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 Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH] Liver Neoplasms: Tumors or cancer of the liver. [NIH]

Dictionary 341

Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Local therapy: Treatment that affects cells in the tumor and the area close to it. [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] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [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] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a person swallows, this muscle relaxes to let food pass from the esophagus to the stomach. It stays closed at other times to keep stomach contents from flowing back into the esophagus. [NIH]

Lubricants: Oily or slippery substances. [NIH] Lubrication: The application of a substance to diminish friction between two surfaces. It may refer to oils, greases, and similar substances for the lubrication of medical equipment but it can be used for the application of substances to tissue to reduce friction, such as lotions for skin and vaginal lubricants. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [EU] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [NIH] Lung volume: The amount of air the lungs hold. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lupus Nephritis: Glomerulonephritis associated with systemic lupus erythematosus. It is classified into four histologic types: mesangial, focal, diffuse, and membranous. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH]

342

Fibrosis

Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [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] 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] 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] Malformation: A morphologic developmental process. [EU]

defect

resulting

from

an

intrinsically

abnormal

Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammogram: An x-ray of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Manic: Affected with mania. [EU] Manic-depressive psychosis: One of a group of psychotic reactions, fundamentally marked by severe mood swings and a tendency to remission and recurrence. [NIH] Mannans: Polysaccharides consisting of mannose units. [NIH] Maple Syrup Urine Disease: A genetic disorder involving deficiency of an enzyme necessary in the metabolism of branched-chain amino acids, and named for the characteristic odor of the urine. [NIH]

Dictionary 343

Matrilysin: The smallest member of the matrix metalloproteinases. It plays a role in tumor progression. EC 3.4.24.23. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Maxillary: Pertaining to the maxilla : the irregularly shaped bone that with its fellow forms the upper jaw. [EU] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Mechanical ventilation: Use of a machine called a ventilator or respirator to improve the exchange of air between the lungs and the atmosphere. [NIH] Meconium: The thick green-to-black mucilaginous material found in the intestines of a fullterm fetus. It consists of secretions of the intestinal glands, bile pigments, fatty acids, amniotic fluid, and intrauterine debris. It constitutes the first stools passed by a newborn. [NIH]

Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Median Nerve: A major nerve of the upper extremity. In humans, the fibers of the median nerve originate in the lower cervical and upper thoracic spinal cord (usually C6 to T1), travel via the brachial plexus, and supply sensory and motor innervation to parts of the forearm and hand. [NIH] Median Neuropathy: Disease involving the median nerve, from its origin at the brachial plexus to its termination in the hand. Clinical features include weakness of wrist and finger flexion, forearm pronation, thenar abduction, and loss of sensation over the lateral palm, first three fingers, and radial half of the ring finger. Common sites of injury include the elbow, where the nerve passes through the two heads of the pronator teres muscle (pronator syndrome) and in the carpal tunnel (carpal tunnel syndrome). [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] 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] 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]

344

Fibrosis

Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mercuric Chloride: Mercury chloride (HgCl2). A highly toxic compound that volatizes slightly at ordinary temperature and appreciably at 100 degrees C. It is corrosive to mucous membranes and used as a topical antiseptic and disinfectant. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesenteric Arteries: Arteries which arise from the abdominal aorta and distribute to most of the intestines. [NIH] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Mesothelial: It lines the peritonealla and pleural cavities. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaphase: The second phase of cell division, in which the chromosomes line up across the

Dictionary 345

equatorial plane of the spindle prior to separation. [NIH] Metaplasia: A condition in which there is a change of one adult cell type to another similar adult cell type. [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] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]

labeled

with

Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Microwaves: That portion of the electromagnetic spectrum lying between UHF (ultrahigh frequency) radio waves and heat (infrared) waves. Microwaves are used to generate heat, especially in some types of diathermy. They may cause heat damage to tissues. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milk Thistle: The plant Silybum marianum in the family Asteraceae containing the bioflavonoid complex silymarin. For centuries this has been used traditionally to treat liver disease. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller

346

Fibrosis

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] Mineralocorticoid: 1. Any of the group of C21 corticosteroids, principally aldosterone, predominantly involved in the regulation of electrolyte and water balance through their effect on ion transport in epithelial cells of the renal tubules, resulting in retention of sodium and loss of potassium; some also possess varying degrees of glucocorticoid activity. Their secretion is regulated principally by plasma volume, serum potassium concentration and angiotensin II, and to a lesser extent by anterior pituitary ACTH. 2. Of, pertaining to, having the properties of, or resembling a mineralocorticoid. [EU] Miotic: 1. Pertaining to, characterized by, or producing miosis : contraction of the pupil. 2. An agent that causes the pupil to contract. 3. Meiotic: characterized by cell division. [EU] 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] Mitotic Index: An expression of the number of mitoses found in a stated number of cells. [NIH]

Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [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] Monocrotaline: A pyrrolizidine alkaloid and a toxic plant constituent that poisons livestock and humans through the ingestion of contaminated grains and other foods. The alkaloid causes pulmonary artery hypertension, right ventricular hypertrophy, and pathological changes in the pulmonary vasculature. Significant attenuation of the cardiopulmonary changes are noted after oral magnesium treatment. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH]

Dictionary 347

Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [NIH]

Mucilaginous: Pertaining to or secreting mucus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, .): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucociliary Clearance: Rate of ciliary and secretory activity of the respiratory submucosal glands. It is a non-specific host defense mechanism, measurable in vivo by mucus transfer, ciliary beat frequency, and clearance of radioactive tracers. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multidose: Occurring in, or using multiple doses. [EU] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [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] Musculature: The muscular apparatus of the body, or of any part of it. [EU] Music Therapy: The use of music as an adjunctive therapy in the treatment of neurological, mental, or behavioral disorders. [NIH] Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). [NIH] Mutagenic: Inducing genetic mutation. [EU]

348

Fibrosis

Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] Mycoplasma: A genus of gram-negative, facultatively anaerobic bacteria bounded by a plasma membrane only. Its organisms are parasites and pathogens, found on the mucous membranes of humans, animals, and birds. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [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] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH]

Dictionary 349

Nasal Cavity: The proximal portion of the respiratory passages on either side of the nasal septum, lined with ciliated mucosa, extending from the nares to the pharynx. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Nasogastric: The process of passing a small, flexible plastic tube through the nose or mouth into the stomach or small intestine. [NIH] Nasolacrimal: Pertaining to the nose and lacrimal apparatus. [EU] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nebramycin: A complex of antibiotic substances produced by Streptomyces tenebrarius. [NIH]

Nebulizer: A device used to turn liquid into a fine spray. [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] Neonatal Hepatitis: Irritation of the liver with no known cause. Occurs in newborn babies. Symptoms include jaundice and liver cell changes. [NIH] Neonatal Screening: The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or laboratory measures. A screening test is designed to sort out healthy neonates from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [NIH] 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] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Netilmicin: Semisynthetic 1-N-ethyl derivative of sisomycin, an aminoglycoside antibiotic with action similar to gentamicin, but less ear and kidney toxicity. [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] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH]

350

Fibrosis

Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] 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] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Neutrophil Activation: The process in which the neutrophil is stimulated by diverse substances, resulting in degranulation and/or generation of reactive oxygen products, and culminating in the destruction of invading pathogens. The stimulatory substances, including opsonized particles, immune complexes, and chemotactic factors, bind to specific cellsurface receptors on the neutrophil. [NIH] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or

Dictionary 351

incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Medicine: A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds in a pharmaceutical form. [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] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Nystagmus: Rhythmical oscillation of the eyeballs, either pendular or jerky. [NIH] Octamer: Eight molecules of histone. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Oculomotor Nerve: The 3d cranial nerve. The oculomotor nerve sends motor fibers to the levator muscles of the eyelid and to the superior rectus, inferior rectus, and inferior oblique muscles of the eye. It also sends parasympathetic efferents (via the ciliary ganglion) to the muscles controlling pupillary constriction and accommodation. The motor fibers originate in the oculomotor nuclei of the midbrain. [NIH] Oestrogen: A generic term for oestrus-producing steroid compounds; the female sex hormones. In humans, oestrogen is formed in the ovary, possibly the adrenal cortex, the testis, and the foetoplacental unit; it has various functions in both sexes. It is responsible for the development of the female secondary sex characteristics, and during the menstrual cycle it acts on the female genitalia to produce an environment suitable for the fertilization, implantation, and nutrition of the early embryo. Oestrogen is used in oral contraceptives and as a palliative in cancer of the breast after menopause and cancer of the prostate; other uses include the relief of the discomforts of menopause, inhibition of lactation, and treatment of osteoporosis, threatened abortion, and various functional ovarian disorders. [EU]

Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount

352

Fibrosis

of urine secreted. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [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] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Ophthalmoplegia: Paralysis of one or more of the ocular muscles due to disorders of the eye muscles, neuromuscular junction, supporting soft tissue, tendons, or innervation to the muscles. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [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] Orbit: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] Orderly: A male hospital attendant. [NIH] Organ Specificity: Restriction of a characteristic or response to a particular organ of the body; it usually refers to that property of the immune response which differentiates one organ from another on the basis of antigen recognition, but the concept is not limited to immunology. [NIH]

Dictionary 353

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] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Osteocalcin: Vitamin K-dependent calcium-binding protein synthesized by osteoblasts and found primarily in bone. Serum osteocalcin measurements provide a noninvasive specific marker of bone metabolism. The protein contains three residues of the amino acid gammacarboxyglutamic acid (GLA), which, in the presence of calcium, promotes binding to hydroxyapatite and subsequent accumulation in bone matrix. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteopetrosis: Excessive formation of dense trabecular bone leading to pathological fractures, osteitis, splenomegaly with infarct, anemia, and extramedullary hemopoiesis. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Otitis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, hearing loss, tinnitus, and vertigo. [EU] Otitis Media: Inflammation of the middle ear. [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] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

354

Fibrosis

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] 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 Ducts: Ducts that collect pancreatic juice from the pancreas and supply it to the duodenum. [NIH] Pancreatic enzymes: A group of proteins secreted by the pancreas which aid in the digestion of food. [NIH] Pancreatic Extracts: Extracts prepared from pancreatic tissue that may contain the pancreatic enzymes or other specific uncharacterized factors or proteins with specific activities. Pancreatin is a specific extract containing digestive enzymes and used to treat pancreatic insufficiency. [NIH] Pancreatic Fistula: Abnormal passage communicating with the pancreas. [NIH] Pancreatic Insufficiency: Absence of or reduced pancreatic exocrine secretion into the duodenum and resultant poor digestion of lipids, vitamins, nitrogen, and carbohydrates. [NIH]

Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be

Dictionary 355

associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Pancrelipase: A preparation of hog pancreatic enzymes standardized for lipase content. [NIH]

Papilla: A small nipple-shaped elevation. [NIH] Papillary: Pertaining to or resembling papilla, or nipple. [EU] Paralysis: Loss of ability to move all or part of the body. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity. [NIH]

Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parasitic Diseases: Infections or infestations with parasitic organisms. They are often contracted through contact with an intermediate vector, but may occur as the result of direct exposure. [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] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] 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] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Advocacy: Promotion and protection of the rights of patients, frequently through a

356

Fibrosis

legal process. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillamine: 3-Mercapto-D-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in Wilson's disease. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penile Prosthesis: Rigid, semi-rigid, or inflatable cylindric hydraulic devices, with either combined or separate reservoir and pumping systems, implanted for the surgical treatment of organic impotence. [NIH] Pentoxifylline: A methylxanthine derivative that inhibits phosphodiesterase and affects blood rheology. It improves blood flow by increasing erythrocyte and leukocyte flexibility. It also inhibits platelet aggregation. Pentoxifylline modulates immunologic activity by stimulating cytokine production. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: An ulceration of the mucous membrane of the esophagus, stomach or duodenum, caused by the action of the acid gastric juice. [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] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [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]

Peridural: Around or external to the dura mater. [EU] Perineal: Pertaining to the perineum. [EU] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Perioral: Situated or occurring around the mouth. [EU] Peripheral blood: Blood circulating throughout the body. [NIH]

Dictionary 357

Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [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] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] 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] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phallic: Pertaining to the phallus, or penis. [EU] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] 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] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [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] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor

358

Fibrosis

of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylbutyrate: An anticancer drug that belongs to the family of drugs called differentiating agents. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [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] Phosphoprotein Phosphatase: A group of enzymes removing the serine- or threoninebound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992) EC 3.1.3.16. [NIH] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] 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 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] Phototransduction: The transducing of light energy to afferent nerve impulses, such as takes place in the retinal rods and cones. After light photons are absorbed by the photopigments, the signal is transmitted to the outer segment membrane by the cyclic GMP second messenger system, where it closes the sodium channels. This channel gating ultimately generates an action potential in the inner retina. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physicochemical: Pertaining to physics and chemistry. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pilocarpine: A slowly hydrolyzed muscarinic agonist with no nicotinic effects. Pilocarpine is used as a miotic and in the treatment of glaucoma. [NIH]

Dictionary 359

Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] 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] 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] 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] 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]

360

Fibrosis

Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH] Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pneumoconiosis: Condition characterized by permanent deposition of substantial amounts of particulate matter in the lungs, usually of occupational or environmental origin, and by the tissue reaction to its presence. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Pneumonitis: A disease caused by inhaling a wide variety of substances such as dusts and molds. Also called "farmer's disease". [NIH] Policy Making: The decision process by which individuals, groups or institutions establish policies pertaining to plans, programs or procedures. [NIH] Polyarteritis Nodosa: A form of necrotizing vasculitis involving small- and medium-sized arteries. The signs and symptoms result from infarction and scarring of the affected organ system. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyphosphates: Linear polymers in which orthophosphate residues are linked with energyrich phosphoanhydride bonds. They are found in plants, animals, and microorganisms. [NIH] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH]

Dictionary 361

Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Porins: Protein molecules situated in the outer membrane of gram-negative bacteria that, in dimeric or trimeric form, constitute a water-filled transmembrane channel allowing passage of ions and other small molecules. Porins are also found in bacterial cell walls, and in plant, fungal, mammalian and other vertebrate cell and mitochondrial membranes. [NIH] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [NIH] Portal Hypertension: High blood pressure in the portal vein. This vein carries blood into the liver. Portal hypertension is caused by a blood clot. This is a common complication of cirrhosis. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Posterior chamber: The space between the back of the iris and the front face of the vitreous; filled with aqueous fluid. [NIH] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [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

362

Fibrosis

convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] 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] Preimplantation Diagnosis: Determination of the nature of a pathological condition or disease in the ovum, zygote, or blastocyst prior to implantation. Cytogenetic analysis is performed to determine the presence or absence of genetic disease. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary Biliary Cirrhosis: A chronic liver disease. Slowly destroys the bile ducts in the liver. This prevents release of bile. Long-term irritation of the liver may cause scarring and cirrhosis in later stages of the disease. [NIH] Primary Sclerosing Cholangitis: Irritation, scarring, and narrowing of the bile ducts inside and outside the liver. Bile builds up in the liver and may damage its cells. Many people with this condition also have ulcerative colitis. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Procollagen: A biosynthetic precursor of collagen containing additional amino acid sequences at the amino-terminal ends of the three polypeptide chains. Protocollagen, a precursor of procollagen consists of procollagen peptide chains in which proline and lysine have not yet been hydroxylated. [NIH] Proctitis: Inflammation of the rectum. [EU] Proenzyme: 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] 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] 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]

Dictionary 363

Proliferating Cell Nuclear Antigen: Nuclear antigen with a role in DNA synthesis, DNA repair, and cell cycle progression. PCNA is required for the coordinated synthesis of both leading and lagging strands at the replication fork during DNA replication. PCNA expression correlates with the proliferation activity of several malignant and non-malignant cell types. [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] Pronation: Applies to movements of the forearm in turning the palm backward or downward or when applied to the foot, a combination of eversion and abduction movements in the tarsal and metatarsal joints, (turning the foot up and in toward the midline of the body). [NIH] Pronator: A muscle which turns a part into the prone position. [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] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the

364

Fibrosis

lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostatectomy: Complete or partial surgical removal of the prostate. Three primary approaches are commonly employed: suprapubic - removal through an incision above the pubis and through the urinary bladder; retropubic - as for suprapubic but without entering the urinary bladder; and transurethral (transurethral resection of prostate). [NIH] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Prosthesis: An artificial replacement of a part of the body. [NIH] Prosthesis Implantation: Surgical insertion of a prosthesis. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein 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] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [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] 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] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoal: Having to do with the simplest organisms in the animal kingdom. Protozoa are single-cell organisms, such as ameba, and are different from bacteria, which are not

Dictionary 365

members of the animal kingdom. Some protozoa can be seen without a microscope. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Prune Belly Syndrome: A syndrome characterized by abdominal wall musculature deficiency, cryptorchism, and urinary tract abnormalities. The syndrome derives its name from its characteristic distended abdomen with wrinkled skin. [NIH] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Ptosis: 1. Prolapse of an organ or part. 2. Drooping of the upper eyelid from paralysis of the third nerve or from sympathetic innervation. [EU] 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] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts.

366

Fibrosis

[NIH]

Pupil: The aperture in the iris through which light passes. [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] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] 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] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radical prostatectomy: Surgery to remove the entire prostate. The two types of radical prostatectomy are retropubic prostatectomy and perineal prostatectomy. [NIH] Radio Waves: That portion of the electromagnetic spectrum beyond the microwaves, with wavelengths as high as 30 KM. They are used in communications, including television. Short Wave or HF (high frequency), UHF (ultrahigh frequency) and VHF (very high frequency) waves are used in citizen's band communication. [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] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and

Dictionary 367

interventional radiology or other planning and guiding medical radiology. [NIH] Radiologist: A doctor who specializes in creating and interpreting pictures of areas inside the body. The pictures are produced with x-rays, sound waves, or other types of energy. [NIH]

Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] 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] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Rebound effect: The characteristic of a drug to produce reverse effects when either the effect of the drug has passed, or when the patient no longer responds to the drug. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Opioid: Cell membrane proteins that bind opioids and trigger intracellular changes which influence the behavior of cells. The endogenous ligands for opioid receptors in mammals include three families of peptides, the enkephalins, endorphins, and dynorphins. The receptor classes include mu, delta, and kappa receptors. Sigma receptors bind several psychoactive substances, including certain opioids, but their endogenous ligands are not known. [NIH] Recessive gene: A gene that is phenotypically expressed only when homozygous. [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] 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] Rectal Prolapse: Protrusion of the rectal mucous membrane through the anus. There are various degrees: incomplete with no displacement of the anal sphincter muscle; complete

368

Fibrosis

with displacement of the anal sphincter muscle; complete with no displacement of the anal sphincter muscle but with herniation of the bowel; and internal complete with rectosigmoid or upper rectum intussusception into the lower rectum. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] 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] Registries: The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal tubular: A defect in the kidneys that hinders their normal excretion of acids. Failure to excrete acids can lead to weak bones, kidney stones, and poor growth in children. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Reoperation: A repeat operation for the same condition in the same patient. It includes reoperation for reexamination, reoperation for disease progression or recurrence, or reoperation following operative failure. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage

Dictionary 369

the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] 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] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Reticulin: A scleroprotein fibril consisting mostly of type III collagen. Reticulin fibrils are extremely thin, with a diameter of between 0.5 and 2 um. They are involved in maintaining the structural integrity in a variety of organs. [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 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 Detachment: Separation of the inner layers of the retina (neural retina) from the pigment epithelium. Retinal detachment occurs more commonly in men than in women, in eyes with degenerative myopia, in aging and in aphakia. It may occur after an uncomplicated cataract extraction, but it is seen more often if vitreous humor has been lost during surgery. (Dorland, 27th ed; Newell, Ophthalmology: Principles and Concepts, 7th ed,

370

Fibrosis

p310-12). [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] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinyl palmitate: A drug being studied in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Retroperitoneal Fibrosis: A slowly progressive condition of unknown etiology, characterized by deposition of fibrous tissue in the retroperitoneal space compressing the ureters, great vessels, bile duct, and other structures. When associated with abdominal aortic aneurysm, it may be called chronic periaortitis or inflammatory perianeurysmal fibrosis. [NIH]

Retroperitoneal Space: An area occupying the most posterior aspect of the abdominal cavity. It is bounded laterally by the borders of the quadratus lumborum muscles and extends from the diaphragm to the brim of the true pelvis, where it continues as the pelvic extraperitoneal space. [NIH] Retropubic: A potential space between the urinary bladder and the symphisis and body of the pubis. [NIH] Retropubic prostatectomy: Surgery to remove the prostate through an incision made in the abdominal wall. [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] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rheology: The study of the deformation and flow of matter, usually liquids or fluids, and of the plastic flow of solids. The concept covers consistency, dilatancy, liquefaction, resistance to flow, shearing, thixotrophy, and viscosity. [NIH] Rheumatic Diseases: Disorders of connective tissue, especially the joints and related structures, characterized by inflammation, degeneration, or metabolic derangement. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH]

Dictionary 371

Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhinorrhea: The free discharge of a thin nasal mucus. [EU] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [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] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]

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 assay those functions in vitro. [NIH] Rod: A reception for vision, located in the retina. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] 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] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a

372

Fibrosis

person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Sclerotic: Pertaining to the outer coat of the eye; the sclera; hard, indurated or sclerosed. [NIH]

Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [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] Secretin: A hormone made in the duodenum. Causes the stomach to make pepsin, the liver to make bile, and the pancreas to make a digestive juice. [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] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] 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] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [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

Dictionary 373

discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septum: A dividing wall or partition; a general term for such a structure. The term is often used alone to refer to the septal area or to the septum pellucidum. [EU] Septum Pellucidum: A triangular double membrane separating the anterior horns of the lateral ventricles of the brain. It is situated in the median plane and bounded by the corpus callosum and the body and columns of the fornix. [NIH] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [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] 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] Serine Proteinase Inhibitors: Exogenous or endogenous compounds which inhibit serine endopeptidases. [NIH] Seroconversion: The change of a serologic test from negative to positive, indicating the development of antibodies in response to infection or immunization. [EU] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] 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] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [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]

Short Bowel Syndrome: A malabsorption syndrome resulting from extensive operative

374

Fibrosis

resection of small bowel. [NIH] Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Sialorrhea: Increased salivary flow. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Sigma Factor: A protein which is a subunit of RNA polymerase. It effects initiation of specific RNA chains from DNA. [NIH] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silicosis: A type of pneumoconiosis caused by inhalation of particles of silica, quartz, ganister or slate. [NIH] Silymarin: A mixture of flavonoids extracted from seeds of the milk thistle, Silybum marianum. It consists primarily of three isomers: silicristin, silidianin, and silybin, its major component. Silymarin displays antioxidant and membrane stabilizing activity. It protects various tissues and organs against chemical injury, and shows potential as an antihepatoxic agent. [NIH] Sinusitis: An inflammatory process of the mucous membranes of the paranasal sinuses that occurs in three stages: acute, subacute, and chronic. Sinusitis results from any condition causing ostial obstruction or from pathophysiologic changes in the mucociliary transport mechanism. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin graft: Skin that is moved from one part of the body to another. [NIH] Skin Transplantation: The grafting of skin in humans or animals from one site to another to replace a lost portion of the body surface skin. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sludge: A clump of agglutinated red blood cells. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round

Dictionary 375

when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Soaps: Sodium or potassium salts of long chain fatty acids. These detergent substances are obtained by boiling natural oils or fats with caustic alkali. Sodium soaps are harder and are used as topical anti-infectives and vehicles in pills and liniments; potassium soaps are soft, used as vehicles for ointments and also as topical antimicrobials. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [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] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] 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]

376

Fibrosis

Sperm: The fecundating fluid of the male. [NIH] Sphenoid: An unpaired cranial bone with a body containing the sphenoid sinus and forming the posterior part of the medial walls of the orbits. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] 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] Spiral Ganglion: The sensory ganglion of the cochlear nerve. The cells of the spiral ganglion send fibers peripherally to the cochlear hair cells and centrally to the cochlear nuclei of the brain stem. [NIH] Spirometry: Measurement of volume of air inhaled or exhaled by the lung. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenic Vein: Vein formed by the union (at the hilus of the spleen) of several small veins from the stomach, pancreas, spleen and mesentery. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sprue: A non febrile tropical disease of uncertain origin. [NIH] Sputa: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Steady state: Dynamic equilibrium. [EU] Steatosis: Fatty degeneration. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stellate: Star shaped. [NIH] 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

Dictionary 377

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] Stenosis: Narrowing or stricture of a duct or canal. [EU] Stents: Devices that provide support for tubular structures that are being anastomosed or for body cavities during skin grafting. [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] 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] Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stimulants: Any drug or agent which causes stimulation. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stomatitis: Inflammation of the oral mucosa, due to local or systemic factors which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. [EU]

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] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stria: 1. A streak, or line. 2. A narrow bandlike structure; a general term for such longitudinal collections of nerve fibres in the brain. [EU] Stria Vascularis: A layer of highly vascular pigmented granular cells on the outer wall of the cochlear duct. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] 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] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other

378

Fibrosis

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] Submucous: Occurring beneath the mucosa or a mucous membrane. [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] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Sulfates: Inorganic salts of sulfuric acid. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Superinfection: A frequent complication of drug therapy for microbial infection. It may result from opportunistic colonization following immunosuppression by the primary pathogen and can be influenced by the time interval between infections, microbial physiology, or host resistance. Experimental challenge and in vitro models are sometimes used in virulence and infectivity studies. [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] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium

Dictionary 379

chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [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] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] 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] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Tear Gases: Gases that irritate the eyes, throat, or skin. Severe lacrimation develops upon irritation of the eyes. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Testicles: The two egg-shaped glands found inside the scrotum. They produce sperm and male hormones. Also called testes. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH]

380

Fibrosis

Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, 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] 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] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thrush: A disease due to infection with species of fungi of the genus Candida. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor.

Dictionary 381

(From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroiditis: Inflammation of the thyroid gland. [NIH] Tibia: The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the fibula laterally, the talus distally, and the femur proximally. [NIH] Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [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] Tobramycin: An aminoglycoside, broad-spectrum antibiotic produced by Streptomyces tenebrarius. It is effective against gram-negative bacteria, especially the Pseudomonas species. It is a 10% component of the antibiotic complex, nebramycin, produced by the same species. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] 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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] 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] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH]

382

Fibrosis

Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [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] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trabecular Meshwork: A porelike structure surrounding the entire circumference of the anterior chamber through which aqueous humor circulates to the canal of Schlemm. [NIH] Trabeculectomy: Any surgical procedure for treatment of glaucoma by means of puncture or reshaping of the trabecular meshwork. It includes goniotomy, trabeculotomy, and laser perforation. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transaminase: Aminotransferase (= a subclass of enzymes of the transferase class that catalyse the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2-keto acid). Most of these enzymes are pyridoxal-phosphate-proteins. [EU]

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] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]

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]

Dictionary 383

Transgenes: Genes that are introduced into an organism using gene transfer techniques. [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] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Traumatology: The branch of surgery which deals with wounds and disability from injuries. [NIH]

Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [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] 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 marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [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] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]

Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This

384

Fibrosis

condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [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] Ultrasound test: A test that bounces sound waves off tissues and internal organs and changes the echoes into pictures (sonograms). [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Unsaturated Fats: A type of fat. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]

Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Urease: An enzyme that catalyzes the conversion of urea and water to carbon dioxide and ammonia. EC 3.5.1.5. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureter: One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uridine Triphosphate: Uridine 5'-(tetrahydrogen triphosphate). A uracil nucleotide containing three phosphate groups esterified to the sugar moiety. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] 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] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Urology: A surgical specialty concerned with the study, diagnosis, and treatment of diseases of the urinary tract in both sexes and the genital tract in the male. It includes the specialty of andrology which addresses both male genital diseases and male infertility. [NIH] Ursodeoxycholic Acid: An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve

Dictionary 385

gallstones. It is used as a cholagogue and choleretic. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, 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]

Vancomycin: Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. [NIH] Varices: Stretched veins such as those that form in the esophagus from cirrhosis. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasectomy: An operation to cut or tie off the two tubes that carry sperm out of the testicles. [NIH]

Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [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] Venter: Belly. [NIH]

386

Fibrosis

Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Dysfunction: A condition in which the ventricles of the heart exhibit a decreased functionality. [NIH] 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] Vertigo: An illusion of movement; a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective vertigo). The term is sometimes erroneously used to mean any form of dizziness. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vibrio: A genus of Vibrionaceae, made up of short, slightly curved, motile, gram-negative rods. Various species produce cholera and other gastrointestinal disorders as well as abortion in sheep and cattle. [NIH] Vibrio cholerae: The etiologic agent of cholera. [NIH] Villous: Of a surface, covered with villi. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vinyl Chloride: A gas that has been used as an aerosol propellant and is the starting material for polyvinyl resins. Toxicity studies have shown various adverse effects, particularly the occurrence of liver neoplasms. [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]

Dictionary 387

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] 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] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vital Capacity: The volume of air that is exhaled by a maximal expiration following a maximal inspiration. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitreous Humor: The transparent, colorless mass of gel that lies behind the lens and in front of the retina and fills the center of the eyeball. [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] Waiting Lists: Prospective patient listings for appointments. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight Perception: Recognition and discrimination of the heaviness of a lifted object. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenobiotics: Chemical substances that are foreign to the biological system. They include

388

Fibrosis

naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. [NIH]

Xenograft: The cells of one species transplanted to another species. [NIH] Xerostomia: Decreased salivary flow. [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] Zonules: The fibers that hold the lens suspended in position and enable it to change shape during accommodation. [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]

389

INDEX A Abdomen, 178, 283, 292, 295, 296, 317, 334, 336, 340, 354, 356, 357, 365, 370, 376, 377, 380 Abdominal Pain, 232, 234, 283, 342, 357, 384 Abducens, 31, 283 Abducens Nerve, 31, 283 Abduction, 283, 343, 363 Abductor, 166, 283 Aberrant, 201, 283 Ablation, 28, 283 Aborigines, 159, 283 Abortion, 283, 331, 351, 386 Abscess, 283, 373 Absenteeism, 283, 308 Acceptor, 283, 340, 354, 380, 382 Accommodation, 217, 283, 348, 351, 388 Acetaminophen, 283, 321 Acetylcholine, 283, 302, 350 Acetylglucosamine, 222, 283 Acidity, 48, 105, 283, 357 Acidosis, 283, 287 Acne, 262, 284 Actin, 12, 24, 48, 49, 51, 53, 204, 284, 323, 348 Actinic keratosis, 231, 284 Action Potentials, 203, 284 Acute renal, 110, 284, 328 Adaptability, 284, 300 Adenocarcinoma, 68, 284, 329, 350 Adenosine, 69, 284, 287, 292, 338, 358 Adenovirus, 15, 69, 78, 192, 193, 194, 284 Adenylate Cyclase, 284, 302 Adhesions, 59, 218, 222, 284 Adipocytes, 284, 306, 339 Adjunctive Therapy, 284, 347 Adjustment, 113, 283, 284 Adjuvant, 284, 323 Adolescence, 231, 232, 284 Adoptive Transfer, 36, 39, 45, 66, 284 Adrenal Cortex, 284, 285, 307, 351, 362 Adrenal Glands, 284, 287 Adrenergic, 12, 68, 210, 284, 317 Adrenoleukodystrophy, 221, 284 Adverse Effect, 43, 285, 374, 386 Aerobic, 121, 285, 287, 318 Aerosol, 98, 181, 196, 285, 386

Afferent, 285, 319, 339, 358 Affinity, 44, 223, 285, 375 Agar, 74, 103, 285, 308, 332, 359 Age of Onset, 264, 285 Agenesis, 236, 285 Agonist, 31, 203, 206, 210, 225, 285, 358 Air Sacs, 228, 285, 286 AK, 86, 113, 118, 124, 154, 159, 163, 285 Alanine, 157, 285 Albinism, 180, 285 Alcohol Drinking, 143, 285 Aldosterone, 28, 109, 285, 326, 346 Alendronate, 106, 181, 285 Alfalfa, 69, 286 Alginates, 89, 286 Algorithms, 232, 286, 295 Alimentary, 286, 294, 316, 355 Alkaline, 284, 286, 287, 297 Alkaloid, 286, 304, 346 Alkylating Agents, 286, 301, 384 Allergen, 286, 310 Allergic Rhinitis, 216, 286, 327 Allogeneic, 286, 326 Allograft, 10, 66, 101, 110, 286 Alopecia, 286, 308 Alpha 1-Antitrypsin, 243, 286 Alpha Particles, 286, 366 Alpha-1, 233, 244, 286 Alpha-fetoprotein, 161, 286, 319 Alternative medicine, 266, 286 Alveolar Process, 286, 369 Alveoli, 268, 286, 386 Alveolitis, 40, 52, 228, 287 Ameliorating, 34, 287 Amino Acid Motifs, 287, 306 Amino Acid Sequence, 207, 287, 289, 306, 323, 362 Amino Acid Substitution, 223, 287, 328 Amino-terminal, 138, 287, 362 Amiodarone, 143, 287 Ammonia, 287, 379, 384 Amniotic Fluid, 287, 343 Ampulla, 287, 302, 315 Amyloidosis, 222, 240, 287 Anaerobic, 138, 287, 348 Anaerobic Threshold, 138, 287 Anaesthesia, 288, 333 Anal, 288, 319, 320, 333, 367

390

Fibrosis

Analgesic, 283, 288, 331, 352 Analog, 288, 322, 332 Analogous, 222, 288, 382 Analytes, 262, 288 Anaphylatoxins, 288, 305 Anaplasia, 288 Anastomosis, 4, 288 Anatomical, 288, 292, 296, 301, 314, 333, 372 Androgens, 284, 288, 291, 308 Anemia, 256, 258, 288, 294, 347, 353, 357, 380 Anesthesia, 285, 288, 314 Aneurism, 208, 288 Angina, 16, 200, 202, 215, 288, 289 Angina Pectoris, 16, 202, 288 Angioedema, 231, 288 Angiogenesis, 14, 16, 33, 52, 165, 171, 212, 224, 288, 343 Angioplasty, 12, 200, 215, 224, 288, 348 Angiotensinogen, 289, 368 Anhydrous, 224, 289 Animal model, 17, 20, 29, 30, 32, 33, 34, 39, 40, 50, 61, 65, 201, 225, 233, 289 Anions, 289, 337, 378 Annealing, 289, 360 Anomalies, 230, 232, 234, 289 Anterior chamber, 217, 289, 326, 337, 382 Anterior Cruciate Ligament, 167, 289 Antianginal, 287, 289 Antiarrhythmic, 287, 289 Antibacterial, 289, 299, 321, 326, 375, 385 Antibiotic, 72, 90, 96, 131, 162, 189, 289, 293, 296, 300, 349, 356, 371, 375, 380, 381 Anticoagulant, 289, 364 Antigen-Antibody Complex, 289, 305 Anti-inflammatory, 20, 22, 26, 32, 57, 66, 142, 283, 289, 308, 311, 324, 331, 362 Antimetabolite, 290, 345, 371 Antimicrobial, 70, 74, 76, 77, 80, 81, 86, 97, 120, 240, 290, 303, 310, 312, 320 Antineoplastic, 286, 290, 295, 298, 308, 322, 324, 345, 386 Antioxidant, 15, 142, 163, 171, 290, 353, 354, 374 Antiseptic, 290, 344 Antiviral, 15, 28, 33, 290, 322, 326, 335, 356, 371 Anuria, 290, 338 Anus, 288, 290, 292, 296, 304, 336, 367 Anxiety, 202, 240, 290 Aorta, 290, 332, 344, 386

Aortic Aneurysm, 290, 370 Aphakia, 290, 369 Apheresis, 185, 290 Apolipoproteins, 290, 340 Apoptosis, 16, 17, 27, 28, 33, 40, 41, 46, 47, 53, 55, 58, 59, 85, 130, 205, 290, 299 Appendicitis, 232, 290 Applicability, 210, 290 Aqueous, 55, 290, 293, 309, 314, 330, 339, 340, 361, 382 Aqueous fluid, 290, 361 Arachidonic Acid, 40, 290, 332, 339, 363 Archaea, 290, 345 Arginine, 164, 288, 291, 350, 383 Aromatase, 203, 225, 291 Arrestin, 211, 291 Arrhythmia, 202, 203, 289, 291 Arterial, 178, 200, 291, 302, 307, 331, 364, 379 Arteries, 208, 226, 269, 290, 291, 295, 296, 307, 332, 341, 344, 345, 348, 360, 365, 380 Arteriolar, 291, 296 Arterioles, 291, 296, 298, 345, 348, 385 Arteriolosclerosis, 291 Arteriosclerosis, 212, 291 Arteritis, 231, 291 Artery, 68, 100, 200, 202, 215, 226, 288, 291, 307, 314, 348, 355, 365, 368 Arthritis, Gouty, 206, 291 Arthritis, Infectious, 206, 291 Arthritis, Psoriatic, 206, 291 Articular, 292, 353 Asbestos, 27, 121, 292 Asbestosis, 97, 115, 292 Ascending Colon, 9, 292 Aspartic, 207, 292 Aspartic Acid, 292 Aspergillosis, 96, 292 Assay, 12, 25, 53, 65, 80, 103, 252, 292, 332, 371 Asymptomatic, 292, 294, 354 Ataxia, 258, 292, 380 Atopic, 140, 216, 219, 292 ATP, 21, 22, 44, 68, 89, 91, 218, 284, 292, 312, 324, 336, 338, 341, 358, 364, 380 Atresia, 18, 232, 236, 292, 294 Atrial, 287, 292, 307, 383 Atrioventricular, 292, 307 Atrium, 292, 307, 383, 386 Atrophy, 17, 145, 257, 258, 292, 340 Attenuation, 143, 218, 292, 346 Auditory, 26, 292, 327

Index 391

Autodigestion, 292, 354 Autoimmune disease, 11, 17, 201, 204, 219, 231, 233, 292, 347 Autoimmunity, 72, 292 Autologous, 209, 292 Autologous bone marrow transplantation, 209, 292 Autopsy, 182, 293 Autoradiography, 26, 293 Aztreonam, 81, 82, 243, 244, 293 B Bacillus, 293, 297 Bacterial Infections, 13, 49, 60, 194, 293 Bactericidal, 26, 293, 318 Bacteriophage, 293, 359, 382 Bacteriostatic, 26, 293 Basal cells, 11, 293 Basal Ganglia, 292, 293, 322 Basal Ganglia Diseases, 292, 293 Base, 17, 24, 235, 293, 310, 320, 321, 323, 337, 338, 379, 384 Base Sequence, 293, 321, 323 Basement Membrane, 50, 293, 298, 318, 338 Basophils, 200, 215, 220, 293, 327, 339 Benign, 203, 225, 231, 233, 291, 293, 322, 349, 367 Benign prostatic hyperplasia, 203, 225, 233, 293 Beta-Lactamases, 293, 294 Beta-Thalassemia, 164, 294 Bezoars, 232, 294 Bilateral, 294, 370 Bile Acids, 294, 323, 377 Bile Acids and Salts, 294 Bile duct, 3, 6, 19, 147, 153, 158, 169, 230, 233, 267, 294, 301, 315, 322, 328, 362, 370 Bile Pigments, 294, 337, 343 Biliary, 3, 5, 18, 19, 21, 113, 153, 169, 183, 229, 230, 231, 236, 294, 302, 304, 354 Biliary Atresia, 18, 113, 294 Biliary Tract, 229, 231, 294, 354 Bilirubin, 294, 322, 331 Bioassays, 63, 294 Bioavailability, 83, 181, 183, 187, 294 Biochemical Phenomena, 294, 295 Biofilms, 60, 294 Biological Phenomena, 205, 294 Biological response modifier, 295, 335 Biological therapy, 45, 295, 327 Biomarkers, 19, 295

Biopsy, 3, 4, 8, 36, 52, 182, 214, 252, 254, 295, 356 Biopsy specimen, 3, 295 Biotechnology, 67, 94, 251, 256, 257, 258, 259, 266, 295 Biotransformation, 295 Bivalent, 89, 295 Bladder, 202, 233, 293, 294, 295, 305, 333, 340, 347, 350, 363, 364, 370, 384 Blastocyst, 295, 306, 359, 362 Bleomycin, 28, 35, 37, 38, 42, 45, 63, 129, 145, 158, 166, 213, 228, 295 Bloating, 295, 342 Blood Coagulation, 295, 297, 320, 371, 380 Blood Glucose, 4, 5, 7, 8, 268, 295, 328, 334 Blood pressure, 178, 208, 219, 233, 239, 267, 269, 295, 298, 331, 346, 361, 365, 375 Blot, 35, 136, 296 Body Fluids, 295, 296, 313, 321, 351, 375, 383 Body Regions, 296, 304 Bone Density, 106, 296 Bone Marrow Transplantation, 137, 296 Bone scan, 296, 371 Bowel, 202, 232, 236, 288, 296, 311, 316, 334, 336, 339, 357, 368, 374, 377, 384 Bowel Movement, 296, 311, 377 Brachial, 296, 343 Brachial Plexus, 296, 343 Brachytherapy, 296, 336, 337, 366, 388 Bradykinin, 82, 164, 296, 337, 350 Brain Stem, 296, 304, 376 Branch, 220, 262, 270, 279, 296, 314, 342, 355, 365, 375, 380, 383 Breakdown, 222, 296, 311, 322, 352 Breeding, 37, 43, 296 Broad Ligament, 296, 319 Broad-spectrum, 296, 299, 381 Bronchi, 296, 297, 317, 382 Bronchial, 52, 68, 100, 220, 297, 328 Bronchiectasis, 77, 183, 297 Bronchioles, 286, 297 Bronchiolitis, 49, 134, 297 Bronchiolitis Obliterans, 134, 297 Bronchiolitis Obliterans Organizing Pneumonia, 134, 297 Bronchiseptica, 87, 297 Bronchitis, 76, 205, 206, 222, 223, 297, 302 Bronchoalveolar Lavage, 19, 38, 76, 103, 184, 297 Bronchopulmonary, 96, 99, 121, 297 Bronchoscopy, 52, 180, 182, 184, 262, 297

392

Fibrosis

Buccal, 297, 331, 341, 377 Bullous, 231, 297 C Cachexia, 216, 297 Cadherins, 209, 297 Calcification, 129, 291, 297 Calcinosis, 95, 168, 297 Calcium, 16, 70, 106, 226, 292, 297, 305, 323, 331, 343, 345, 348, 353, 374 Candidiasis, 240, 297 Candidosis, 298 Capillary, 7, 72, 296, 298, 385, 386 Capillary Permeability, 296, 298 Capsid, 298, 387 Capsular, 216, 217, 298 Capsules, 9, 195, 217, 298, 316, 323 Carbohydrate, 5, 7, 48, 59, 212, 222, 234, 298, 308, 325, 326, 360, 373 Carbon Dioxide, 298, 320, 322, 359, 369, 384 Carboplatin, 160, 298 Carcinogen, 54, 298, 347 Carcinogenic, 286, 298, 311, 334, 352, 363, 377 Carcinoma, 146, 169, 170, 213, 298, 350, 376 Carcinoma in Situ, 298 Cardiomyopathy, 16, 26, 84, 298 Cardiopulmonary, 17, 298, 346 Cardiovascular, 46, 133, 146, 203, 224, 226, 298, 318, 339, 385 Cardiovascular disease, 203, 224, 226, 298 Cardiovascular System, 46, 298 Carnitine, 158, 298 Carotene, 158, 164, 242, 299, 369 Carpal Tunnel Syndrome, 299, 343 Case report, 7, 8, 115, 128, 156, 162, 166, 169, 299, 303 Case series, 299, 303 Caspase, 27, 41, 299 Catabolism, 59, 205, 299 Catalyse, 299, 382 Cataract, 290, 298, 299, 369 Catheter, 299, 314, 315, 340 Catheterization, 288, 299, 348 Cathode, 299 Cations, 204, 205, 299, 337 Caudal, 299, 361 Causal, 299, 336 Cause of Death, 19, 60, 200, 206, 226, 299 Caustic, 232, 299, 375 Ceftazidime, 74, 81, 299

Celiac Disease, 232, 299 Cell Adhesion, 200, 208, 209, 213, 215, 218, 297, 300, 335 Cell Adhesion Molecules, 209, 300 Cell Cycle Proteins, 40, 300 Cell Death, 28, 73, 162, 290, 300, 324 Cell Differentiation, 300, 374 Cell Division, 257, 293, 300, 327, 343, 344, 346, 359, 363 Cell membrane, 203, 227, 300, 301, 310, 322, 336, 358, 361, 367 Cell motility, 300, 329 Cell proliferation, 58, 66, 200, 203, 218, 225, 291, 300, 335, 374 Cell Survival, 45, 300, 327 Cell Transplantation, 300 Cellulose, 300, 322, 359 Central Nervous System, 216, 283, 285, 300, 313, 322, 325, 331, 339, 347, 352, 361 Centrifugation, 185, 300 Cephaloridine, 299, 300 Cerebellar, 292, 300, 368 Cerebral, 202, 254, 292, 293, 296, 300, 301, 307, 317, 318 Cerebral Cortex, 292, 300, 318 Cerebral Palsy, 254, 300 Cerebrospinal, 300, 301, 374 Cerebrospinal fluid, 301, 374 Cerebrovascular, 293, 298, 301, 380 Cerebrum, 300, 301, 383 Ceroid, 180, 301, 340 Cervical, 296, 301, 343 Character, 288, 301, 309, 325 Chemical Warfare, 301, 309 Chemical Warfare Agents, 301, 309 Chemokines, 57, 65, 101, 129, 220, 301 Chemotactic Factors, 220, 301, 305, 350 Chemotherapy, 97, 105, 120, 137, 160, 170, 224, 228, 301 Chenodeoxycholic Acid, 301, 384 Chin, 73, 155, 158, 167, 301, 344 Chlorambucil, 268, 301 Chloride Channels, 79, 217, 301 Chlorophyll, 301, 322 Cholangiography, 230, 301 Cholangitis, 236, 301 Cholecystectomy, 230, 231, 301 Cholecystitis, 230, 231, 236, 301 Cholera, 235, 302, 386 Cholera Toxin, 235, 302 Choleretic, 301, 302, 385 Cholestasis, 72, 154, 167, 187, 225, 233, 302

Index 393

Cholesterol, 20, 154, 203, 225, 226, 230, 294, 302, 307, 322, 340, 341, 344, 377 Cholesterol Esters, 20, 302, 340 Choline, 143, 162, 203, 225, 302 Chondrocytes, 302, 320 Chondroitin sulfate, 218, 302 Chorioretinitis, 302, 370 Choroid, 302, 369, 370 Chromatin, 221, 290, 300, 302 Chromium, 54, 302 Chromosomal, 131, 302, 359 Chromosome, 284, 302, 340 Chronic Disease, 140, 220, 226, 252, 297, 302, 308, 339 Chronic leukemia, 302, 327 Chronic Obstructive Pulmonary Disease, 200, 202, 205, 215, 216, 222, 223, 302 Chronic renal, 10, 34, 64, 99, 153, 302, 360, 384 Chylomicrons, 302, 340 Cicatrix, 303, 337 Cicatrix, Hypertrophic, 303, 337 Ciliary, 206, 217, 290, 303, 347, 351 Ciliated cells, 10, 303 Ciprofloxacin, 74, 81, 83, 86, 87, 88, 303 CIS, 42, 65, 203, 225, 303, 369 Clamp, 22, 303 Cleave, 206, 303 Clinical Medicine, 116, 212, 303, 362 Clinical study, 155, 157, 303 Clone, 11, 31, 45, 303 Cloning, 31, 233, 295, 303 Clot Retraction, 303, 359 Coagulation, 134, 295, 303, 328, 380 Coal, 139, 303 Cochlea, 25, 303, 304, 334 Cochlear, 25, 304, 376, 377, 381 Cochlear Duct, 304, 377 Cochlear Implantation, 25, 304 Cochlear Nerve, 304, 376 Cofactor, 304, 350, 364, 380 Cohort Studies, 8, 304 Colchicine, 233, 304 Colic, 230, 304 Colitis, 32, 236, 304 Collagenases, 206, 207, 304 Collapse, 49, 296, 304 Colloidal, 304, 314 Colon, 213, 257, 292, 304, 334, 338, 339, 383 Colonopathy, 161, 304 Combination Therapy, 233, 304 Combinatorial, 47, 304

Common Bile Duct, 3, 65, 95, 230, 304, 308, 328 Complement, 7, 210, 288, 305, 323, 335 Complementary and alternative medicine, 151, 152, 176, 305 Complementary medicine, 152, 305 Complementation, 145, 305 Complete remission, 305, 368 Compliance, 15, 305 Computational Biology, 14, 251, 256, 305 Computed tomography, 296, 305, 306, 371 Computerized tomography, 190, 305 Conception, 283, 306, 320, 377 Concomitant, 9, 43, 65, 306 Conduction, 43, 70, 306 Cones, 306, 358, 369 Confounding, 13, 306 Congestion, 306, 317 Conjugated, 294, 301, 306, 309 Conjunctiva, 306 Conjunctivitis, 200, 209, 215, 306, 327 Conjunctivitis, Allergic, 209, 306 Connective Tissue Cells, 306 Consciousness, 288, 306, 310, 312, 328, 365 Consensus Sequence, 135, 287, 306 Conserved Sequence, 287, 306 Constipation, 232, 234, 306, 357 Constitutional, 306, 370 Constriction, 306, 337, 351 Consumption, 8, 130, 226, 306, 310, 311, 351, 354 Contamination, 135, 306, 329 Contractility, 46, 49, 54, 306 Contraindications, ii, 306 Control group, 7, 307 Controlled study, 16, 307 Convulsions, 202, 307 Coordination, 307, 347 Cor, 56, 307 Cornea, 55, 217, 289, 290, 307, 325, 372, 377, 385 Coronary, 16, 43, 200, 202, 215, 288, 298, 307, 345, 348 Coronary Arteriosclerosis, 307, 348 Coronary Circulation, 288, 307 Coronary heart disease, 200, 298, 307 Coronary Thrombosis, 307, 345, 348 Coronary Vessels, 43, 307 Corpus, 307, 362, 373, 387 Cortex, 307, 368 Cortical, 40, 307, 372, 380 Corticosteroid, 307, 362, 377

394

Fibrosis

Cortisone, 308, 311, 362 Cost of Illness, 102, 308 Cranial, 31, 283, 304, 308, 318, 319, 351, 352, 355, 357, 376 Creatinine, 33, 308, 338, 384 Critical Care, 14, 61, 99, 101, 102, 106, 107, 111, 117, 118, 119, 124, 125, 129, 130, 134, 145, 308 Crystallization, 230, 308 Culture Media, 285, 308 Curative, 226, 308, 380 Cutaneous, 45, 156, 230, 297, 308, 337, 341 Cyclic, 59, 204, 284, 308, 327, 350, 358, 361, 363 Cyclin, 66, 300, 308 Cyclin-Dependent Kinases, 300, 308 Cyclophosphamide, 268, 308 Cyclosporine, 101, 146, 268, 308 Cystic Duct, 304, 308, 328 Cytochrome, 227, 291, 309 Cytomegalovirus, 309, 322 Cytomegalovirus Infections, 309, 322 Cytoplasm, 290, 293, 300, 302, 309, 316, 327 Cytoskeleton, 48, 309, 335, 345 Cytotoxic, 6, 55, 309, 333, 366, 367, 374 D De novo, 49, 182, 183, 309 Decompensation, 5, 253, 309 Decompression, 3, 21, 121, 309 Decontamination, 88, 309 Defense Mechanisms, 309, 335 Degenerative, 309, 328, 353, 369 Dehydration, 240, 302, 309 Deletion, 17, 42, 45, 51, 64, 65, 290, 309 Delivery of Health Care, 308, 309, 327 Delusions, 310, 365 Dementia, 202, 209, 216, 310 Demography, 233, 310 Denaturation, 310, 360 Density, 32, 34, 67, 102, 114, 194, 296, 300, 310, 331, 340, 352, 375 Dental Caries, 240, 310 Deoxycytidine, 243, 244, 310 Deoxyribonucleases, 205, 310 Depolarization, 310, 374 Deprivation, 203, 224, 310 Dermal, 30, 59, 209, 310 Dermatitis, 200, 215, 216, 219, 231, 310 Dermatosis, 231, 310 Dermis, 288, 310, 337, 379 Desensitization, 135, 210, 211, 310

Desmosine, 19, 310 Detergents, 310, 320 Developed Countries, 226, 310 Developing Countries, 271, 311 Dexamethasone, 21, 92, 311 Diabetes Mellitus, 6, 7, 9, 50, 64, 102, 151, 311, 324, 325, 328 Diabetic Retinopathy, 200, 213, 215, 311, 358 Diagnostic procedure, 199, 265, 266, 311 Dialyzer, 311, 328 Diaphragm, 311, 360, 370 Diarrhea, 92, 232, 311, 316, 342 Diarrhoea, 202, 311, 331 Diastole, 311 Diastolic, 16, 119, 311, 331 Dietary Fats, 311, 340 Digestion, 48, 240, 286, 294, 296, 311, 336, 340, 354, 356, 377 Digestive system, 198, 229, 232, 311, 323, 347 Digestive tract, 311, 375, 376 Dilatation, 16, 283, 288, 297, 311, 362, 385 Dilation, 296, 311, 385 Dimethyl, 12, 311 Dimethylnitrosamine, 158, 311 Diploid, 305, 311, 359 Direct, iii, 6, 11, 22, 23, 30, 37, 38, 49, 54, 63, 66, 241, 287, 303, 311, 341, 355, 368, 379 Discrimination, 76, 312, 387 Disease Progression, 8, 36, 253, 312, 368, 387 Disinfectant, 312, 318, 344 Disparity, 63, 312 Dissociation, 285, 312 Distal, 9, 28, 64, 104, 312, 323, 365 Diverticula, 312 Diverticulitis, 236, 312 Diverticulum, 312 DNA Topoisomerase, 312, 324 Docetaxel, 156, 312 Dorsal, 236, 312, 317, 361 Double-blind, 16, 179, 184, 312 Doxycycline, 64, 312 Drive, ii, vi, 4, 5, 6, 8, 11, 18, 50, 56, 62, 141, 230, 231, 232, 234, 235, 252, 268, 312, 337 Drug Delivery Systems, 13, 312 Drug Interactions, 242, 313 Duct, 4, 19, 69, 70, 154, 205, 230, 287, 299, 304, 313, 315, 318, 336, 371, 377, 379

Index 395

Ductal carcinoma in situ, 203, 225, 313, 336 Duodenum, 95, 234, 294, 313, 315, 322, 337, 354, 356, 372, 377 Dura mater, 313, 344, 354, 356 Dyes, 93, 293, 313, 378 Dynorphins, 313, 367 Dyskinesia, 206, 313 Dysmenorrhea, 202, 313 Dysplasia, 134, 160, 258, 313 Dyspnea, 39, 309, 313, 365 Dystrophy, 257, 313 E Eating Disorders, 232, 313 Ectopic, 212, 313 Edema, 288, 309, 311, 313, 347, 348, 384 Effector, 26, 35, 41, 47, 64, 65, 283, 305, 313, 358 Effector cell, 47, 64, 313 Efficacy, 16, 25, 34, 45, 51, 58, 106, 140, 178, 179, 181, 184, 185, 189, 193, 194, 195, 196, 210, 313 Elastic, 217, 222, 313, 325, 375, 378 Elasticity, 61, 291, 307, 313 Elastin, 19, 212, 222, 304, 310, 313, 318, 339 Elective, 91, 103, 313 Electrocoagulation, 303, 313 Electrolysis, 289, 299, 313 Electrolyte, 235, 285, 308, 314, 321, 326, 338, 346, 351, 361, 375, 384 Electrophoresis, 56, 72, 314, 332 Electrophysiological, 44, 314 Emboli, 100, 314 Embolization, 100, 314 Embolus, 314, 333 Embryo, 283, 295, 300, 314, 319, 333, 351 Embryology, 236, 314 Emphysema, 19, 137, 209, 210, 223, 286, 302, 314 Emulsion, 293, 314, 320 Enamel, 310, 314 Encephalopathy, 252, 314 Encopresis, 232, 314 Endarterectomy, 289, 314 Endemic, 253, 302, 314, 376 Endocarditis, 298, 314 Endocrine System, 314, 349 Endogenous, 11, 33, 38, 45, 59, 106, 226, 315, 316, 353, 367, 373, 382 Endometrial, 315 Endometriosis, 203, 224, 225, 315 Endometrium, 212, 315, 344

Endorphins, 315, 350, 367 Endoscope, 315 Endoscopic, 144, 208, 230, 232, 297, 315 Endoscopic retrograde cholangiopancreatography, 232, 315 Endoscopy, 179, 232, 315 Endothelial cell, 14, 40, 49, 59, 136, 200, 215, 315, 320, 380 Endothelins, 49, 315 Endothelium, 161, 200, 202, 215, 315, 350, 359 Endothelium, Lymphatic, 315 Endothelium, Vascular, 315 Endothelium-derived, 315, 350 Endotoxemia, 210, 315 Endotoxic, 315, 340 Endotoxin, 315, 316, 383 End-stage renal, 34, 178, 302, 316, 360 Energy balance, 316, 339 Enhancer, 64, 316 Enkephalins, 316, 350, 367 Enteral Nutrition, 157, 232, 316 Enteric Nervous System, 235, 316 Enteric-coated, 9, 316 Enterocolitis, 33, 316 Enteropeptidase, 316, 383 Enterotoxins, 235, 316 Environmental Exposure, 316, 352 Environmental Health, 139, 250, 252, 316 Enzymatic, 206, 218, 226, 287, 297, 299, 305, 308, 310, 316, 320, 344, 360, 369 Enzyme Activators, 56, 316 Enzyme-Linked Immunosorbent Assay, 76, 316 Eosinophil, 62, 316 Eosinophilia, 316, 331 Eosinophilic, 107, 316, 331 Epidemic, 33, 77, 81, 94, 317, 376 Epidemiological, 54, 77, 159, 317 Epidermis, 293, 310, 317 Epigastric, 317, 354 Epinephrine, 284, 317, 350, 383 Epitope, 40, 317 Epoprostenol, 317, 332 Erythema, 231, 317, 385 Erythema Multiforme, 231, 317 Erythrocytes, 142, 288, 296, 317, 368 Esophageal, 5, 168, 179, 232, 317 Esophageal Motility Disorders, 232, 317 Esophageal Varices, 5, 179, 317 Esophagus, 178, 232, 234, 236, 292, 311, 317, 323, 341, 356, 357, 368, 377, 385

396

Fibrosis

Essential Tremor, 258, 317 Estrogen, 144, 159, 203, 224, 225, 291, 317 Ethanol, 24, 171, 318 Ethmoid, 318, 355 Ethnic Groups, 52, 318 Eukaryotic Cells, 318, 333, 353 Evacuation, 217, 306, 318, 322, 339 Evoke, 318, 377 Excipient, 204, 318 Excrete, 267, 290, 318, 338, 368 Exercise Test, 180, 318 Exocrine, 4, 9, 269, 270, 271, 272, 318, 354 Exogenous, 34, 38, 39, 63, 196, 227, 295, 315, 318, 373 Exotoxin, 74, 76, 88, 318 Expiration, 318, 369, 387 Expiratory, 191, 318 Extensor, 318, 365 External-beam radiation, 318, 337, 366, 388 Extracellular Matrix Proteins, 10, 29, 235, 318, 343 Extracellular Space, 318, 319 Extraction, 47, 290, 319, 369 Extraocular, 31, 73, 114, 257, 319 Extremity, 296, 319, 343 Exudate, 297, 302, 319, 352 Eye Infections, 284, 319 F Facial, 319, 355 Facial Nerve, 319, 355 Faecal, 121, 160, 311, 319 Failure to Thrive, 232, 254, 319 Fallopian tube, 90, 319 Family Planning, 251, 319 Fatigue, 233, 319, 327 Fatty acids, 109, 160, 161, 319, 325, 343, 363, 375 Fatty Liver, 8, 64, 319 Febrile, 231, 319, 376 Fecal Incontinence, 234, 319, 333 Feces, 306, 314, 319, 377 Femur, 289, 319, 381 Fetal Development, 213, 319 Fetoprotein, 319 Fetus, 59, 283, 286, 319, 320, 321, 343, 359, 362, 385 Fibril, 320, 369 Fibrin, 38, 41, 51, 224, 295, 303, 320, 357, 359, 380 Fibrinogen, 51, 320, 359, 380 Fibrinolysis, 42, 224, 320

Fibroblast Growth Factor, 16, 320 Fibronectins, 318, 320 Fibrotic tissue, 55, 218, 320 Fish Oils, 145, 166, 320 Fixation, 47, 320 Flatus, 319, 320, 322 Fleroxacin, 74, 320 Flexion, 321, 343 Fluid Therapy, 321, 351 Foetoplacental, 321, 351 Fold, 41, 42, 83, 219, 296, 321, 344 Follicles, 17, 310, 321 Foramen, 301, 321, 329 Forced Expiratory Volume, 137, 321 Forearm, 295, 321, 343, 363 Fovea, 320, 321 Frameshift, 227, 321 Free Radicals, 290, 312, 321, 348 Friction, 321, 341 Fructose, 236, 321, 326 Fructose Intolerance, 236, 321 Fulminant Hepatic Failure, 231, 234, 321 Fungi, 268, 291, 292, 319, 321, 322, 345, 380, 388 Fungus, 65, 297, 321 G Gadolinium, 21, 144, 322 Galactosemia, 236, 322 Galenical, 226, 322 Gallbladder, 229, 231, 232, 283, 294, 301, 308, 311, 315, 322, 323, 340 Gallstones, 230, 231, 294, 301, 322, 385 Gamma Rays, 322, 366, 367 Gamma-interferon, 322, 335 Ganciclovir, 28, 322 Ganglia, 283, 293, 316, 322, 349, 357 Ganglion, 322, 351, 352, 376 Gap Junctions, 322, 379 Gas, 262, 287, 298, 320, 322, 330, 342, 347, 350, 365, 369, 386 Gas exchange, 287, 322, 369, 386 Gastric, 48, 105, 133, 232, 292, 298, 317, 322, 323, 336, 356 Gastric Emptying, 133, 322 Gastric Juices, 322, 356 Gastrin, 48, 322, 329 Gastritis, 232, 236, 256, 323 Gastroesophageal Reflux, 144, 232, 236, 323 Gastrointestinal Hemorrhage, 232, 323 Gastrointestinal Neoplasms, 292, 323

Index 397

Gastrointestinal tract, 4, 205, 220, 230, 234, 236, 318, 323, 331, 339, 383 Gastrostomy, 316, 323 Gelatin, 35, 308, 323, 325, 378, 380 Gelatinases, 207, 323 Gelsolin, 244, 323 Gene Therapy, 10, 25, 30, 34, 72, 92, 186, 187, 227, 244, 264, 271, 284, 323 Genetic Code, 323, 351 Genetic Engineering, 295, 303, 323 Genetic Markers, 11, 179, 323 Genetic Screening, 52, 324 Genetic testing, 112, 324, 360 Genetics, 11, 53, 105, 108, 114, 124, 128, 143, 179, 181, 184, 264, 324 Genistein, 152, 161, 171, 172, 177, 324 Genital, 303, 324, 384 Genotype, 5, 8, 31, 40, 89, 104, 159, 324, 357 Germ Cells, 324, 343, 352, 353, 375, 379 Giant Cells, 324, 371 Gingival Hyperplasia, 231, 324 Gingivitis, 231, 324 Ginkgo biloba, 158, 324 Ginseng, 176, 324 Gland, 70, 73, 88, 91, 231, 240, 284, 308, 324, 342, 354, 355, 359, 363, 364, 372, 377, 379, 381 Glomerular, 50, 211, 324, 338 Glomeruli, 110, 324 Glomerulonephritis, 57, 122, 200, 207, 209, 210, 215, 324, 341 Glomerulosclerosis, 40, 324 Glomerulus, 64, 324, 349 Glucocorticoid, 311, 324, 346, 362 Gluconeogenesis, 183, 321, 325 Glucose Intolerance, 311, 325 Glucose tolerance, 4, 5, 9, 125, 196, 325 Glucose Tolerance Test, 9, 325 Glucuronic Acid, 325, 328 Glutamic Acid, 325, 350, 363 Glutathione Peroxidase, 325, 372 Gluten, 299, 325 Glycerol, 325, 358 Glycerophospholipids, 325, 358 Glycine, 287, 294, 301, 325, 350, 373 Glycopeptides, 76, 325 Glycoprotein, 48, 212, 286, 320, 324, 325, 326, 336, 338, 347, 380, 383 Glycosaminoglycan, 218, 302, 325 Glycoside, 326, 330, 371 Glycosylation, 79, 84, 111, 136, 326

Glycyrrhetinic Acid, 144, 326 Goblet Cells, 227, 326 Gonadal, 326, 377 Goniotomy, 326, 382 Gout, 291, 304, 326 Governing Board, 326, 361 Government Agencies, 236, 326, 361 Gp120, 326, 356 Grade, 4, 8, 120, 326 Grading, 4, 112, 326 Graft, 66, 101, 104, 220, 231, 233, 240, 326, 330, 333, 348 Graft Rejection, 220, 326, 333 Graft Survival, 66, 104, 326 Grafting, 326, 333, 374 Graft-versus-host disease, 231, 326, 348 Gram-negative, 60, 103, 138, 293, 297, 299, 315, 316, 326, 348, 361, 381, 386 Gram-Negative Bacteria, 60, 316, 327, 361, 381 Gram-positive, 293, 327 Granulation Tissue, 38, 63, 297, 327 Granulocytes, 327, 339, 374, 387 Growth factors, 33, 37, 41, 47, 63, 64, 67, 79, 113, 201, 218, 224, 327 Guanylate Cyclase, 327, 350 Gyrase, 320, 327 H Hair Cells, 304, 327, 376 Hairy cell leukemia, 92, 327 Half-Life, 327, 332 Halitosis, 231, 327 Haptens, 285, 327 Hay Fever, 286, 327 Health Care Costs, 308, 327 Heart attack, 225, 226, 298, 327 Heart failure, 14, 16, 17, 43, 90, 210, 219, 327, 365 Heme, 66, 294, 309, 327, 328, 354, 361 Hemochromatosis, 98, 231, 328 Hemodialysis, 4, 311, 328, 338 Hemoglobin, 288, 294, 317, 327, 328, 361, 380 Hemoglobin M, 328 Hemoglobinopathies, 221, 323, 328 Hemoglobinuria, 257, 328 Hemolytic, 328, 380 Hemophilia, 36, 258, 328 Hemoptysis, 100, 328 Hemorrhage, 231, 268, 313, 328, 348, 377, 387 Hemostasis, 328, 335

398

Fibrosis

Heparin, 218, 243, 328 Hepatic Duct, Common, 315, 328 Hepatic Encephalopathy, 179, 231, 328 Hepatitis A, 103, 253, 328 Hepatocellular, 15, 49, 109, 143, 214, 253, 329 Hepatocellular carcinoma, 15, 109, 253, 329 Hepatocyte, 34, 102, 302, 329 Hepatocyte Growth Factor, 34, 102, 329 Hepatotoxicity, 157, 329 Hepatovirus, 328, 329 Hereditary, 98, 230, 235, 286, 326, 328, 329, 370, 380 Heredity, 234, 323, 324, 329 Hernia, 232, 329 Herniated, 207, 329 Herpes, 28, 329 Herpes Zoster, 329 Heterodimer, 28, 329 Heterogeneity, 71, 80, 81, 98, 285, 329 Heterotrophic, 321, 329 Histocompatibility, 23, 329 Histology, 6, 7, 31, 61, 120, 214, 329 Histone Deacetylase, 204, 221, 329 Homeostasis, 30, 212, 234, 329 Homodimer, 329, 382 Homologous, 82, 295, 323, 329, 379 Hormonal, 292, 308, 329 Horseradish Peroxidase, 316, 329 Host, 17, 25, 39, 50, 205, 206, 214, 220, 224, 240, 253, 293, 298, 320, 326, 330, 332, 333, 339, 347, 378, 385, 387 Human growth hormone, 131, 330 Humoral, 13, 131, 214, 326, 330 Humour, 330 Hybrid, 30, 64, 303, 330 Hybridomas, 330, 335 Hydration, 53, 205, 206, 330 Hydrogel, 32, 330 Hydrogen, 162, 283, 284, 293, 298, 310, 318, 325, 330, 340, 346, 350, 351, 354, 357, 364, 378 Hydrogen Bonding, 330, 351 Hydrogen Peroxide, 325, 330, 340, 378 Hydrolases, 56, 310, 330, 358 Hydrolysis, 56, 89, 205, 218, 292, 294, 295, 330, 336, 338, 339, 356, 358, 364, 383 Hydrophilic, 310, 330 Hydrophobic, 310, 325, 330, 340 Hydroxylysine, 304, 330 Hydroxyproline, 47, 287, 304, 330

Hyperbilirubinemia, 331, 337 Hypercalcemia, 11, 331 Hypereosinophilic Syndrome, 123, 331 Hyperglycemia, 26, 331 Hyperkeratosis, 160, 331 Hyperlipidemia, 64, 203, 224, 225, 331 Hyperoxia, 14, 331 Hyperplasia, 45, 65, 222, 331 Hypersensitivity, 38, 209, 216, 286, 306, 310, 316, 331, 339, 370 Hypersensitivity, Immediate, 331 Hypertension, 26, 49, 165, 178, 202, 203, 233, 267, 291, 298, 331, 346, 361, 381, 384 Hypertrophic cardiomyopathy, 43, 331 Hypertrophy, 13, 16, 26, 43, 46, 92, 144, 158, 211, 219, 294, 307, 331, 346, 383 Hypnotic, 151, 331 Hypobetalipoproteinemia, 114, 331 Hypoglycemia, 7, 321, 331 Hypoplasia, 236, 331 Hypotension, 307, 331 Hypoxia, 50, 268, 331, 380 I Ibuprofen, 106, 130, 195, 331 Id, 148, 173, 256, 257, 265, 278, 280, 331 Ileum, 332, 337 Ileus, 5, 165, 332 Iliac Artery, 133, 332 Iloprost, 268, 332 Immune function, 332, 333, 382 Immune system, 17, 40, 62, 202, 268, 292, 295, 313, 332, 333, 339, 342, 347, 357, 385, 387 Immunity, 40, 45, 90, 126, 151, 212, 285, 332, 352 Immunization, 284, 332, 333, 373 Immunoassay, 36, 252, 316, 332 Immunochemistry, 74, 332 Immunocompromised, 8, 332 Immunodeficiency, 117, 257, 332 Immunodiffusion, 285, 332 Immunoelectrophoresis, 285, 332 Immunofluorescence, 56, 332 Immunogenic, 332, 340 Immunoglobulin, 71, 289, 332, 346 Immunohistochemistry, 61, 332 Immunologic, 36, 38, 253, 284, 301, 332, 356, 367 Immunology, 49, 61, 110, 116, 131, 165, 284, 285, 330, 333, 352 Immunosuppressant, 204, 233, 286, 333, 345

Index 399

Immunosuppressive, 117, 268, 308, 324, 333, 379 Immunosuppressive Agents, 268, 333 Immunotherapy, 284, 295, 310, 333 Impairment, 39, 121, 132, 152, 292, 302, 313, 319, 333, 336, 344, 365 Imperforate Anus, 236, 333 Implant radiation, 333, 336, 337, 366, 388 Implantation, 32, 233, 306, 333, 351, 362 Impotence, 333, 356 In situ, 18, 40, 110, 333 In Situ Hybridization, 18, 91, 110, 333 In vivo, 11, 13, 16, 21, 22, 24, 25, 29, 30, 31, 32, 33, 34, 35, 37, 39, 41, 42, 44, 45, 48, 49, 50, 51, 53, 55, 57, 58, 64, 73, 75, 78, 82, 91, 106, 153, 187, 211, 226, 323, 328, 333, 347, 353, 379, 380 Incision, 326, 333, 336, 364, 370 Incompetence, 323, 333 Incontinence, 202, 232, 233, 314, 333 Indicative, 333, 355, 385 Indolent, 41, 333 Induction, 17, 25, 27, 28, 33, 37, 38, 45, 57, 63, 134, 160, 201, 206, 227, 288, 333 Infancy, 235, 267, 333 Infarction, 16, 46, 333, 360, 368 Inferior vena cava, 95, 334 Infertility, 217, 334, 384 Infiltration, 14, 28, 38, 58, 115, 210, 212, 213, 324, 331, 334 Inflammatory bowel disease, 200, 201, 209, 215, 219, 232, 234, 334 Infusion, 28, 182, 334, 348, 382 Ingestion, 22, 57, 58, 76, 232, 321, 325, 327, 331, 334, 346 Inhalation, 55, 62, 98, 188, 189, 192, 194, 242, 245, 285, 292, 297, 334, 374 Initiation, 41, 50, 201, 220, 334, 374, 382 Inlay, 334, 369 Inner ear, 334, 338, 385 Innervation, 296, 319, 334, 343, 352, 365 Inorganic, 203, 334, 347, 378 Inpatients, 135, 334 Insecticides, 334, 388 Insight, 18, 38, 40, 63, 334 Instillation, 25, 334 Insulator, 334, 347 Insulin, 5, 7, 9, 33, 42, 118, 125, 142, 196, 325, 334, 335 Insulin-dependent diabetes mellitus, 334 Insulin-like, 33, 42, 118, 335 Integrins, 47, 209, 213, 335

Intensive Care, 74, 335 Intercellular Adhesion Molecule-1, 200, 215, 335 Interferon-alpha, 154, 335 Interleukin-1, 36, 55, 214, 335 Interleukin-10, 36, 214, 335 Interleukin-2, 335 Interleukin-6, 34, 36, 335 Interleukins, 333, 335 Intermittent, 202, 253, 321, 335 Intermittent Claudication, 202, 203, 335 Internal Medicine, 17, 39, 47, 50, 116, 135, 144, 146, 323, 336 Internal radiation, 336, 337, 366, 388 Interstitial, 9, 10, 23, 26, 28, 34, 35, 38, 39, 41, 49, 50, 53, 54, 64, 67, 77, 90, 96, 105, 109, 118, 129, 132, 134, 138, 139, 146, 153, 168, 169, 170, 186, 191, 219, 220, 262, 268, 296, 319, 336, 337, 349, 388 Intervention Studies, 151, 336 Intervertebral, 329, 336 Intestinal, 9, 32, 48, 81, 91, 100, 104, 229, 234, 235, 299, 301, 302, 316, 325, 336, 342, 343, 385 Intestinal Mucosa, 299, 316, 336, 385 Intestinal Obstruction, 9, 104, 234, 336 Intestine, 33, 48, 161, 180, 232, 235, 294, 296, 336, 338 Intoxication, 336, 387 Intracellular, 47, 56, 69, 145, 334, 335, 336, 344, 350, 361, 363, 367, 371, 372, 374 Intraductal carcinoma, 313, 336 Intrahepatic, 49, 328, 336 Intramuscular, 336, 355 Intraocular, 216, 217, 336 Intravenous, 105, 179, 194, 210, 232, 334, 336, 355 Intrinsic, 56, 83, 285, 293, 336 Intrinsic Factor, 56, 336 Intussusception, 9, 336, 368 Invasive, 19, 47, 126, 127, 165, 203, 225, 332, 336, 342 Involuntary, 293, 317, 319, 336, 348, 381 Ion Channels, 22, 203, 336, 379 Ion Transport, 13, 19, 22, 25, 125, 130, 167, 193, 235, 336, 346 Ionizing, 286, 316, 337, 367 Ions, 52, 203, 217, 283, 293, 301, 312, 314, 323, 330, 336, 337, 346, 361 Iris, 217, 289, 307, 326, 337, 361, 366 Irradiation, 40, 337, 388 Irritants, 227, 337

400

Fibrosis

Ischemia, 16, 33, 200, 215, 292, 337, 348, 368 J Jaundice, 231, 232, 234, 331, 337, 349 Jejunostomy, 316, 337 Jejunum, 69, 337 Joint, 206, 292, 303, 337, 353, 379 K Kallidin, 296, 337 Kb, 250, 337 Keloid, 220, 303, 337 Keratolytic, 310, 337 Keratosis, 284, 337 Keto, 337, 382 Kidney Disease, 9, 10, 58, 178, 184, 186, 189, 193, 198, 202, 220, 250, 258, 267, 338 Kidney Failure, 34, 178, 316, 324, 338 Kidney Failure, Acute, 338 Kidney Failure, Chronic, 338 Kidney Pelvis, 338, 384 Kinesin, 114, 338 Kinetic, 337, 338 L Labile, 305, 338 Labyrinth, 26, 303, 334, 338, 386 Labyrinthine, 25, 338 Labyrinthitis, 25, 338 Lacrimal, 319, 338, 349 Lacrimal Apparatus, 338, 349 Lactation, 338, 351 Laminin, 21, 119, 212, 293, 318, 338 Large Intestine, 311, 336, 338, 367, 368, 375 Latency, 28, 37, 338 Latent, 26, 35, 37, 39, 62, 207, 339, 362 Latent period, 39, 339 Lavage, 99, 339 Laxative, 285, 301, 339 Lectin, 59, 222, 339, 344 Lens, 55, 216, 217, 290, 298, 299, 339, 387, 388 Leptin, 64, 339 Lethal, 18, 29, 35, 52, 64, 191, 210, 293, 339, 347 Leucocyte, 244, 286, 316, 339 Leukaemia, 204, 339 Leukapheresis, 290, 339 Leukemia, 105, 122, 173, 257, 323, 331, 339 Leukocyte Elastase, 209, 210, 339 Leukocytes, 59, 200, 201, 213, 215, 293, 296, 301, 327, 335, 339, 383 Leukoplakia, 159, 174, 231, 339 Leukotrienes, 290, 339

Library Services, 278, 339 Life cycle, 321, 339 Life Expectancy, 5, 7, 190, 339 Ligament, 26, 289, 340, 364 Ligands, 20, 30, 51, 57, 59, 300, 335, 340, 367 Ligation, 57, 65, 68, 147, 153, 158, 169, 210, 340 Linkage, 11, 30, 31, 186, 271, 323, 340 Lip, 240, 340 Lipase, 9, 56, 133, 175, 340, 355 Lipid A, 157, 340 Lipid Peroxidation, 20, 340, 354 Lipodystrophy, 236, 340 Lipofuscin, 180, 301, 340 Lipopolysaccharide, 70, 93, 326, 340 Lipoprotein, 225, 226, 326, 331, 340, 341, 387 Liposome, 186, 193, 340 Lithotripsy, 230, 340 Liver cancer, 214, 226, 253, 286, 340 Liver Cirrhosis, 162, 174, 220, 340 Liver Neoplasms, 340, 386 Liver scan, 341, 371 Liver Transplantation, 5, 33, 104, 131, 231, 232, 234, 252, 254, 341 Lobe, 137, 330, 341, 355 Local therapy, 203, 225, 341 Localization, 21, 23, 81, 332, 341 Localized, 21, 283, 287, 288, 310, 320, 334, 338, 340, 341, 359, 372, 383, 385 Longitudinal Studies, 192, 341 Loop, 20, 47, 55, 223, 329, 341 Low-density lipoprotein, 340, 341 Lower Esophageal Sphincter, 317, 323, 341 Lubricants, 341 Lubrication, 240, 341 Lucida, 338, 341 Luciferase, 25, 341 Lumen, 25, 48, 208, 315, 341 Lung Transplantation, 101, 106, 110, 135, 146, 182, 185, 341 Lung volume, 107, 341 Lupus, 164, 200, 215, 231, 240, 268, 341, 379 Lupus Nephritis, 164, 341 Lymph, 301, 315, 330, 341, 342, 371 Lymph node, 301, 342, 371 Lymphatic, 315, 334, 341, 342, 344, 375, 376 Lymphatic system, 341, 342, 375, 376

Index 401

Lymphocyte, 35, 39, 72, 136, 201, 289, 342, 343 Lymphocytic, 49, 342 Lymphoid, 289, 327, 339, 342 Lymphoma, 105, 169, 174, 257, 342 Lysine, 310, 330, 342, 362, 383 Lytic, 342, 373 M Macrophage, 14, 20, 21, 27, 28, 37, 40, 58, 63, 86, 335, 342 Magnetic Resonance Imaging, 84, 342, 371 Malabsorption, 9, 174, 232, 234, 257, 299, 342, 373 Malabsorption syndrome, 232, 234, 342, 373 Malformation, 267, 342 Malignant, 169, 231, 257, 284, 290, 291, 298, 340, 342, 347, 349, 363, 367 Malignant tumor, 231, 298, 342, 347 Malnutrition, 292, 297, 342, 347 Mammogram, 297, 342, 345 Mandible, 286, 301, 342, 369 Manic, 342, 365 Manic-depressive psychosis, 342, 365 Mannans, 322, 342 Maple Syrup Urine Disease, 236, 342 Matrilysin, 79, 343 Matrix metalloproteinase, 21, 35, 50, 51, 104, 343 Maxillary, 343, 355 Maximum Tolerated Dose, 187, 343 Mechanical ventilation, 126, 267, 343 Meconium, 5, 165, 343 Medial, 256, 291, 318, 343, 376, 381 Median Nerve, 61, 299, 343 Median Neuropathy, 61, 343 Mediate, 23, 27, 29, 33, 38, 41, 54, 69, 300, 304, 343 Mediator, 22, 23, 24, 33, 57, 62, 64, 66, 335, 343 Medicament, 204, 343, 378 MEDLINE, 251, 256, 258, 343 Meiosis, 224, 295, 343, 379 Melanin, 337, 343, 358, 383 Melanocytes, 343 Melanoma, 257, 343 Membrane Glycoproteins, 344 Membrane Lipids, 344, 358 Membrane Proteins, 344 Memory, 53, 151, 202, 310, 344 Meninges, 293, 300, 313, 344 Meningitis, 25, 209, 344

Menopause, 344, 351, 361 Menstrual Cycle, 344, 351, 362 Menstruation, 313, 344 Mental, iv, 10, 15, 198, 250, 255, 259, 300, 301, 310, 312, 319, 333, 344, 347, 365, 372, 384 Mental Disorders, 15, 198, 344, 365 Mental Health, iv, 10, 198, 250, 255, 344, 365 Mercuric Chloride, 33, 344 Mesenchymal, 28, 61, 77, 107, 344 Mesenteric, 95, 344, 361 Mesenteric Arteries, 95, 344 Mesentery, 344, 357, 376 Mesothelial, 222, 344 Metabolic disorder, 221, 326, 344 Metabolite, 24, 295, 311, 344 Metaphase, 295, 344 Metaplasia, 125, 345 Metastasis, 29, 151, 209, 212, 213, 224, 300, 343, 345 Metastatic, 203, 225, 345, 372 Methionine, 117, 311, 345, 378 Methotrexate, 233, 268, 345 MI, 46, 67, 74, 82, 109, 220, 281, 345 Microbe, 345, 382 Microcalcifications, 297, 345 Microcirculation, 340, 345, 359 Microorganism, 304, 345, 355, 387 Micro-organism, 310, 345, 358 Microscopy, 15, 26, 31, 56, 293, 330, 345 Microspheres, 9, 345 Microtubules, 338, 345 Microwaves, 345, 366 Migration, 13, 29, 54, 66, 106, 201, 208, 209, 212, 218, 220, 223, 224, 335, 345 Milk Thistle, 175, 345, 374 Milliliter, 296, 345 Mineralocorticoid, 90, 346 Miotic, 346, 358 Mitosis, 290, 346 Mitotic, 109, 312, 346 Mitotic Index, 109, 346 Mobility, 65, 346 Modification, 30, 156, 221, 287, 323, 346, 366 Molecular Structure, 205, 223, 346 Monitor, 12, 187, 308, 346, 351 Monoclonal, 80, 201, 330, 337, 346, 366, 388 Monocrotaline, 143, 156, 346 Monocyte, 65, 78, 201, 346

402

Fibrosis

Mononuclear, 63, 104, 118, 201, 220, 346, 383 Morphogenesis, 236, 346 Morphological, 314, 322, 343, 346 Morphology, 31, 54, 72, 291, 299, 346 Motility, 78, 230, 232, 323, 346 Motor Activity, 307, 346 Motor nerve, 347, 351 Mucilaginous, 343, 347 Mucins, 136, 206, 223, 326, 347, 371 Mucociliary, 223, 227, 347, 374 Mucociliary Clearance, 227, 347 Mucolytic, 297, 347 Mucosa, 195, 220, 230, 341, 347, 349, 377, 378 Mucositis, 347, 380 Mucus, 77, 206, 223, 227, 269, 272, 347, 371, 384 Multicenter study, 185, 347 Multidose, 181, 347 Multiple Myeloma, 209, 347 Multiple sclerosis, 200, 201, 209, 215, 219, 220, 347 Muscle Fibers, 347, 348 Muscular Atrophy, 221, 257, 347 Muscular Dystrophies, 313, 347 Musculature, 347, 365 Music Therapy, 151, 154, 347 Mustard Gas, 337, 347 Mutagenic, 286, 311, 347 Mycophenolate mofetil, 143, 348 Mycoplasma, 291, 348 Myelin, 347, 348 Myelofibrosis, 105, 116, 123, 125, 174, 257, 348 Myocardial infarction, 46, 200, 225, 307, 345, 348 Myocardial Ischemia, 47, 288, 348 Myocardial Reperfusion, 348, 369 Myocardial Reperfusion Injury, 348, 369 Myocarditis, 209, 348 Myocardium, 16, 26, 43, 46, 47, 67, 288, 345, 348 Myopia, 256, 348, 368, 369 Myosin, 43, 54, 348 Myotonic Dystrophy, 257, 348 N Narcolepsy, 202, 348 Nasal Cavity, 349, 355 Nasal Mucosa, 73, 349 Nasogastric, 316, 349 Nasolacrimal, 205, 349

NCI, 1, 187, 197, 249, 303, 349 Nebramycin, 349, 381 Nebulizer, 8, 188, 349 Neonatal, 18, 102, 117, 129, 137, 144, 158, 165, 189, 234, 349 Neonatal Hepatitis, 18, 234, 349 Neonatal Screening, 165, 190, 349 Neoplasia, 222, 257, 349 Neoplasm, 349 Neoplastic, 213, 288, 330, 342, 349 Nephritis, 118, 201, 209, 211, 349 Nephron, 324, 349 Nephropathy, 10, 77, 170, 201, 207, 211, 338, 349 Nervous System, 258, 285, 300, 327, 343, 349, 350, 357, 379 Netilmicin, 86, 349 Neural, 240, 285, 320, 330, 349, 369 Neuroendocrine, 19, 349 Neurogenic, 233, 350 Neuromuscular, 269, 283, 350, 352, 384 Neuromuscular Junction, 283, 350, 352 Neurons, 304, 322, 350, 379 Neuropathy, 61, 187, 350 Neuroretinitis, 350, 370 Neurotransmitter, 283, 284, 287, 292, 296, 325, 336, 350, 374, 378, 379, 385 Neutrons, 286, 337, 350, 366 Neutrophil, 106, 165, 195, 207, 210, 223, 286, 335, 350 Neutrophil Activation, 210, 350 Nickel, 132, 350 Nitric Oxide, 13, 26, 46, 59, 77, 162, 211, 350 Nitrogen, 133, 195, 286, 288, 308, 318, 320, 338, 350, 354, 383 Non-small cell lung cancer, 160, 350 Norepinephrine, 165, 284, 350 Nosocomial, 85, 232, 350 Nuclear, 20, 35, 51, 88, 180, 203, 225, 293, 318, 322, 351, 363 Nuclear Medicine, 180, 351 Nuclei, 286, 304, 323, 342, 346, 350, 351, 352, 364, 376 Nucleic acid, 12, 28, 206, 224, 227, 293, 298, 323, 333, 350, 351, 366, 371 Nucleic Acid Hybridization, 12, 351 Nucleotidases, 330, 351 Nutritional Status, 4, 6, 9, 351 Nutritional Support, 234, 323, 351 Nystagmus, 338, 351

Index 403

O Octamer, 221, 351 Ocular, 110, 351, 352 Oculomotor, 31, 351 Oculomotor Nerve, 31, 351 Oestrogen, 172, 351 Oliguria, 338, 351 Omega-3 fatty acid, 145, 157, 166, 352 Oncogene, 257, 329, 352 Oncogenic, 335, 352 Oocytes, 80, 144, 161, 352 Opacity, 55, 299, 310, 352 Operon, 352, 369 Ophthalmology, 55, 129, 320, 352, 369 Ophthalmoplegia, 31, 352 Opiate, 210, 352 Opium, 352 Opsin, 352, 369, 371 Optic Disk, 311, 352 Optic Nerve, 350, 352, 354, 369, 370, 372 Oral Health, 8, 352 Oral Hygiene, 8, 327, 352 Orbit, 352 Orbital, 31, 352 Orderly, 22, 221, 352 Organ Specificity, 205, 352 Organ Transplantation, 209, 353 Organelles, 300, 309, 338, 343, 353 Ossification, 25, 353 Osteoarthritis, 212, 353 Osteoblasts, 26, 353 Osteocalcin, 99, 353 Osteoclasts, 95, 353 Osteopetrosis, 207, 211, 353 Osteoporosis, 86, 181, 190, 203, 212, 224, 225, 233, 285, 351, 353 Otitis, 205, 353 Otitis Media, 205, 353 Outpatient, 7, 353 Ovaries, 291, 353, 373 Ovary, 351, 353, 377 Overdose, 321, 353 Ovulation, 224, 353 Ovum, 339, 353, 362, 388 Oxidants, 47, 353 Oxidation, 283, 290, 295, 309, 325, 328, 340, 353, 354 Oxidation-Reduction, 295, 353, 354 Oxidative Stress, 6, 15, 354 Oxygen Consumption, 287, 318, 354, 369 Oxygenase, 66, 354

P Pachymeningitis, 344, 354 Palate, 354, 377 Palliative, 159, 351, 354, 380 Pancreatic cancer, 230, 257, 354 Pancreatic Ducts, 315, 354 Pancreatic enzymes, 9, 184, 354, 355 Pancreatic Extracts, 9, 354 Pancreatic Fistula, 232, 354 Pancreatic Insufficiency, 4, 9, 174, 183, 236, 354 Pancreatic Juice, 323, 354 Pancreatitis, 3, 83, 97, 102, 104, 125, 129, 201, 217, 230, 232, 234, 236, 354 Pancrelipase, 195, 355 Papilla, 315, 355 Papillary, 331, 355 Paralysis, 352, 355, 365 Paranasal Sinuses, 206, 355, 374 Parasite, 355 Parasitic, 231, 234, 355, 371 Parasitic Diseases, 231, 355 Parenteral, 157, 232, 234, 355 Parenteral Nutrition, 232, 355 Parietal, 355, 357, 360 Parotid, 231, 355, 371 Paroxysmal, 257, 288, 355 Partial remission, 355, 368 Patch, 19, 22, 339, 355 Pathogen, 60, 99, 145, 355, 378 Pathologic, 12, 25, 55, 127, 210, 283, 290, 295, 297, 298, 307, 331, 355, 365, 369, 385 Pathologic Processes, 290, 355 Pathologies, 55, 62, 209, 355 Pathophysiology, 19, 129, 235, 355 Patient Advocacy, 269, 355 Patient Education, 8, 156, 263, 264, 276, 278, 281, 356 Pelvic, 315, 356, 363, 370 Pelvis, 283, 296, 332, 334, 353, 356, 370, 385 Penicillamine, 105, 268, 356 Penicillin, 71, 356, 385 Penile Prosthesis, 233, 356 Pentoxifylline, 106, 196, 197, 356 Pepsin, 356, 372 Peptic, 232, 356 Peptic Ulcer, 232, 356 Peptide Hydrolases, 330, 356 Peptide T, 22, 211, 356 Percutaneous, 166, 340, 356 Perforation, 321, 356, 382 Perfusion, 331, 356, 381

404

Fibrosis

Pericardium, 356, 379 Peridural, 121, 356 Perineal, 356, 366 Periodontitis, 324, 356 Perioral, 230, 356 Peripheral blood, 17, 104, 118, 135, 335, 356 Peripheral Nervous System, 316, 350, 357, 378, 385 Peripheral stem cells, 326, 357 Peritoneal, 59, 106, 236, 357 Peritoneum, 296, 344, 357, 370 Peritonitis, 210, 357 Pernicious, 336, 357 Pernicious anemia, 336, 357 Peroxide, 162, 357 PH, 73, 91, 119, 121, 128, 153, 158, 233, 296, 357 Phagocyte, 22, 63, 353, 357 Phagocytosis, 22, 57, 85, 357 Phallic, 320, 357 Pharmaceutical Preparations, 300, 318, 323, 357 Pharmacodynamics, 87, 357 Pharmacokinetic, 357 Pharmacologic, 10, 46, 130, 288, 327, 357, 381, 382 Pharynx, 323, 349, 357 Phenotype, 11, 27, 31, 37, 41, 42, 43, 46, 47, 49, 53, 58, 62, 64, 75, 93, 104, 111, 219, 305, 357 Phenyl, 200, 215, 357 Phenylalanine, 357, 383 Phenylbutyrate, 152, 177, 358 Phosphodiesterase, 216, 356, 358 Phospholipases, 358, 374 Phospholipids, 109, 160, 319, 340, 344, 358 Phosphoprotein Phosphatase, 300, 358 Phosphoric Monoester Hydrolases, 330, 358 Phosphorus, 297, 358 Phosphorylate, 23, 211, 358 Phosphorylated, 14, 53, 65, 210, 218, 291, 358 Phosphorylation, 13, 30, 57, 89, 218, 308, 358, 364 Photocoagulation, 303, 358 Phototransduction, 291, 358 Physical Examination, 178, 184, 188, 358 Physicochemical, 205, 332, 358 Physiologic, 26, 48, 52, 132, 187, 285, 319, 327, 344, 358, 363, 367, 369

Pigmentation, 180, 231, 358 Pigments, 294, 299, 358, 369 Pilocarpine, 240, 358 Pilot Projects, 25, 359 Pilot study, 359 Pituitary Gland, 308, 320, 359 Placenta, 291, 321, 359, 362 Plants, 286, 292, 294, 295, 296, 298, 302, 324, 325, 326, 339, 346, 350, 358, 359, 360, 371, 382 Plaque, 200, 225, 226, 288, 359 Plasma cells, 289, 327, 347, 359 Plasmapheresis, 290, 359 Plasmid, 34, 78, 359, 385 Plasmin, 42, 207, 224, 359 Plasminogen, 28, 40, 41, 51, 77, 223, 224, 359 Plasminogen Activators, 224, 359 Platelet Activation, 359, 374 Platelet Aggregation, 288, 317, 332, 350, 356, 359, 380 Plateletpheresis, 290, 359 Platelets, 59, 350, 359, 380 Platinum, 341, 360 Pleura, 360 Pleural, 121, 344, 360 Pneumoconiosis, 360, 374 Pneumonia, 49, 87, 119, 134, 205, 268, 297, 306, 360 Pneumonitis, 38, 41, 268, 360 Policy Making, 326, 360 Polyarteritis Nodosa, 231, 360 Polycystic, 178, 202, 258, 267, 360 Polymerase, 23, 70, 252, 360, 369, 374 Polymerase Chain Reaction, 70, 252, 360 Polymers, 294, 360, 364 Polymorphism, 6, 71, 72, 76, 98, 108, 360 Polyphosphates, 205, 206, 360 Polyposis, 236, 360 Polysaccharide, 76, 87, 289, 300, 325, 360, 364 Polyunsaturated fat, 20, 115, 360, 380 Pons, 283, 296, 361 Porins, 152, 361 Porphyria, 236, 361 Porphyrins, 361 Portal Hypertension, 5, 49, 120, 179, 231, 233, 234, 267, 361 Portal Vein, 178, 361 Posterior, 216, 217, 288, 292, 302, 312, 337, 354, 361, 370, 372, 376 Posterior chamber, 217, 361

Index 405

Postmenopausal, 285, 353, 361 Postnatal, 59, 361, 377 Postprandial, 5, 361 Postsynaptic, 361, 374, 379 Post-translational, 30, 48, 59, 361 Potassium, 76, 202, 242, 285, 346, 361, 375 Potassium Channels, 76, 202, 361 Potentiates, 38, 55, 335, 361 Potentiation, 361, 374 Practice Guidelines, 255, 361 Precancerous, 284, 362 Predisposition, 59, 212, 362 Prednisolone, 362 Prednisone, 52, 362 Preimplantation Diagnosis, 137, 362 Prenatal, 131, 314, 324, 362 Presynaptic, 350, 362, 379 Prevalence, 9, 36, 72, 81, 192, 268, 362 Primary Biliary Cirrhosis, 232, 233, 362 Primary Sclerosing Cholangitis, 230, 232, 362 Probe, 53, 94, 178, 362 Procollagen, 135, 138, 153, 362 Proctitis, 236, 362 Proenzyme, 224, 362 Progesterone, 362, 377 Progressive disease, 214, 362 Proliferating Cell Nuclear Antigen, 160, 363 Proline, 209, 304, 330, 362, 363 Promoter, 10, 12, 23, 28, 35, 44, 51, 62, 64, 65, 93, 363 Pronation, 343, 363 Pronator, 343, 363 Prophase, 295, 352, 363, 379 Prophylaxis, 205, 220, 221, 363, 385 Proportional, 316, 363 Prospective study, 3, 167, 363 Prostaglandin, 45, 53, 210, 317, 363, 380 Prostaglandins A, 363 Prostate, 187, 203, 225, 257, 294, 295, 351, 363, 364, 366, 370, 383 Prostatectomy, 364, 366 Prostatic Hyperplasia, 364 Prosthesis, 233, 364 Prosthesis Implantation, 233, 364 Protease, 22, 41, 92, 207, 211, 244, 286, 304, 364 Protein C, 48, 90, 180, 205, 210, 220, 287, 290, 293, 340, 353, 364, 384, 387 Protein Conformation, 90, 287, 364

Protein S, 22, 24, 26, 47, 48, 212, 258, 295, 306, 323, 330, 353, 364, 380 Protein-Tyrosine Kinase, 324, 364 Proteinuria, 324, 347, 364 Proteoglycan, 62, 206, 212, 364 Proteolytic, 42, 206, 207, 286, 305, 316, 320, 359, 364 Protocol, 122, 185, 364 Protons, 286, 330, 337, 364, 366 Protozoa, 345, 364 Protozoal, 204, 231, 364 Proximal, 23, 64, 312, 349, 362, 365, 373 Prune Belly Syndrome, 236, 365 Pruritus, 187, 233, 365, 384 Psoriasis, 200, 201, 209, 213, 215, 216, 218, 219, 231, 291, 347, 365 Psychiatry, 320, 365, 386 Psychic, 344, 365, 372 Psychoactive, 365, 367, 387 Psychosis, 202, 365 Ptosis, 31, 365 Public Health, 95, 130, 143, 254, 255, 365 Public Policy, 251, 365 Pulmonary Artery, 295, 346, 365, 386 Pulmonary Edema, 338, 365 Pulmonary hypertension, 14, 17, 135, 307, 317, 365 Pulmonary Ventilation, 365, 369 Pulse, 346, 365 Pupil, 307, 311, 346, 366 Purines, 293, 366, 373 Purulent, 366, 385 Pyridoxal, 366, 382 Pyrimidines, 293, 366, 373 Q Quality of Life, 6, 25, 138, 179, 181, 188, 190, 191, 194, 240, 270, 272, 308, 366 Quaternary, 364, 366 Quiescent, 49, 366 R Race, 345, 366 Radiation therapy, 187, 239, 240, 318, 336, 337, 366, 388 Radical prostatectomy, 233, 366 Radio Waves, 178, 345, 366 Radioactive, 293, 296, 309, 327, 330, 333, 336, 337, 341, 347, 351, 352, 366, 371, 388 Radiography, 262, 366 Radioimmunotherapy, 366, 367 Radiolabeled, 337, 366, 388 Radiological, 63, 262, 356, 366 Radiologist, 230, 367

406

Fibrosis

Radiology, 97, 100, 132, 262, 351, 367 Radiotherapy, 39, 121, 160, 203, 225, 296, 337, 366, 367, 388 Randomized, 16, 98, 122, 179, 181, 184, 186, 190, 193, 194, 195, 270, 313, 367 Randomized clinical trial, 190, 367 Reactivation, 253, 367 Reagent, 207, 211, 341, 367 Reality Testing, 365, 367 Rebound effect, 195, 367 Receptors, Opioid, 210, 313, 367 Recessive gene, 189, 271, 367 Recombinant Proteins, 37, 367 Recombination, 323, 367 Rectal, 9, 367 Rectal Prolapse, 9, 367 Rectum, 290, 296, 304, 311, 320, 322, 333, 334, 338, 362, 364, 367, 368, 378 Recur, 36, 368 Recurrence, 203, 225, 233, 342, 368 Red blood cells, 317, 328, 354, 368, 371, 374 Red Nucleus, 292, 368 Reductase, 291, 345, 368 Refer, 1, 237, 297, 305, 315, 320, 321, 324, 329, 341, 350, 351, 365, 366, 368, 373, 382, 386 Reflux, 232, 317, 323, 368 Refraction, 348, 368, 375 Regeneration, 36, 320, 368 Regimen, 7, 181, 313, 368 Registries, 138, 368 Regurgitation, 317, 323, 368 Reliability, 15, 368 Remission, 123, 342, 368 Renal tubular, 10, 368 Renin, 40, 109, 289, 368 Reoperation, 233, 368 Reperfusion, 200, 215, 348, 368, 369 Reperfusion Injury, 200, 215, 369 Repressor, 30, 352, 369 Resection, 109, 364, 369, 374 Resorption, 21, 353, 369 Respiration, 161, 298, 346, 369 Respirator, 343, 369, 386 Respiratory distress syndrome, 209, 210, 220, 369 Respiratory failure, 28, 369, 386 Respiratory Physiology, 96, 97, 100, 118, 138, 152, 162, 369, 386 Respiratory System, 263, 269, 270, 271, 272, 285, 347, 369, 385

Restoration, 21, 28, 348, 367, 368, 369, 387 Reticulin, 92, 137, 369 Retina, 55, 217, 302, 306, 311, 339, 348, 350, 352, 358, 369, 370, 371, 385, 387 Retinal, 124, 205, 220, 291, 311, 312, 352, 358, 369, 371 Retinal Detachment, 205, 220, 311, 369 Retinitis, 209, 370 Retinoblastoma, 257, 370 Retinoid, 56, 370 Retinol, 56, 369, 370, 371 Retinyl palmitate, 56, 370 Retrograde, 370 Retroperitoneal, 95, 97, 117, 118, 129, 131, 169, 284, 370 Retroperitoneal Fibrosis, 95, 97, 117, 118, 129, 131, 169, 370 Retroperitoneal Space, 370 Retropubic, 364, 366, 370 Retropubic prostatectomy, 366, 370 Retrospective, 117, 146, 370 Retroviral vector, 323, 370 Reversion, 41, 370 Rheology, 356, 370 Rheumatic Diseases, 39, 105, 110, 129, 370 Rheumatism, 96, 109, 331, 370 Rheumatoid, 11, 29, 179, 180, 182, 206, 209, 210, 212, 216, 219, 220, 240, 291, 353, 370 Rheumatoid arthritis, 11, 29, 179, 180, 182, 206, 209, 210, 212, 216, 219, 220, 240, 370 Rhinitis, 200, 209, 215, 297, 371 Rhinorrhea, 202, 371 Rhodopsin, 291, 352, 369, 371 Ribavirin, 15, 98, 133, 214, 371 Riboflavin, 15, 169, 371 Rickettsiae, 291, 371 Risk factor, 5, 6, 36, 190, 191, 253, 363, 371 Ristocetin, 371, 385 Rod, 293, 303, 315, 371 Rubella, 291 S Saliva, 90, 239, 240, 371 Salivary, 239, 240, 269, 270, 271, 272, 309, 311, 319, 354, 371, 374, 388 Salivary glands, 239, 240, 269, 270, 271, 272, 309, 311, 319, 371 Saponins, 371, 377 Sarcoidosis, 38, 125, 132, 219, 236, 240, 371 Scans, 180, 190, 371 Schizoid, 371, 387 Schizophrenia, 372, 387

Index 407

Schizotypal Personality Disorder, 372, 387 Sclera, 302, 306, 372, 385 Scleroderma, 29, 43, 44, 110, 135, 136, 191, 218, 220, 231, 240, 268, 291, 372 Sclerosis, 11, 42, 96, 105, 146, 192, 258, 268, 291, 347, 372 Sclerotic, 50, 372 Sebaceous, 310, 337, 372 Sebaceous gland, 310, 337, 372 Secondary tumor, 345, 372 Secretin, 19, 372 Secretory, 6, 19, 48, 69, 92, 111, 202, 206, 244, 347, 372, 379 Sedimentation, 300, 372 Segmental, 324, 372 Seizures, 202, 203, 355, 372 Selenium, 171, 372 Self Care, 268, 372 Semen, 363, 372 Senile, 284, 353, 373 Sensor, 32, 98, 373 Septal, 134, 373 Septic, 209, 210, 373 Septum, 29, 349, 373 Septum Pellucidum, 373 Sequence Analysis, 74, 373 Sequence Homology, 223, 356, 373 Sequencing, 87, 93, 360, 373 Serine, 41, 207, 209, 210, 218, 224, 358, 373, 383 Serine Endopeptidases, 373 Serine Proteinase Inhibitors, 210, 373 Seroconversion, 253, 373 Serologic, 36, 332, 373 Serous, 70, 315, 360, 373 Sex Characteristics, 284, 288, 351, 373 Sex Determination, 258, 373 Shock, 103, 210, 216, 315, 340, 373, 383 Short Bowel Syndrome, 232, 373 Shunt, 28, 374 Sialorrhea, 231, 374 Side effect, 33, 187, 231, 240, 241, 243, 269, 285, 295, 308, 374, 381 Sigma Factor, 75, 374 Signal Transduction, 23, 53, 54, 63, 65, 67, 374 Signs and Symptoms, 360, 368, 374, 384 Silicosis, 38, 62, 374 Silymarin, 153, 155, 170, 226, 345, 374 Sinusitis, 205, 206, 374 Skeletal, 37, 288, 303, 347, 374 Skeleton, 284, 319, 337, 363, 374, 381

Skin graft, 374, 377 Skin Transplantation, 59, 374 Skull, 352, 374, 379 Sludge, 230, 374 Small cell lung cancer, 374 Small intestine, 48, 301, 303, 309, 313, 315, 329, 332, 336, 337, 349, 375, 383 Smoking Cessation, 20, 140, 375 Soaps, 320, 375 Social Environment, 366, 375 Sodium, 4, 52, 147, 161, 269, 271, 272, 285, 317, 326, 346, 358, 375, 378 Soft tissue, 127, 296, 352, 374, 375 Solid tumor, 288, 295, 375 Solvent, 318, 325, 375 Soma, 375 Somatic, 70, 88, 284, 330, 343, 346, 357, 375 Sound wave, 178, 306, 367, 375, 384 Soybean Oil, 109, 160, 360, 375 Specialist, 229, 272, 311, 375 Specificity, 11, 51, 60, 285, 297, 339, 375, 381 Spectrum, 4, 59, 135, 320, 345, 366, 375 Sperm, 111, 288, 302, 376, 379, 385 Sphenoid, 355, 376 Sphincter, 233, 367, 376 Spinal cord, 231, 296, 300, 301, 302, 313, 316, 322, 343, 344, 349, 350, 354, 357, 376 Spiral Ganglion, 26, 304, 376 Spirometry, 105, 262, 376 Spleen, 178, 287, 309, 342, 371, 376 Splenic Vein, 361, 376 Splenomegaly, 353, 376 Sporadic, 370, 376 Sprue, 236, 376 Sputa, 71, 76, 79, 85, 88, 91, 94, 103, 111, 376 Sputum, 19, 75, 80, 82, 83, 86, 88, 89, 91, 94, 100, 105, 117, 124, 125, 184, 192, 194, 206, 376 Squamous, 350, 376 Squamous cell carcinoma, 350, 376 Stabilization, 65, 376 Staging, 112, 155, 191, 212, 371, 376 Steady state, 53, 376 Steatosis, 8, 114, 120, 139, 319, 376 Steel, 303, 376 Stellate, 8, 12, 20, 24, 35, 49, 51, 54, 56, 64, 78, 82, 85, 114, 125, 142, 144, 147, 157, 162, 170, 376 Stem cell transplantation, 268, 376 Stem Cells, 93, 357, 376, 377

408

Fibrosis

Stenosis, 3, 16, 377 Stents, 233, 377 Sterility, 308, 334, 377 Steroid, 170, 180, 291, 294, 308, 351, 371, 377 Steroid therapy, 170, 180, 377 Stimulants, 324, 377 Stimulus, 63, 306, 312, 313, 334, 336, 338, 377, 380 Stomach, 179, 232, 234, 283, 292, 311, 317, 322, 323, 325, 329, 339, 341, 349, 356, 357, 368, 372, 375, 376, 377 Stomatitis, 231, 377 Stool, 184, 304, 333, 338, 377 Strand, 30, 72, 360, 377 Stress, 4, 58, 75, 129, 146, 163, 164, 166, 354, 362, 370, 377, 385 Stria, 26, 377 Stria Vascularis, 26, 377 Stricture, 377 Stroke, 198, 209, 225, 226, 250, 298, 377 Stroma, 337, 377 Stromal, 40, 55, 315, 377 Stromal Cells, 40, 56, 377 Subacute, 15, 334, 374, 377 Subarachnoid, 25, 377 Subclinical, 213, 214, 334, 372, 377 Subcutaneous, 129, 184, 185, 189, 196, 284, 288, 313, 340, 355, 378 Submucous, 95, 121, 143, 144, 155, 156, 159, 160, 163, 166, 168, 172, 231, 378 Subspecies, 375, 378 Substance P, 344, 371, 372, 378 Substrate, 6, 43, 56, 60, 316, 330, 378 Substrate Specificity, 56, 60, 378 Sulfates, 218, 378 Sulfur, 318, 345, 378 Sulfuric acid, 378 Superinfection, 293, 378 Superoxide, 39, 378 Superoxide Dismutase, 39, 378 Supplementation, 101, 109, 139, 142, 155, 158, 159, 160, 161, 163, 164, 172, 378 Support group, 269, 271, 378 Suppositories, 323, 378 Suppression, 21, 22, 51, 134, 143, 170, 202, 203, 209, 221, 233, 308, 378 Surfactant, 99, 130, 137, 228, 378 Survival Rate, 180, 210, 253, 378 Sweat, 70, 107, 177, 184, 265, 269, 270, 271, 272, 310, 378, 379

Sweat Glands, 177, 269, 270, 271, 272, 310, 378, 379 Symphysis, 301, 364, 379 Symptomatic, 267, 354, 379 Synapse, 284, 350, 362, 379, 383 Synapsis, 379 Synaptic, 203, 350, 374, 379 Synaptic Transmission, 203, 379 Synergistic, 33, 92, 228, 379, 381 Synovial, 61, 379 Systemic disease, 231, 240, 379 Systemic lupus erythematosus, 240, 341, 379 Systolic, 331, 379 T Tacrolimus, 135, 379 Tear Gases, 337, 379 Telangiectasia, 168, 258, 379 Temporal, 16, 25, 43, 64, 67, 379 Testicles, 379, 385 Testicular, 132, 233, 291, 379 Testis, 351, 379 Tetracycline, 64, 312, 380 Thalamic, 292, 380 Thalamic Diseases, 292, 380 Thalassemia, 204, 294, 380 Therapeutics, 24, 60, 106, 130, 152, 155, 159, 177, 188, 208, 209, 219, 243, 380 Thermal, 208, 292, 312, 350, 360, 380 Thoracic, 39, 128, 146, 161, 296, 311, 343, 360, 380, 387 Thorax, 99, 127, 158, 165, 213, 283, 380 Threonine, 356, 358, 373, 380 Threshold, 287, 331, 380 Thrombin, 320, 359, 364, 380 Thrombocytes, 359, 380 Thrombolytic, 359, 380 Thrombomodulin, 364, 380 Thrombosis, 200, 218, 335, 364, 377, 380 Thromboxanes, 290, 380 Thrombus, 307, 333, 348, 359, 380 Thrush, 297, 380 Thymidine, 28, 380 Thymidine Kinase, 28, 380 Thyroid, 17, 381, 383 Thyroid Gland, 381 Thyroiditis, 17, 381 Tibia, 289, 381 Tic, 189, 271, 381 Tinnitus, 353, 381 Tissue Distribution, 297, 381

Index 409

Tobramycin, 69, 74, 75, 82, 87, 189, 194, 245, 381 Tolerance, 4, 284, 325, 381 Tomography, 305, 306, 371, 381 Tone, 352, 381 Tonic, 317, 381 Topical, 230, 318, 330, 344, 375, 381 Torsion, 333, 381 Toxic, iv, 15, 28, 204, 209, 227, 231, 286, 310, 316, 318, 332, 344, 346, 350, 372, 381, 382, 385 Toxicity, 12, 38, 39, 75, 118, 226, 313, 343, 349, 371, 382, 386 Toxicokinetics, 382 Toxicology, 54, 62, 143, 146, 147, 156, 158, 169, 171, 252, 382 Toxin, 34, 39, 315, 316, 381, 382 Trabecular Meshwork, 382 Trabeculectomy, 55, 382 Trace element, 9, 302, 350, 382 Trachea, 297, 357, 381, 382 Traction, 303, 382 Transaminase, 214, 382 Transcription Factors, 30, 45, 50, 55, 64, 65, 300, 382 Transduction, 19, 53, 54, 65, 374, 382 Transfection, 15, 51, 66, 295, 323, 382 Transferases, 6, 326, 382 Transforming Growth Factor beta, 62, 382 Transfusion, 164, 382 Transgenes, 25, 37, 383 Translation, 287, 383 Translational, 25, 45, 48, 49, 383 Transmitter, 283, 336, 343, 350, 383 Trauma, 32, 61, 206, 210, 222, 231, 240, 291, 293, 355, 380, 381, 383 Traumatology, 36, 168, 383 Tricuspid Atresia, 307, 383 Triglyceride, 145, 383 Trypsin, 208, 209, 210, 286, 316, 362, 383 Tryptophan, 304, 383 Tuberous Sclerosis, 11, 258, 383 Tumor marker, 295, 383 Tumor Necrosis Factor, 71, 126, 129, 383 Tunica, 314, 347, 383 Tyrosine, 23, 364, 383 U Ulcer, 212, 327, 383 Ulceration, 187, 356, 383 Ulcerative colitis, 209, 216, 232, 334, 362, 383 Ultrasonography, 5, 146, 384

Ultrasound test, 185, 384 Unconscious, 309, 331, 384 Unsaturated Fats, 320, 384 Uracil, 366, 384 Uraemia, 355, 384 Urea, 338, 379, 384 Urease, 350, 384 Uremia, 338, 384 Ureter, 68, 338, 340, 384 Urethra, 294, 363, 384 Uridine Triphosphate, 196, 384 Urinary, 138, 178, 202, 210, 233, 303, 333, 351, 364, 365, 370, 384 Urinary tract, 365, 384 Urokinase, 51, 224, 384 Urology, 233, 384 Ursodeoxycholic Acid, 6, 183, 187, 233, 384 Urticaria, 231, 385 Uterus, 283, 296, 301, 307, 315, 321, 344, 353, 362, 385 Uveitis, 291, 385 V Vaccination, 252, 253, 385 Vaccine, 75, 284, 364, 385 Vagina, 297, 344, 385 Vaginal, 205, 341, 385 Vaginitis, 228, 297, 385 Valine, 356, 385 Vancomycin, 87, 385 Varices, 178, 385 Vascular Resistance, 287, 385 Vasculitis, 18, 268, 355, 360, 385 Vasectomy, 132, 385 Vasoactive, 19, 49, 385 Vasoactive Intestinal Peptide, 19, 385 Vasodilation, 332, 385 Vasodilator, 296, 348, 385 Vector, 11, 20, 30, 34, 62, 91, 186, 187, 192, 193, 205, 207, 211, 227, 244, 355, 382, 385 Vein, 178, 184, 185, 334, 336, 351, 355, 361, 376, 385 Vena, 170, 385 Venous, 309, 364, 383, 385 Venter, 385, 386 Ventilation, 6, 127, 165, 386 Ventilator, 343, 369, 386 Ventral, 236, 351, 361, 386 Ventricle, 219, 292, 307, 365, 379, 383, 386 Ventricular, 43, 47, 93, 119, 210, 287, 307, 346, 348, 383, 386 Ventricular Dysfunction, 93, 386

410

Fibrosis

Venules, 296, 298, 315, 345, 386 Vertebrae, 336, 376, 386 Vertigo, 353, 386 Vesicular, 231, 329, 386 Vestibular, 327, 338, 386 Vestibule, 303, 334, 386 Veterinary Medicine, 251, 386 Vibrio, 235, 302, 386 Vibrio cholerae, 302, 386 Villous, 299, 386 Vinca Alkaloids, 386 Vinorelbine, 160, 386 Vinyl Chloride, 146, 386 Viral Hepatitis, 33, 54, 120, 231, 234, 253, 386 Viral Load, 114, 387 Viremia, 214, 387 Virion, 30, 387 Virulence, 75, 89, 378, 382, 387 Viscosity, 6, 89, 91, 370, 387 Vital Capacity, 39, 181, 321, 387 Vitamin A, 9, 56, 148, 370, 387 Vitreous, 217, 302, 311, 339, 361, 369, 387 Vitreous Body, 302, 369, 387 Vitreous Hemorrhage, 311, 387 Vitreous Humor, 217, 369, 387 Vitro, 11, 13, 17, 20, 21, 24, 25, 29, 30, 31, 32, 33, 36, 42, 45, 47, 48, 50, 53, 56, 57,

58, 62, 64, 73, 74, 81, 82, 129, 153, 156, 208, 226, 323, 328, 333, 360, 371, 378, 379, 387 W Waiting Lists, 33, 387 Weight Gain, 5, 187, 319, 387 Weight Perception, 170, 387 White blood cell, 289, 327, 339, 342, 346, 347, 350, 359, 387 Windpipe, 357, 381, 387 Withdrawal, 41, 387 Wound Healing, 12, 34, 49, 54, 57, 59, 67, 187, 212, 213, 300, 303, 320, 335, 343, 387 X Xenobiotics, 226, 387 Xenograft, 289, 388 Xerostomia, 231, 239, 240, 388 X-ray, 179, 180, 190, 203, 225, 262, 296, 299, 305, 315, 322, 337, 342, 351, 366, 367, 371, 388 X-ray therapy, 337, 388 Y Yeasts, 298, 321, 357, 388 Z Zonules, 217, 388 Zygote, 306, 362, 388 Zymogen, 362, 364, 388

Index 411

412

Fibrosis

Fibrosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cystic Fibrosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Pulmonary Fibrosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Influenza A - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Facial Paralysis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Wine - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Breast Augmentation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lipomas - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Barbiturates - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cephalexin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Body Dysmorphic Disorder: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lymphedema - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Dermabrasion: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Septra: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Vaginitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Feet - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Glioblastoma Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Female Infertility - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Living Will - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hip Pain: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Benzene - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Erythema Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Fibrosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cystic Fibrosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Pulmonary Fibrosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Influenza A - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Facial Paralysis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Wine - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Breast Augmentation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lipomas - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Barbiturates - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cephalexin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Body Dysmorphic Disorder: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lymphedema - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Dermabrasion: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Septra: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Vaginitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Feet - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Glioblastoma Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Female Infertility - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Living Will - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hip Pain: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Benzene - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Erythema Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Recommend Documents