CYSTIC FIBROSIS A
3-in-1
Medical
Reference
A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES
CYSTIC FIBROSIS A BIBLIOGRAPHY AND DICTIONARY FOR PHYSICIANS, PATIENTS, AND GENOME RESEARCHERS
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 7404 Trade Street San Diego, CA 92121 USA Copyright ©2007 by ICON Group International, Inc. Copyright ©2007 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., 1960Cystic Fibrosis: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers/ James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11364-3 1. Cystic Fibrosis-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cystic 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.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Chaired Professor of Management Science at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 7404 Trade Street San Diego, CA 92121 USA Fax: 858-635-9414 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CYSTIC FIBROSIS ........................................................................................ 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Cystic Fibrosis? ................................................................................................................ 3 How Common Is Cystic Fibrosis?.................................................................................................. 4 What Genes Are Related to Cystic Fibrosis? ................................................................................. 4 How Do People Inherit Cystic Fibrosis?........................................................................................ 4 Where Can I Find Additional Information about Cystic Fibrosis?................................................ 5 References....................................................................................................................................... 7 What Is the Official Name of the CFTR Gene?.............................................................................. 8 What Is the Normal Function of the CFTR Gene? ........................................................................ 8 What Conditions Are Related to the CFTR Gene? ........................................................................ 8 Where Is the CFTR Gene Located? ................................................................................................ 9 References....................................................................................................................................... 9 Federally Funded Research on Cystic Fibrosis............................................................................. 10 The National Library of Medicine: PubMed ................................................................................ 68 CHAPTER 2. ALTERNATIVE MEDICINE AND CYSTIC FIBROSIS...................................................... 112 Overview.................................................................................................................................... 112 National Center for Complementary and Alternative Medicine................................................ 112 Additional Web Resources ......................................................................................................... 149 General References ..................................................................................................................... 150 CHAPTER 3. PATENTS ON CYSTIC FIBROSIS .................................................................................. 151 Overview.................................................................................................................................... 151 Patent Applications on Cystic Fibrosis...................................................................................... 151 Keeping Current ........................................................................................................................ 157 CHAPTER 4. BOOKS ON CYSTIC FIBROSIS ...................................................................................... 158 Overview.................................................................................................................................... 158 Book Summaries: Online Booksellers......................................................................................... 158 The National Library of Medicine Book Index ........................................................................... 164 CHAPTER 5. MULTIMEDIA ON CYSTIC FIBROSIS ........................................................................... 167 Overview.................................................................................................................................... 167 Bibliography: Multimedia on Cystic Fibrosis ............................................................................ 167 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 170 Overview.................................................................................................................................... 170 The Basics: Genes and How They Work..................................................................................... 170 Genetic Mutations and Health................................................................................................... 181 Inheriting Genetic Conditions ................................................................................................... 187 Genetic Consultation ................................................................................................................. 195 Genetic Testing .......................................................................................................................... 197 Gene Therapy ............................................................................................................................. 203 The Human Genome Project and Genomic Research................................................................. 206 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 209 Overview.................................................................................................................................... 209 NIH Guidelines.......................................................................................................................... 209 NIH Databases........................................................................................................................... 210 Other Commercial Databases..................................................................................................... 213 The Genome Project and Cystic Fibrosis ................................................................................... 213 APPENDIX C. PATIENT RESOURCES .............................................................................................. 217 Overview.................................................................................................................................... 217 Patient Guideline Sources.......................................................................................................... 217
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Finding Associations.................................................................................................................. 220 Resources for Patients and Families........................................................................................... 221 ONLINE GLOSSARIES................................................................................................................ 222 Online Dictionary Directories ................................................................................................... 226 CYSTIC FIBROSIS DICTIONARY ............................................................................................ 227 INDEX .............................................................................................................................................. 299
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FORWARD In March 2001, the National Institutes of Health issued the following warning: “The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.”1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with cystic 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 cystic 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 cystic fibrosis, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of cystic fibrosis. 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 cystic 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 cystic 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. We hope these resources will prove useful to the widest possible audience seeking information on cystic fibrosis. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.
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CHAPTER 1. STUDIES ON CYSTIC FIBROSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cystic fibrosis. For those interested in basic information about cystic fibrosis, we begin with a condition summary published by the National Library of Medicine.
Genetics Home Reference Genetics Home Reference (GHR) is the National Library of Medicine’s Web site for consumer information about genetic conditions and the genes or chromosomes responsible for those conditions. Here you can find a condition summary on cystic fibrosis that describes the major features of the condition, provides information about the condition’s genetic basis, and explains its pattern of inheritance. In addition, a summary of the gene or chromosome related to cystic fibrosis is provided. 2 The Genetics Home Reference has recently published the following summary for cystic fibrosis:
What Is Cystic Fibrosis?3 Cystic fibrosis is an inherited disease of the mucus glands that affects many body systems. In particular, this disorder causes progressive damage to the respiratory system and chronic digestive system problems. Mucus is a slippery substance that lubricates and protects the linings of the airways, digestive system, reproductive system, and other organs and tissues. In people with cystic fibrosis, the body produces mucus that is abnormally thick and sticky. This abnormal mucus can obstruct the airways, leading to severe problems with breathing and bacterial infections 2 3
This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=cysticfibrosis.
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Cystic Fibrosis
in the lungs. These infections cause chronic coughing, wheezing, and inflammation. Over time, mucus buildup and infections result in permanent lung damage, including the formation of scar tissue (fibrosis) and cysts in the lungs. Most people with cystic fibrosis also have digestive problems because thick, sticky mucus interferes with the function of the pancreas. The pancreas is an organ that produces insulin (a hormone that helps control blood sugar levels) and enzymes that help digest food. Mucus blocks the ducts of the pancreas, preventing these enzymes from reaching the intestines to aid digestion. Problems with digestion can lead to diarrhea, malnutrition, poor growth, and weight loss. Some babies with cystic fibrosis have meconium ileus, a blockage of the intestine that occurs shortly after birth. Men with cystic fibrosis are often unable to father a child (infertile) because the tubes that carry sperm (the vas deferens) are blocked by mucus and do not develop properly. Infertility is also possible, though less common, in women with cystic fibrosis.
How Common Is Cystic Fibrosis? Cystic fibrosis is a common genetic disease in the Caucasian (white) population in the United States. The disease occurs in about 1 in 3,200 Caucasian newborns. Cystic fibrosis is less common in other ethnic groups, affecting 1 in 15,000 African Americans and 1 in 31,000 Asian Americans.
What Genes Are Related to Cystic Fibrosis? Mutations in the CFTR (http://ghr.nlm.nih.gov/gene=cftr) gene cause cystic fibrosis. The CFTR gene provides instructions for making a channel that transports negatively charged particles called chloride ions into and out of cells. The flow of chloride ions helps control the movement of water in tissues and regulates the fluid consistency of mucus. Mutations in the CFTR gene disrupt the normal function of this channel, preventing the usual flow of chloride ions and water. As a result, cells that line the passageways of the lungs, pancreas, and other organs produce mucus that is abnormally thick and sticky. This mucus obstructs the airways and glands, causing the characteristic signs and symptoms of cystic fibrosis. Other genetic and environmental factors likely influence the course of the condition. For example, mutations in genes other than CFTR might help explain why some people with cystic fibrosis are more severely affected than others. Most of these genetic changes have not been identified, however.
How Do People Inherit Cystic Fibrosis? This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not show signs and symptoms of the disorder.
Studies
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Where Can I Find Additional Information about Cystic Fibrosis? You may find the following resources about cystic fibrosis helpful. These materials are written for the general public. NIH Publications - National Institutes of Health •
National Center for Biotechnology Information: Genes and Disease: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gn d.section.168
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National Heart, Lung, and Blood Institute: http://www.nhlbi.nih.gov/health/dci/Diseases/cf/cf_what.html
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National Human Genome Research Institute: http://www.genome.gov/10001213 MedlinePlus - Health Information
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Encyclopedia: Cystic Fibrosis: http://www.nlm.nih.gov/medlineplus/ency/article/000107.htm
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Encyclopedia: Cystic fibrosis - nutritional considerations: http://www.nlm.nih.gov/medlineplus/ency/article/002437.htm
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Encyclopedia: Cystic fibrosis - resources: http://www.nlm.nih.gov/medlineplus/ency/article/002176.htm
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Health Topic: Cystic Fibrosis: http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html
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Health Topic: Newborn Screening: http://www.nlm.nih.gov/medlineplus/newbornscreening.html
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Tutorials: Cystic Fibrosis: http://www.nlm.nih.gov/medlineplus/tutorials/cysticfibrosis/htm/index.htm Educational Resources - Information Pages
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American College of Obstetricians and Gynecologists: http://www.acog.com/from_home/wellness/cf002.htm
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Centre for Genetics Education: http://www.genetics.com.au/factsheet/33.htm
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Children's Hospital Boston: http://www.childrenshospital.org/az/Site1711/mainpageS1711P0.html
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Emory University School of Medicine: http://www.genetics.emory.edu/pdf/Emory_Human_Genetics_Cystic_Fibrosis_Carrier .PDF
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KidsHealth from the Nemours Foundation: http://kidshealth.org/kid/health_problems/heart/cystic_fibrosis.html
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Madisons Foundation: http://www.madisonsfoundation.org/content/3/1/display.asp?did=73
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Merck Manual of Medical Information, Second Home Edition: http://www.merck.com/mmhe/sec04/ch053/ch053a.html
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New York Online Access to Health (NOAH): http://www.noah-health.org/en/lung/conditions/cystic/
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Office of Science, U.S. Department of Energy: http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/cf.shtml
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Orphanet: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=586
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Pacific Northwest Regional Genetics Group (PacNoRGG): http://mchneighborhood.ichp.edu/pacnorgg/media/CysticFibrosis/BothCarriers.pdf
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Save Babies Through Screening Foundation, Inc.: http://www.savebabies.org/diseasedescriptions/cysticfibrosis.php
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The Cleveland Clinic Health Information Center: http://www.clevelandclinic.org/health/health-info/docs/2300/2372.asp?index=9358
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The Wellcome Trust: http://genome.wellcome.ac.uk/doc_WTD020856.html
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Virginia Department of Health: http://www.vahealth.org/genetics/ParentfactsPDF/Cystic%20Fibrosis%20%20Parent%20Fact%20Sheet.pdf Patient Support - for Patients and Families
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American Lung Association: http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=35042
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Canadian Cystic Fibrosis Foundation: http://www.cysticfibrosis.ca/
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Cystic Fibrosis Foundation: http://www.cff.org
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Cystic Fibrosis Trust (UK): http://www.cftrust.org.uk/
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March of Dimes: http://www.marchofdimes.com/pnhec/4439_1213.asp
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National Organization for Rare Disorders: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Cystic+Fibrosis
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Resource list from the University of Kansas Medical Center: http://www.kumc.edu/gec/support/cystic_f.html
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Professional Resources You may also be interested in these resources, which are designed for healthcare professionals and researchers. •
Gene Reviews - Clinical summary: http://www.genetests.org/query?dz=cf
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Gene Tests - DNA tests ordered by healthcare professionals: http://www.genetests.org/query?testid=2220
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Genetic Tools - Teaching cases: http://www.genetests.org/servlet/access?fcn=y&filename=/tools/cases/cf-12/
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ACTion Sheets - Newborn screening follow up (1 link): http://ghr.nlm.nih.gov/condition=cysticfibrosis/show/ACTion+Sheets;jsessionid=F3A 4EE5C00DA4C61FDE029F99A80F3DE
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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22cystic+fibrosis%22?recruiting=false
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PubMed - Recent literature: http://ghr.nlm.nih.gov/condition=cysticfibrosis/show/PubMed;jsessionid=F3A4EE5C0 0DA4C61FDE029F99A80F3DE
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Online Books - Medical and science texts: http://books.mcgrawhill.com/getommbid.php?isbn=0071459960&template=ommbid&c=201
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OMIM - Genetic disorder catalog: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=219700
References These sources were used to develop the Genetics Home Reference condition summary on cystic fibrosis. •
Accurso FJ. Update in cystic fibrosis 2005. Am J Respir Crit Care Med. 2006 May 1;173(9):944-7. Review. No abstract available. PubMed citation
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Gene Review
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Merlo CA, Boyle MP. Modifier genes in cystic fibrosis lung disease. J Lab Clin Med. 2003 Apr;141(4):237-41. Review. PubMed citation
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Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003 Feb 22;361(9358):681-9. Review. PubMed citation
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Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005 May 12;352(19):19922001. No abstract available. PubMed citation
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Scriver, Charles R; The metabolic & molecular bases of inherited disease; 8th ed.; New York : McGraw-Hill, c2001. p5121-5161. NLM Catalog
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Cystic Fibrosis
A summary of the gene related to cystic fibrosis is provided below:
What Is the Official Name of the CFTR Gene?4 The official name of this gene is “cystic fibrosis transmembrane conductance regulator (ATPbinding cassette sub-family C, member 7).” CFTR is the gene's official symbol. The CFTR gene is also known by other names, listed below.
What Is the Normal Function of the CFTR Gene? The CFTR gene provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports negatively charged particles called chloride ions into and out of cells. The transport of chloride ions helps control the movement of water in tissues and maintain the fluidity of mucus and other secretions. Mucus is a slippery substance that lubricates and protects the lining of the airways, digestive system, reproductive system, and other organs and tissues. The CFTR protein also regulates the function of other channels, such as those that transport positively charged particles called sodium ions across cell membranes. These channels are necessary for the normal function of organs such as the lungs and pancreas.
What Conditions Are Related to the CFTR Gene? Congenital Bilateral Absence of the Vas Deferens - Caused by Mutations in the CFTR Gene Many CFTR mutations have been identified in males with congenital bilateral absence of the vas deferens. Most often, affected males have a mutation that allows partial function of one copy of the CFTR gene in each cell and a cystic fibrosis-causing mutation in the other copy of the gene. Mutations in the CFTR gene disrupt the function of the chloride channel, preventing the usual flow of chloride ions and water into and out of cells. As a result, cells in the male genital tract produce mucus that is abnormally thick and sticky. This mucus interferes with the development of the tubes that carry sperm from the testes (the vas deferens). Because sperm cannot be transported to become part of semen, men with congenital bilateral absence of the vas deferens are unable to father a child (infertile). Cystic Fibrosis - Caused by Mutations in the CFTR Gene Many CFTR mutations have been identified in males with congenital bilateral absence of the vas deferens. Most often, affected males have a mutation that allows partial function of one 4
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=cftr;jsessionid=F3A4EE5C00DA4C61FDE029F99A80F3DE.
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copy of the CFTR gene in each cell and a cystic fibrosis-causing mutation in the other copy of the gene. Mutations in the CFTR gene disrupt the function of the chloride channel, preventing the usual flow of chloride ions and water into and out of cells. As a result, cells in the male genital tract produce mucus that is abnormally thick and sticky. This mucus interferes with the development of the tubes that carry sperm from the testes (the vas deferens). Because sperm cannot be transported to become part of semen, men with congenital bilateral absence of the vas deferens are unable to father a child (infertile). Other Disorders - Associated with the CFTR Gene More than 1,000 mutations in the CFTR gene have been identified in people with cystic fibrosis. Most of these mutations change a single protein building block (amino acid) in the CFTR protein or delete a small amount of DNA from the CFTR gene. The most common mutation, called delta F508, is a deletion of one amino acid at position 508 in the CFTR protein. The altered channel breaks down shortly after it is made, so it never reaches the cell membrane to transport chloride.
Where Is the CFTR Gene Located? Cytogenetic Location: 7q31.2 Molecular Location on chromosome 7: base pairs 116,907,252 to 117,095,950
The CFTR gene is located on the long (q) arm of chromosome 7 at position 31.2. More precisely, the CFTR gene is located from base pair 116,907,252 to base pair 117,095,950 on chromosome 7.
References These sources were used to develop the Genetics Home Reference gene summary on the CFTR gene. •
Cohn JA. Reduced CFTR function and the pathobiology of idiopathic pancreatitis. J Clin Gastroenterol. 2005 Apr;39(4 Suppl 2):S70-7. Review. PubMed citation
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Cuppens H, Cassiman JJ. CFTR mutations and polymorphisms in male infertility. Int J Androl. 2004 Oct;27(5):251-6. Review. PubMed citation
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Gadsby DC, Vergani P, Csanady L. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature. 2006 Mar 23;440(7083):477-83. Review. PubMed citation
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Gene Review
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Kulczycki LL, Kostuch M, Bellanti JA. A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations. Am J Med Genet. 2003 Jan 30;116A(3):262-7. Review. PubMed citation
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Nick JA, Rodman DM. Manifestations of cystic fibrosis diagnosed in adulthood. Curr Opin Pulm Med. 2005 Nov;11(6):513-8. Review. PubMed citation
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Noone PG, Knowles MR. 'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations. Respir Res. 2001;2(6):328-32. Epub 2001 Aug 9. Review. PubMed citation
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Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005 May 12;352(19):19922001. No abstract available. PubMed citation
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Scriver, Charles R; The metabolic & molecular bases of inherited disease; 8th ed.; New York : McGraw-Hill, c2001. p5134-5161. NLM Catalog
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Vankeerberghen A, Cuppens H, Cassiman JJ. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. J Cyst Fibros. 2002 Mar;1(1):13-29. Review. PubMed citation
Federally Funded Research on Cystic Fibrosis The U.S. Government supports a variety of research studies relating to cystic fibrosis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.5 CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP 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 cystic 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 cystic fibrosis. The following is typical of the type of information found when searching the CRISP database for cystic fibrosis:
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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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Project Title: A 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 2005; Project Start 01-APR-2002; Project End 31-MAR-2007 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 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.
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Project Title: A NEW PATHWAY FOR NEUTROPHIL-INDUCED AIRWAY INFLAMMATION Principal Investigator & Institution: Blalock, J Edwin.; Professor; Physiology and Biophysics; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2010 Summary: (provided by applicant): Under certain circumstances, polymorphonuclear leukocyte (PMN) recruitment to sites of airway inflammation can lead to tissue damage via the production of proteases, reactive oxygen species, proinflammatory cytokines and chemokines. PMN are thought to play a role in acute lung diseases as well as chronic obstructive pulmonary diseases and contribute to inflammation and lung damage in cystic fibrosis. We herein describe a novel pathway of PMN influx and damage to the airways that may represent a new therapeutic target for certain pulmonary diseases. In particular, when collagen is chemically or enzymatically degraded a tripeptide, PGP, is generated that is chemotactic for PMN in vitro. In vivo, airway exposure to PGP elicits a marked influx of PMN, but not monocytes. More chronic airway exposure to PGP causes alveolar enlargement and right ventricular hypertrophy. Using electrospray ionization-liquid chromatography- mass spectrometry (ESI-LC-MS/MS), PGP is detected in the airways of animals exposed to endotoxin (LPS). In addition, the peptide substantially contributes to PMN influx into inflamed airways. The chemotactic activity
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of PGP apparently results from an extraordinary structural relatedness to a receptor binding motif of CXC chemokines, like IL-8 that contain this sequence or a close analog. We have designed a novel peptide with the sequence arginine-threonine-arginine (RTR) that binds PGP and potently blocks the peptide's in vitro chemotactic activity and in vivo pathophysiologic effects. RTR also inhibits CXC chemokine activity apparently as a result of the shared structure between PGP and the chemokines. Thus, RTR represents a potential therapeutic agent that can block both the chemokine and PGP pathways of inflammation. These results have led to the following goals for this application. 1. Determine whether PGP binds CXC chemokine receptors (R) and activates CXCR coupled effector pathways. 2. Evaluate the spectrum of PGP-containing peptides that are produced during airway inflammation and whether PGP recruits PMN to the airways during acute inflammation. 3. Determine whether PMN are necessary for PGPmediated alveolar enlargement and right ventricular hypertrophy. 4. Evaluate the relative pathophysiologic roles of PGP as compared to CXC chemokines in a model of persistent LPS-mediated pulmonary disease. 5. Test RTR as an antagonist of the PGP and CXC chemokine pathways in the LPS-mediated pulmonary disease model. •
Project Title: ANALYSIS OF P. AERUGINOSA GENOME DIVERSITY AND EVOLUTION Principal Investigator & Institution: Lory, Stephen; Professor; Microbiology and Molecular Genetics; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 01-AUG-2004; Project End 31-JUL-2008 Summary: (provided by applicant): Pseudomonas aeruginosa, a common inhabitant of water and soil, is also responsible for a range of serious human infections including the chronic respiratory disease of patients with cystic fibrosis (CF). The goal of this proposal is to apply molecular tools to define genetic variations within the genomes of various P. aeruginosa isolates. The project will test the hypothesis that unlike most strains of P. aeruginosa, the flexible gene pool of strains that are capable of colonizing patients with CF, consists of a specific repertoire of genes encoded within horizontallyacquired genes, often present in genomic islands. Moreover, during the chronic phase of infection these strains accumulate pathoadaptive mutations in the P. aeruginosa genome, which allow the bacteria to persist for many years in the respiratory tract. First, using DNA microarrays, analyzing variable segments of DNA by PCR, applying a targeted DNA capture method, and a differential hybridization strategy, we will identify genes in environmental and clinical strains which are not part of the core gene set and therefore may reside in genomic islands. A DNA microarray will be constructed which consist entirely of the genes from this flexible gene pool and it will be used to further analyze the changes in the genomes of a large set of CF isolates, including established lineages of early and late isolates from individual CF patients. The array will be also used to generate a transcriptome of in vivo expressed genes within the CFspecific islands, which will be used to guide the subsequent prioritization of relevant genes. In the second aim, those genomic island-containing genes that are (i) present in great majority of CF isolates, and (ii) expressed in animal models of infection, will be deleted or individual genes will be mutagenized. The effect of these mutations on the virulence of P. aeruginosa will be assessed in two animal models of respiratory infection. In the third aim, the appearance of point mutations in the genome will be also monitored in the clones of P. aeruginosa isolated over several years from individual CF patients. These mutations may be a required for P. aeruginosa to cause a chronic, longlasting infection in the CF respiratory tract. This hypothesis will be tested in a rat chronic infection model, where accumulation of mutations will be compared to those
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seen in human infections. The results of the studies proposed in this application should provide new insights into the evolution of a highly successful opportunistic pathogen and shed light on some unexpected virulence mechanisms that function during chronic respiratory tract infections. Moreover, findings from this work should greatly supplement the currently available genomic resources for the research community, particularly those who work with different P. aeruginosa isolates. The availability of a "virtual genome", based on complete or partially-completed genome sequences as well as sequences of horizontally-acquired islands, should result in an improved understanding of the interplay between strain specific and core virulence determinants. •
Project Title: ANALYSIS OF UBIQUITINATION ENZYMES IN C. ELEGANS Principal Investigator & Institution: Boyd, Lynn; Biological Sciences; University of Alabama in Huntsville 301 Sparkman Drive Huntsville, Al 35899 Timing: Fiscal Year 2005; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Protein localization, activity, and degradation are often controlled by post-translational modifications. One such modification is the covalent attachment of the small protein, ubiquitin. The work proposed here focuses on mechanistic aspects of protein ubiquitination. Ubiquitin is a highly conserved protein, with greater than 90% identity between ubiquitins of different species. The nematode, Caenorhabditis elegans, will be used as a model system for understanding the ubiquitination pathway. C. elegans provides an excellent system for this type of study because the genome is sequenced and annotated, a collection of ORF clones is available, a large database of known mutant phenotypes exists and many genetic and cell biological tools are available for studying cellular pathways. Since ubiquitination has been implicated in diseases such as breast cancer, Parkinson's disease, and Cystic Fibrosis it is important to have an understanding of the basic mechanisms of ubiquitination. Ubiquitination is typically achieved via a three-step pathway utilizing the E1 ubiquitin activating enzyme (E1), the E2 ubiquitin conjugating enzymes (Ubc), and the E3 ubiquitin ligases (E3). Interactions among the Ubcs and E3s are important for selecting which target proteins will be modified and for determining the nature of ubiquitination on the target protein. In addition, some Ubcs are known to associate with Ubc variants (Uev). Our preliminary studies on the ubiquitination pathway in C. elegans have included two-hybrid interaction studies and RNAi analysis of the Ubcs and E3s. In addition, an in vitro system for studying ubiquitination by C. elegans proteins has been developed. These studies will be extended via the following four specific aims. First, a yeast two-hybrid screen will used to test for interactions among the C. elegans Ubcs and Uevs. Identified interactions will be followed up by in vitro ubiquitination assays. Second, mutant analysis of Ubcs will be continued using varied RNAi conditions and available mutant alleles. Third, potential Ubc-E3 interactions will be identified using a two-hybrid screen. Again, these interactions will be tested using the in vitro ubiquitination assay. Fourth, the two interacting pairs, UBC-13 with UBC-1 and UBC-13 with UEV-1, will be studied in vitro to determine the nature of those interactions and how they affect E3 interaction and ubiquitin chain formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANTIBIOTIC-MEDIATED ADAPTATION OF PSEUDOMONAS AERUGINOSA Principal Investigator & Institution: Hoffman, Lucas R.; Pediatrics; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 15-JUL-2005; Project End 31-MAY-2008
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Summary: (provided by applicant): This application describes a 5-year plan to establish an independent career in academic pediatric pulmonology. The candidate's long-term goal is to develop an interdisciplinary research program focusing on microbial pathogenesis in lung infections while maintaining a clinical practice encompassing 20% of the candidate's time. The training environment consists of the laboratory of Dr. Samuel Miller at the University of Washington and the Pulmonary Division at Children's Hospital & Regional Medical Center, both in Seattle. The candidate will expand his research expertise through a project with basic and translational components, augmented by collaboration and advising from senior scientists and clinicians. The formation of bacterial biofilms is associated with antibiotic resistance. One of the best-studied model systems is the chronic Pseudomonas aeruginosa airway infection in people with cystic fibrosis (CF). P. aeruginosa infects CF airways as a biofilm, and it adapts to the CF airway environment during infection. These adaptations affect bacterial responses to antibiotics. Preliminary data demonstrate that P. aeruginosa responds specifically to subinhibitory concentrations of the antibiotic tobramycin with increased biofilm formation. Tobramycin-induced biofilms are more resistant to further antibiotic challenge. Preliminary evidence suggests a role for two cell signaling systems, quorum sensing and the cyclic diguanylate pathway, in the response to tobramycin. Published data led to the hypothesis that responses to tobramycin vary among CF P. aeruginosa isolates, with variable effects on progression of lung disease. We propose to determine the molecular mechanism of the biofilm response of a laboratory strain of P. aeruginosa to tobramycin using available resources (Specific Aim 1). The clinical relevance of this response will then be determined by examining archived clinical isolates from CF patients, as well as environmental strains of P. aeruginosa (Specific Aim 2). The ultimate goal of this project is to identify novel therapeutic targets to inhibit the development of antibiotic resistance, and to aid eradication of chronic infections. The techniques and environments in this proposal are ideal for preparing for a career in the study of lung infections in children. •
Project Title: ANTI-INFLAMMATORY ROLE OF MUC1 MUCIN Principal Investigator & Institution: Kim, K Chul.; Professor; Lovelace Biomedical & Environmental Res 2425 Ridgecrest Drive, S.E. Albuquerque, Nm 87108 Timing: Fiscal Year 2006; Project Start 03-FEB-2006; Project End 31-DEC-2010 Summary: (provided by applicant): Pseudomonas aeruginosa (PA) is an opportunistic bacterial pathogen responsible for a number of clinically important lung diseases including pneumonia and cystic fibrosis (CF). In the case of CF, the major cause of morbidity and mortality among afflicted patients is airway obstruction due to the presence of thick and tenacious mucus that becomes heavily infected with PA. Because PA exposure occurs in the respiratory system of both normal and CF individuals, "selective"' infection by this pathogen among CF patients suggests the presence of a disease-causing mechanism that is not present in non-CF airways. A number of different theories have been proposed to account for the etiology of CF. Our laboratory made the interesting observation that MUC1 mucin on the surface of airway epithelial cells is a specific binding site for PA mediated through bacterial flagellin. The structure of the MUC1 glycoprotein suggests that it acts as a receptor to transmit signals intracellularly following interaction with flagellin. Using mice genetically modified to block MUC1 expression (MUC1 knockout mice), our preliminary studies showed that, compared with wild type mice, Muc1 knockout animals exhibited increased PA clearance from the lungs and greater recruitment of airway leukocytes and higher levels of the proinflammatory cytokines in bronchoalveolar lavage fluid following PA flagellin stimulation. Interestingly, TLR5 is another cell surface receptor that generates an
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intracellular signaling pathway following binding to flagellin. Based on this similarity, we conducted additional experiments to investigate the functional relationship between MUC1 and TLR5. We observed that expression of MUC1 inhibited the flagellin-TLR5 signaling pathway in normal lung cells but not CF airway epithelial cells. Based on these results, we formed the hypothesis that MUC1 is an anti-inflammatory cell surface receptor that acts, at least in part, through antagonism of flagellin-TLR5 signaling. In this proposal, we will test our theory by determining the mechanisms by which MUC1 attenuates TLR5 signal transduction. Successful completion of this project will provide important insights for the role of MUC1 in inflammation, innate immunity, and the early stages of PA infection in CF. •
Project Title: BASIC AND CLINICAL STUDIES OF CYSTIC FIBROSIS Principal Investigator & Institution: Frizzell, Raymond A.; Professor and Chairman; Cell Biology and Physiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2005; Project Start 15-SEP-2005; Project End 31-JUL-2010 Summary: A Cystic Fibrosis Research Center has existed at the University of Pittsburgh since 1997, although its structure and support mechanisms have, and continue to, change. The current center gathers over $9.6M in external grants and contracts in support of CF-related research. It consists of 39 investigators in 7 departments, whose research is focused in three major areas. The area of Cell and Molecular Biology of CF, directed at studies of CFTR in model systems and human airway cells, is led by Drs. Raymond Frizzell and Joseph Pilewski, and is supported largely through NIH R01 and Cystic Fibrosis Foundation (CFF) grants, as well as pharmaceutical industry contracts. This group studies mechanisms of CFTR biogenesis, trafficking and regulation, the role of CFTR in airway cell and pancreatic physiology, airway stem cells, and the epithelial sodium channel (ENaC), its regulation and its relation to the activity of CFTR. Therapeutic approaches evolving from several of these basic studies are being pursued as well. A second research area, Lung Infection and Inflammation, headed by Dr. Jay Kolls, focuses on-the pulmonary inflammatory response to bacterial infection in human airway cell and animal models, defining the underlying mechanisms of these responses and how they can be modified therapeutically. This work is also supported primarily by NIH and CFF grants, and it represents a new and rapidly growing area within the Center. The third and also expanding area of focus is Clinical Research in CF, headed by Drs. Joseph Pilewski and David Orenstein. This group is pursuing several clinical studies that have emerged from the basic science initiatives of the Center, as well as projects within the Therapeutic Development Network (TON) of the CFF; it is supported primarily by CFF grants at present. The proposed CF Research and Translation Core Center will be directed by Dr. Raymond Frizzell, who also directs the CFF-sponsored Research Development Program, a current NIH SCOR entitled 'CFTR in Airway Cell Function', is co-investigator on a T32-supported training program in epithelial cell biology, and participates in two other T32 training programs. Drs. Jay Kolls and Joseph Pilewski will serve as Associate Directors of the Center. The Center will be comprised of three cores other than the Administrative: Human Airway Cell Physiology (Raymond Frizzell and Joseph Pilewski, co-directors), Clinical Studies/Outcomes (Jay Kolls and Joseph Pilewski, co-directors), and Imaging (Simon Watkins, director). In addition, the Core Center will operate a Pilot and Feasibility Program to encourage new ideas and investigators in CF research. Of past P/F projects within the NTH SCOR application, 100% have received NIH R01 grant support and all continue to be involved in CF research. This Center emphasizes the translation of basic knowledge into applied
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therapeutics. The projected funding period should witness the clinical testing of several novel strategies originating at the Center in CF patients. •
Project Title: CF EPITHELIAL CELLS: INTERACTIONS WITH PSEUDOMONAS Principal Investigator & Institution: Prince, Alice S.; Professor; Pediatrics; Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 01-JUL-1991; Project End 31-MAY-2006 Summary: (Applicant's Abstract): The respiratory epithelium provides a major defense mechanism against the many pathogens that are inadvertently inhaled, responding with the expression of chemokines such as IL-8 and mucin. In cystic fibrosis, there is excessive inflammatory response to these organisms, particularly P. aeruginosa, which initiates the airway inflammation characteristic of this disease. In the experiments described, the ligands and receptors involved in this host-pathogen interaction will be defined in detail. Caveolae, spatially organized clusters of membrane glycolipids, scaffolding proteins, and signaling kinases appear to be important in mediating bacterial attachment and directing the epithelial IL-8 response. The components of caveolae that present the GalNAcGal bacterial receptor will be established, and how they may differ in cells with CFTR mutations will be explored. As several different P. aeruginosa ligands interact with epithelial components, additional receptors will be sought, including those which may activate other epithelial signaling cascades. Many of the known P. aerugunosa ligands are glycosylated, such as pilin, flagellin, and lipopolysaccharide (LPS). Exactly how glycosylation affects the adhesin function of these gene products or their ability to stimulate the host immune response is not well established. By using genetically defined mutants of P. aeruginosa, and comparing glycosylated and nonglycosylated ligands, especially flagella, we will determine how glycosylation affects bacterial-epithelial interactions, and if these carbohydrate structures may serve as targets for the development of therapeutic strategies. LPS is an important glycosylated virulence factor that activates both immune and epithelial cells. The role of specific carbohydrate components of P. aeruginosa LPS in pathogenesis will be examined and how LPS carbohydrate side chains alter host pathogen interactions in normal and CF cells will be explored. Other bacterial virulence factors, such as phospholipases, are important is activating epithelial responses. P. aeruginosa express several PLC'S which can interact with membrane components and activate cytokine signaling. Using genetically defined mutants, the contribution of PLC to epithelial damage in normal and CF cells will be examined.
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Project Title: CFTR AND ION CHANNELS: MECHANISM OF INTERACTION Principal Investigator & Institution: Egan, Marie E.; Associate Professor; Pediatrics; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2005; Project Start 07-APR-1998; Project End 31-MAR-2007 Summary: (provided by applicant): Cystic fibrosis (CF), one of the most common genetic disorders in the Caucasian population. Mutations in the gene that encodes for the CFTR are the genetic basis for CF. CFTR is a multifunctional protein that acts as a cAMP-activated CI- channel and an ion conductance regulator. CFTR is a member of the ATP-Binding Cassette Transporter superfamily of transmembrane proteins. This family is characterized by a highly conserved ATP binding cassette known as a nucleotide binding fold (NBF). Many of the disease-producing mutations reside within the NBF domains of CFTR. The first nucleotide binding domain(NBF1) has been identified as an essential region for CFTR's interactions with other ion channels. Our general hypothesis
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is that in CF, there is an inability of CFTR to function as an ion conductance regulator, as well as a cAMP-stimulated CI- channel. We postulate that it is the combination of these functions that leads to ion transport abnormalities and alterations in airway surface fluid that eventually result in lung disease. Therefore, understanding the mechanisms that underlie CFTR's ability to act as a conductance regulator may be extremely important in our basic understanding of the pathophysiology of CF. The proposed studies will examine CFTR's interactions with ion channels concentrating on NBF1, a region implicated in both CFTR's ability to function as a conductance regulator and chloride channel. Specifically, DF508-CFTR, the most common mutation, will be examined. Electrophysiological, biochemical and molecular techniques will be used to determine the effects of the DF508 mutation on CFTR's ability to function as a conductance regulator. The ultimate goal of this project is to apply the insights gained from these basic science studies of CFTR function to improve the clinical management of cystic fibrosis patients. •
Project Title: CFTR PROTEIN INTERACTIONS Principal Investigator & Institution: Milgram, Sharon L.; Professor; Cell and Developmental Biology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2010 Summary: (provided by applicant): Cystic fibrosis (CF) is caused by mutation in the single gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), an apical membrane Cl- channel. Despite extensive study, there are significant gaps in our understanding of how CFTR is synthesized and processed and how CFTR is regulated and functions at the apical membrane. CFTR associates with a number of proteins that facilitate its trafficking or function, but our understanding of these interactions and how they are altered in CF is relatively poor. We find that the actin binding proteins filamin A (FLN-A) and FLN-B associate directly with residues 1-25 of human CFTR. This interaction enhances receptor-stimulated activation of CFTR and a known disease-causing mutation in the N-terminus of CFTR (S13F) decreases the affinity of the interaction. In addition, the half-life of S13F CFTR is significantly decreased when compared to CFTR proteins that can bind FLN. We also find that a novel sorting nexin, SNX27, associates with CFTR. SNX27 accumulates on subapical endosomes and RNA interference-mediated depletion of SNX27 significantly decreased the levels of cell surface-associated CFTR. Since FLNs and SNX27 associate with CFTR at the cell surface or in endosomal compartments, we hypothesize that these novel CFTRinteracting proteins modulate aspects of CFTR internalization and recycling in polarized cells. Therefore, we propose to fully characterize the biological significance of the CFTRFLN and CFTR-SNX27 interactions using biochemical, cellular, and functional assays in airway epithelial cells. Our data suggest that CFTR is tethered to the actin cytoskeleton via two distinct linkages - an N-terminal interaction with FLN and C-terminal interaction with actin-associated PDZ proteins. Therefore we will test the hypothesis that these two cytoskeletal anchors work in concert to stabilize CFTR at the apical membrane of polarized cells. The characterization of protein interactions that modulate CFTR trafficking, stability and/or function provide one prospect for new therapies for CF and will increase our understanding of the trafficking and regulation of this complex epithelial ion channel. Lay Summary: Mutations in CFTR cause the lethal childhood disease, cystic fibrosis; our experiments address the question of how other proteins that bind CFTR alter its function in the human lung.
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Project Title: CHIMERIC BACTERIAL TOXINS AND CANCER THERAPY Principal Investigator & Institution: Dirienzo, Joseph M.; Assistant Dean and Professor; Microbiology; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2008 Summary: (provided by applicant): Recombinant toxins, hybrid proteins composed of a bacterial toxin and either a growth factor or a portion of a recombinant monoclonal antibody, have received significant attention in cancer therapeutics. This application proposes a unique study to develop and evaluate a recombinant toxin based on the similarities between a human digestive enzyme and a bacterial cytotoxin. Human DNase I has been used as a therapeutic agent for the treatment of wounds and ulcers, bronchitis, inflammatory conditions, herpes infection and most notably, cystic fibrosis. The cytolethal distending toxin (Cdt) is a genotoxin, produced by the periodontal pathogen Actinobacillus actinomycetemcomitans. The Cdt contains a subunit protein, CdtB, that has been shown to be a nuclease that is genetically and functionally related to mammalian type I DNases. Human DNase I has 100 to 1000 times the specific activity of CdtB. In contrast, CdtB has a built-in cell delivery system, a functional domain that targets the protein to the cell nucleus and a DMA-damaging activity that leads to the growth arrest or apoptosis of rapidly proliferating epithelial-like cells. Our hypothesis is that chimeras of human DNase I and bacterial CdtB can be genetically constructed to combine potent DNA- damaging activity, cell delivery and nuclear localization mechanisms. The objective of this study is to develop the efficacy of these chimeric proteins for use as the potential anti-cancer cell reagents. The specific aims of the study are: (1) to construct human DNase l/CdtB chimeric genes and site-specific mutants of the chimeras and to isolate the mutant gene products. (2) To compare the in vitro biological activities of the chimeric and mutated chimeric gene products. (3) To evaluate the efficacy of the chimeric and mutant chimeric constructs in cell culture and transfection systems. Mutant chimeric proteins that demonstrate the ability to enter cells and induce cell cycle arrest will be evaluated using a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. If these studies are successful, future applications will be focused on the effects of these mutant chimeras on sqamous carcinoma cells from cancer patients and on tumors in appropriate mouse models.
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Project Title: CLEARANCE OF APOPTOTIC CELLS IN CYSTIC FIBROSIS Principal Investigator & Institution: Vandivier, Richard W.; Medicine; University of Colorado Denver/Hsc Aurora P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2005; 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 anti-
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inflammatory 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 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. •
Project Title: CONTEXTUAL FACTORS IN CYSTIC FIBROSIS CARRIER TESTING Principal Investigator & Institution: Sparbel, Kathleen J H.; None; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2005; Project Start 01-AUG-2004; Project End 31-JUL-2006 Summary: (provided by applicant): The 1997 NIH Consensus Statement on Cystic Fibrosis (CF) testing recommended CF carrier testing for high-risk individuals, pregnant women, and couples planning pregnancy. Informed consent in CF carrier testing is predicated upon individuals making rational decisions based on genetic testing information received in the clinical encounter. The decision making process also involves the interaction of patient and contextual factors within the unique features of decision-making. Little is known about how these factors influence the use of genetic knowledge in the decision making process. The purpose of this study is to describe patient and context variables contributing to decision making in Cystic Fibrosis Carrier Testing (CFCT) in pregnant females in the primary care setting. This descriptive qualitative study will use semi-structured interviews to identify how patients use genetic information of CFCT within the patient's own personal and contextual factors to make CFCT testing decisions in primary care practices in Iowa and Illinois. The study sample will consist of pregnant women receiving prenatal care in a community based clinic or private practice, who are offered CF carrier testing during their pregnancy. Demographic questions will describe the sample, which will be analyzed through descriptive statistics. Qualitative computer software will be used to categorize interview data, which will then be analyzed through content analysis of audiotaped and transcribed interview transcripts and field notes. Understanding patient and contextual factors influencing patient genetic decision-making is important for promoting rational and autonomous patient health care decisions. Understanding patient health care decision-making is key information in building knowledge of patient/health care system interplay and developing patient sensitive health care systems.
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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 2005; Project Start 01-JAN-1983; Project End 31-MAR-2007 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 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.
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Project Title: CYTOSKELETAL LINKING PROTEINS IN LIVER FUNCTION Principal Investigator & Institution: Doctor, Robert B.; Medicine; University of Colorado Denver/Hsc Aurora P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2005; Project Start 15-JUN-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The formation of bile by the liver results from apical secretion of bile salts and organic solutes from hepatocytes and chloride, bicarbonate and water from cholagniocytes. This vectorial secretion requires the strict polarization and coordinated regulation of distinct transporters in both cell types. The distribution and activity of essential transporter proteins in hepatocytes (e.g. multi-drug resistance protein 2; mrp2) and cholangiocytes (e.g. cystic fibrosis transmembrane conductance regulator; CFTR) is regulated through cAMP. Decreased activity or distribution of transporters represents a putative basis of many cholestatic liver diseases. In other cell types, PDZ domain-expressing proteins tether membrane proteins to the cytoskeleton and moderate their distribution, retention, clustering and activity within membrane microdomains. In epithelial cells, Ezrin-Radixin-Moesin binding phosphoprotein 50 (EBP50) has been implicated in modulating cAMP-dependent apical transport events. Recent studies in our laboratory demonstrate EBP50 is highly concentrated at the apical domain of hepatocytes and cholangiocytes. Disruption of the EBP50-CFTR interaction in
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cholangiocytes results in the loss of cAMP activation of CFTR and CFTR-dependent cell volume regulation. A mechanism for EBP50 to amplify these effects on CFTR were revealed in studies that showed EBP50 is capable of oligomerizing both in vitro and in vivo. Hypothesizing that EBP50 serves a pivotal role in the capacity and regulation of bile formation, the proposed studies will (1) characterize the regulation and functional implications of EBP50 oligomerization; (2) delineate the physiologic role of EBP50 in modulating CFTR distribution and activity in cholangiocytes; and (3) compare and contrast the EBP50-CFTR functional paradigm developed cholangiocytes to the functional consequences of the EBP50-mrp2 interaction in hepatocytes. This line of investigation holds great promise in providing novel insights into the mechanisms underlying regulated bile formation and cholestatic liver disease. •
Project Title: DESIGN, PREPARATION, AND ASSAY OF SYNTHETIC CI CHANNEL Principal Investigator & Institution: Gokel, George W.; Professor and Director; Molecular Biol & Pharmacology; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2005; Project Start 01-JUN-2002; Project End 31-JUL-2007 Summary: Channel or "porin" molecules reside in cellular membranes and regulate the flow of cations, anions, water, and other molecular species through the bilayer. While a great deal is known about what channels do (transport rates, kinetic and open-close behavior, ion selectivity), the chemical mechanisms that underlie these processes remain largely obscure. It is clear that channels are critical for cellular regulation and various diseases result from their malfunction. The amino acid sequences of many channel proteins have been analyzed and various domains within the structures have been identified. Recently, crystal structures for the potassium-selective KcsA channel, a mechanosensitive channel, and of a water-transporting pore have also provided important new insight into the three-dimensional arrangement of the proteins. Important mechanistic insights have accompanied these structural developments. Not withstanding these recent advances, functional understanding of channel behavior remains a profound and important challenge. Of all channel types known in nature, perhaps the least is known about anion channels. We have now succeeded in developing a structurally simple, chemically accessible, modular anion channel we believe will be an important tool for understanding anion channel function. We propose here to develop and study our novel, modular, synthetic chloride-conducting channel using a broad range of techniques applied to natural ion and molecular channels. The biomedical importance of chloride channels became apparent when studies on the pathogenesis of cystic fibrosis demonstrated the CFTR, the cystic fibrosis transport regulator, was a chloride ion channel as well as a regulator of other transport systems. The mutations in this protein that result in systic fibrosis produce the commonest fatal genetic disease of Caucasion humans.
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Project Title: DETECTION OF FOLDING DEFECTS IN MUTANT CFTR BY ERQC Principal Investigator & Institution: Cyr, Douglas M.; Associate Professor; Cell and Developmental Biology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2007; Project Start 01-JAN-1998; Project End 31-DEC-2010 Summary: (provided by applicant): Cystic Fibrosis is a fatal lung disease caused by misfolding and premature proteasomal degradation of the mutant Cl- channel CFTRAF508. CFTRAF508 is synthesized in the endoplasmic reticulum (ER), but its
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folding arrests at an unknown intermediate step and it is selected for degradation prior to passage to the plasma membrane (PM). Loss of CFTR function leads to defects in the hydration of mucosal layers that line glands and airways and chronic infections that death occurs due to lung failure. Hope for the treatment of CF comes from observations that folding defects in CFTRAF508 are rescued by compounds that either alter the cellular folding environment. This competitive renewal application for 2RO1 GM56981 seeks to aid in the development of therapeutics to treat Cystic Fibrosis by elucidating defective steps in the CFTRAF508 folding pathway and identifying ER quality control (ERQC) factors that select CFTRAF508 for degradation. The three major objectives of the proposal are as follows 1. We seek to define the mechanism by which mutations in CFTR cause it to misfold and be degraded the ubiquitin proteasome system. 2. CFTR is a polytopic protein that exposes surfaces in the ER lumen, ER membrane, and cytosol. 'Thus, we will identify the components of the ERQC machinery that sense the folded state of different sub-domains in CFTR. Then, we will determine how the action of the ER localized and cytosolic QC factors is coordinated. 3. We propose to apply the knowledge obtained in our basic studies to develop approaches to block the selection of CFTRAF508 for premature degradation and promote its proper folding. Overall, our studies will provide basic information on protein QC that will aid in the development of therapeutics to treat CF. •
Project Title: DEVELOPMENT OF MEMBRANE PROTEIN STRUCTURE Principal Investigator & Institution: Thomas, Philip J.; Professor; Physiology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2005; Project Start 10-FEB-1996; Project End 31-JAN-2008 Summary: (provided by applicant): The long-range project objectives are to understand how folding information is encoded in the sequence of membrane proteins and the means by which the cell recognizes failure of this process. Studies of the cystic fibrosis transmembrane conductance regulator (CFTR) supported by this grant have provided fundamental information relevant to understanding the structure of the nucleotide binding (NBD) and transmembrane (TMD) domains, the kinetic and thermodynamic effects of cystic fibrosis (CF)-causing folding mutants, and the quality control mechanisms that assist folding and recognize misfolding CFTR molecules. Future studies build on this foundation by detailing the folding pathway of the NBD and the final assembly of CFTR domains with each other and with domains of other proteins at the membrane. To this end the four specific aims are to: 1. Characterize the folding pathway of NBD1 and determine the effects of the deltaF508 and other CFmutations. Building on the high resolution structure of CFTR-NBD1, biophysical and biochemical methods will be employed to characterize the pathway(s) of folding and the effects of nucleotide and CF-causing mutations on the pathway. 2. Assess the ability of NBD1 and NBD2 to form dimers and determine the effect of CF-causing mutations on these interactions. Nucleotide binding domains of ABC transporter homologues of the CFTR channel form ATP-dependent dimers, with two nucleotides sandwiched at two active ATPase sites formed at the dimer interface. We will test the hypothesis that CFTR NBD1 and NBD2 form an ATP sandwich dimer with a single active ATPase site and an inactive "regulatory" site. 3. Assess the ability of the NBDs and the transmembrane domains (TMDs) to interact and determine the effect of CF-causing mutations on these interactions. The backbone at the F508 position is critical for NBD1 folding, but the side chain is important for the later folding steps of domain association. We will test the hypothesis that F508 lies at the TMD/NBD1 interface. 4. Assess the ability of the STAS domain of SLC26A3 to bind CFTR and determine the effect of this on CFTR domaindomain association. To understand the coordinated regulation of CFTR channel and
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apical SLC26A anion exchange activity, we will elucidate the molecular mechanism by which the STAS domain of SLC26A3 activates CFTR. To accomplish these four goals, a combination of biochemical, biophysical, and cell biological approaches will be employed. These studies are necessary for and fundamental to a detailed understanding of the mechanisms by which membrane proteins fold. •
Project Title: DIABETES THERAPY TO IMPROVE BMI AND LUNG FUNCTION IN CF Principal Investigator & Institution: Moran, Antoinette M.; Professor and Chief; Pediatrics; University of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070 Timing: Fiscal Year 2005; Project Start 01-JUL-2001; Project End 31-MAY-2007 Summary: The majority of cystic fibrosis (CF) patients now survive beyond childhood, and CF related diabetes (CFRD), due to insulin deficiency, is common. CFRD without fasting hyperglycemia (FH) is found in 25 percent of CF adults and is associated with increased morbidity and mortality. BMI and pulmonary function deteriorate much more rapidly in these patients than in CF patients with normal glucose tolerance. Insulin deficiency alters protein and fat metabolism resulting in loss of weight and lean body mass and contributing to pulmonary disease and clinical decline. Preliminary isotopic data have shown that insulin and, to a lesser extent, the oral diabetes agent repaglinide acutely improve protein synthesis in patients with CFRD without FH. The objective of this research is to recruit 150 adult patients with CFRD without fasting hyperglycemia for a multi-center, twelve month, placebo- controlled intervention trial testing the ability of insulin or repaglinide to improve BMI and stabilize pulmonary function. It will test the hypotheses that: 1. Participants receiving either insulin or repaglinide will increase their BMI compared to control participants. 2. Insulin will be more effective than repaglinide at increasing BMI. 3. The increase in BMI will be primarily due to increased muscle mass. 4. The increase in BMI will be accomplished without significant changes in dietary macronutrient or calorie composition. 5. Insulin or repaglinide therapy will prevent pulmonary function decline compared to both control subjects and to their own baseline as measured the previous year. This will be associated with improvement in NIH clinical score and will be directly related to weight gain and increase in thigh muscle volume. 6. Participants receiving insulin or repaglinide will improve hand grip strength, and this will be directly related to weight gain and increase in thigh muscle volume. If it can be shown that insulin or repaglinide also improves body mass and pulmonary function, it would have a major impact on the current therapy and prognosis for adult CF patients. The question of whether these patients should receive diabetes therapy was given the highest priority for future research funding at a national consensus conference on CFRD
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Project Title: DISSECTING ELECTROSTATIC EFFECTS IN CYSTIC FIBROSIS MUCO Principal Investigator & Institution: Wong, Gerard C.; Materials Science and Engineering; University of Illinois Urbana-Champaign Office of Sponsored Programs & Research Admin Champaign, Il 61820 Timing: Fiscal Year 2005; Project Start 01-AUG-2004; Project End 31-JUL-2007 Summary: (provided by applicant): The accumulation of viscous mucus in the airways is the primary cause of long-term bacterial infections, respiratory failure, and eventually death in cystic fibrosis (CF). The inflammatory response to infections in the airways leads to the pathological release of cytoskeletal proteins, DNA and other
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Cystic Fibrosis
polyelectrolytes, which cause the electrostatic assembly of large aggregates stabilized by cationic ligands in CF mucus, and results in the sequestration of endogenous antibacterial polypeptides and contributes to the loss of antimicrobial function. The long-range goal of this proposal is the rational design of therapeutic strategies in the restoration of antimicrobial function in CF, based on a biophysical understanding of electrostatic interactions in CF mucus. The three specific aims of the proposal are: (1) To determine the ionic strength within the airway surface liquid (ASL) expressed on cultured human airway epithelial cell lines with and without a functioning cystic fibrosis transmembrane conductance regulator (CFTR). (2) To characterize quantitatively the structural form and thermodynamic stability of electrostatic complexes of endogenous antibacterial peptides and anionic polyelectrolytes in the ASL under CF physiological conditions, and design biophysical therapeutic strategies to unbind these sequestered antibacterial peptides. (3) To develop, via directed molecular evolution, an anionic DNAzyme which mimics the biofilm suppression action of cationic lactoferrin, but will not be sequestered due to its opposite charge. •
Project Title: DISSOLUTION OF POLYELECTROLYTE BUNDLES IN AIRWAY FLUIDS Principal Investigator & Institution: Janmey, Paul A.; Professor; Physiology; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2005; Project Start 01-JUN-2001; Project End 31-MAY-2007 Summary: The long term objective of this proposal is to test the hypothesis that the introduction of highly charged anionic polyelectrolytes into lung airway fluid as a result of inflammation and cell death contributes to the pathology of cystic fibrosis. Specifically the work will focus on the polyelectrolyte properties of F-actin and DNA as they relate to the abilities of these polymers to 1) increase the elasticity of CF sputum; 2) inactivate cationic antimicrobial proteins and peptides in the lung epithelium, and 3) interfere with gene therapy strategies that employ DNA-cationic lipid complexes for gene delivery into the epithelium. The experimental work will employ light scattering, fluorescence and polarization microscopy, rheology, and bacterial growth and lysis assays to study purified systems in which F-actin and DNA are caused to form bundles by lysozyme, defensins, histories and other cationic peptides released by epithelial cells and leukocytes. These studies will be expanded into determining how similar effects occur in sputum. Theories developed for polyelectrolyte condensation will be exploited to design soluble, polyvalent anions that independently or in combination with DNA- or actin-directed proteins such as DNAse and gelsolin can dissociate filament bundles and liberate antimicrobial function. The long term outcome of this work would be to determine if strategies based on depolymerizing DNA and cytoskeletal fibers or on dissociating bundles of these filaments by manipulating the ionic environment of airway fluid have potential to alleviate the pathology of CF.
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Project Title: EFFECTS OF PROBIOTICS IN PATIENTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Hibberd, Patricia L.; Professor of Medicine & Pediatrics; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2005; Project Start 15-SEP-2004; Project End 31-JUL-2007 Summary: (provided by applicant): Emergence of antimicrobial resistance is an everincreasing threat to our ability to treat a wide range of infections caused by microbes that thwart or block antimicrobial therapy. Staphylococcus aureus, an organism frequently resistant to multiple antibiotics, is an important early cause of infectious
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morbidity in children with cystic fibrosis (CF), usually occurring before infection with Pseudomonas aeruginosa. Since oropharygeal carriage of S aureus generally precedes infection of the lower airways, eradication of this organism from the throat is of major clinical importance to children with CF. Current strategies, particularly use of antibiotics, often lead to antimicrobial resistance, side effects and relapse. Probiotics, particularly Lactobacillus GG (LGG) are capable of killing various bacteria, including S aureus and P aeruginosa, in vitro, by a variety of mechanisms. Preliminary data from one small study in healthy volunteers suggests that LGG may be able to eradicate nasal carriage of S aureus, although effects on oropharygeal carriage is unknown. We propose to conduct a pilot double-blind randomized placebo controlled clinical trial to refine methodology and determine feasibility of evaluating whether orally administered LGG is effective in eliminating oropharygeal colonization with S aureus in children with CF, without emergence of colonization with P aeruginosa. If safe and effective, LGG may provide an alternative way to eliminate this bacteria without use of antimicrobials that risk emergence of resistant organisms. Forty CF patients will be recruited into the study, 30 will receive oral LGG, 10 will receive matching oral placebo. The specific aims are to: (1) refine methods of administering probiotics and matching placebo, in preparation for future studies that will investigate effects of probiotics on eradication of throat carriage of S aureus; (2) collect pilot data on elimination of oropharyngeal colonization with S aureus to power future studies that will evaluate whether LGG is an effective alternative to antimicrobials; and (3) determine whether LGG colonizes the oropharynx as a first step to exploring potential mechanisms by which LGG may influence mucosal Staphylococcus aureus colonization and (4) explore effects on clinical status (weight gain and pulmonary function). This study has the potential to provide insight into a novel alternative approach to eradicate and prevent the spread of antimicrobial resistant pathogens. •
Project Title: ELECTROYTE TRANSPORT IN SMALL AIRWAYS Principal Investigator & Institution: Quinton, Paul M.; Professor, Nancy Olmsted Endowed Chair i; Pediatrics; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2010 Summary: (provided by applicant): Lung disease in cystic fibrosis (CF) arises from obstruction and destruction of small airways (bronchioles). A fluid layer over the inner bronchiolar epithelial surface is normally the first line of airway defense against inhaled pathogens. Since fluid transport in CF is defective and bronchioles invariably become infected in CF, it is evident that proper fluid transport is essential to respiratory health. Despite the importance of this conclusion, small airways have largely evaded studies of their native fluid transport components because it is very difficult to obtain intact bronchiolar epithelium without destroying it. Recently, we successfully applied techniques to small airways that we developed much earlier for microperfusing single sweat duct tubules. We propose here to determine the properties of fluid transport in freshly isolated native, intact epithelia of bronchioles. In contrast to the common notion that the same cells both secrete and absorb, we now have evidence that this epithelium is made up of distinct secretory and absorptive cells. This proposal will define the previously undetermined basic fluid transport properties of small airway epithelia and test the novel hypothesis that in small airways some cells secrete while others absorb fluid. Three specific aims will use a combination of electrophysiological, RT-PCR gene expression assays, and immunocytochemistry to: 1.) optimize conditions and systems to preserve and examine bronchioles, 2.) determine basic absorptive and secretory properties of small airway epithelia, and 3.) show that there are functionally and
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Cystic Fibrosis
structurally separate zones of absorptive and secretory cells in small airway epithelia. Lay Abstract: The genetic disease of cystic fibrosis (CF) is a rare form of obstructive lung disease in which the very small airways or bronchioles become so damaged and plugged with mucus that the patient dies. Normal bronchioles are hollow with a thin layer of fluid that coats their inner surfaces and helps remove inhaled debris, bacteria, and viruses. The basic problem in CF is abnormal fluid formation, which tells us that problems in the CF lung start in this fluid layer. Studies of small airways in their natural state are difficult, and very few have been attempted. We have applied a micro-method we used on small sweat gland tubes to study small intact bronchiole tubes. We propose to test a new finding that cells that secrete fluid are different from those that absorb fluid as opposed to the common idea that the same cells do both. This work may fundamentally change how we think about how normal bronchioles handle fluid and how bronchioles in CF and other forms of inflammatory lung diseases are destroyed. Correctly understanding this fundamental structure/function is critical to developing effective therapies. •
Project Title: ER ASSOCIATED DEGRADATION OF MEMBRANE PROTEINS IN YEAST Principal Investigator & Institution: Brodsky, Jeffrey L.; Associate Professor; Biological Sciences; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 31-MAY-2010 Summary: (provided by applicant): Cystic fibrosis (CF) is the most common, inherited lethal disease in Caucasians in North America, and arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The majority of disease-causing mutations block the maturation of this secreted protein, such that CFTR becomes trapped in the endoplasmic reticulum (ER) and is degraded by the proteasome. This process is referred to as ER associated degradation (ERAD), and >30 ERAD substrates from yeast to man have been identified, many of which are linked to specific diseases. ERAD substrate selection and targeting are catalyzed by molecular chaperones, but to date it has been difficult to define how and specifically at which step the chaperones impact CFTR degradation. Moreover, it has been challenging to define how a membrane protein, like CFTR, is delivered to the proteasome, and to identify uncharacterized genes required for maximal ERAD efficiency. To surmount existing technical barriers, the PI's laboratory established a yeast CFTR expression system and showed that unique chaperones play distinct roles during ERAD. To identify novel factors that catalyze ERAD, a micro-array "screen" was performed and a chaperone class with no previous connection to ERAD was found to facilitate CFTR degradation in yeast. In parallel with these studies, an in vitro system was established that recapitulates the polyubiquitination of CFTR and a CFTR homologue in yeast membranes. Based on these new data and tools, the goals of this grant application are to determine at which step in the CFTR degradation pathway known and newly identified chaperones function. And, for the first time, the requirements for substrate de-ubiquitination and proteasome targeting during ERAD will be investigated in a defined system. Importantly, data obtained from the in vitro assay will be complemented through in vivo studies in wild type and mutant yeast strains. This project reflects the PI's long-term interest in defining the molecular machines responsible for protein biogenesis in the ER, and this grant application constitutes the primary focus of ongoing research in the PI's laboratory. Finally, the results obtained from the experiments described in this application will direct future efforts to delineate the CFTR maturation pathway in mammalian cells, an effort that is vital as ongoing chaperone-based therapies to treat CF and other protein conformational diseases are entering clinical trials.
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Project Title: ER EXPORT AND THE QUALITY CONTROL CHECKPOINT DURING MEMBRANE PROTEIN BIOGENESIS Principal Investigator & Institution: Miller, Elizabeth A.; Biological Sciences; Columbia Univ New York Morningside Research Administration New York, Ny 100277003 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2011 Summary: (provided by applicant): Eukaryotic cells dedicate significant resources to the deployment of proteins to the membrane compartments that comprise the secretory pathway. Biogenesis of all membrane proteins starts with the folding and assembly of newly synthesized proteins within the endoplasmic reticulum (ER), often with the aid of cellular chaperones. Cells must strike a precise balance between ensuring that only fully folded proteins are allowed to leave the ER and avoiding the accumulation of misfolded proteins within the ER lumen. Uptake of newly synthesized cargo molecules into ERderived transport vesicles only occurs once proteins are fully folded. These transport vesicles, known as COPII vesicles for the cytoplasmic coat proteins that drive membrane curvature and select cargo, thus play a critical role in regulating forward transport of new proteins. We study the close relationship between protein folding and packaging into ER- derived COPII vesicles in the model organism, Saccharomyces cerevisiae. Using a combination of genetics and biochemistry, we aim to define the cellular machinery that acts at the interface between protein folding and ER export. A model for examining this process is the yeast ABC transporter, Yor1, a plasma membrane protein that acts as a drug pump to clear toxic substances from the yeast cytoplasm. Yor1 is a homolog of the human cystic fibrosis transmembrane conductance regulator (CFTR), defects in which cause cystic fibrosis. Deletion of a Phe residue in Yor1, equivalent to the major disease-related mutation in human cystic fibrosis, causes Yor1, like mutant CFTR, to be ER-retained and degraded by the cytoplasmic ubiquitin/proteasome pathway. Thus Yor1 is a useful model that allows the direct comparison of the intracellular itineraries of native and aberrant forms of a single protein. This research proposal consists of four specific aims. (1) To define the molecular mechanisms that drive uptake of Yor1 into COPII vesicles and assess how protein folding influences this event. (2) To determine how cellular chaperones contribute to Yor1 biogenesis and assess how the kinetics of chaperone/client interactions may influence COPII binding and thereby regulate ER export. (3) To identify and characterize novel factors that may facilitate Yor1 biogenesis, including specific membrane chaperones and more general folding factors. (4) To determine the mechanisms by which the unfolded protein response improves the folding and/or transport of misfolded proteins. Ultimately, a better understanding of cellular machinery that acts to regulate protein folding and forward transport may lead to novel therapeutic approaches to treat the many diseases associated with aberrant protein folding within the secretory pathway.
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Project Title: FEVERFEW AND PARTHENOLIDE IN MOUSE MODELS OF CF Principal Investigator & Institution: Berger, Melvin; Professor; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2005; Project Start 15-SEP-2004; Project End 31-JUL-2007 Summary: (provided by applicant): Feverfew (Tanacetum parthenium) has a long history of use for analgesic and anti-inflammatory effects. Some, but not all, controlled trials have shown beneficial effects of feverfew powder or extracts in migraine. Studies which have primarily been done in cell cultures have shown that parthenolide and other sesquiterpene lactones in feverfew extracts may have anti-inflammatory effects mediated by inhibiting the signaling enzyme I-kappa- kinase (I-kappaK) and/or the transcription factor NF-kappaB. However, there have been few studies of the
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importance of these effects in animal models of human disease. Furthermore, it is not clear how the anti-inflammatory effects of feverfew relate to its anti-migraine activities. Cystic Fibrosis (CF) is the most common genetic cause of early death amongst Caucasians. Multiple lines of evidence from human, mouse and cell culture studies all suggest that CF lung disease is characterized by inflammatory responses which are excessive because of exaggerated production of NF-kappaB dependent cytokines and adhesion molecules. Additional evidence suggests that this, in turn, may be due to excessive activation of I-kappaK and depletion of its substrate, I-kappaB, following inflammatory stimuli. Decreases in I-kappaB lead to excessive and prolonged NF-kB activation and excessive NF-kB dependent pro-inflammatory gene transcription. Our hypothesis is that feverfew extracts and parthenolide will attenuate the excessive inflammatory responses in mouse models of CF lung disease by inhibiting I-kappaK activity and/or DNA binding of NF-kappaB. To test this, we will determine the effects of parthenolide and feverfew extracts on I-kappaK activity, I-kappaB protein, NFkappaB and lung and systemic inflammatory responses in CF mice after intratracheal challenge with LPS, acute lung infection with P. aeruginosa (P.a.), and chronic lung infection with P.a. We will also determine if p38 MAP kinase, JNK and/or AP-1 pathways are affected by these potential therapeutic agents. Results of these studies should not only help to define the anti-inflammatory mechanisms of feverfew in vivo, they should also pave the way for clinical trials of feverfew and/or parthenolide in CF and provide a basis for future studies aimed at determining how their antiinflammatory effects relate to their use in migraine. •
Project Title: FUNCTION OF MVFR IN PSEUDOMONAS AERUGINOSA VIRULENCE Principal Investigator & Institution: Rahme, Laurence G.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2011 Summary: (provided by applicant): Infections caused by Pseudomonas aeruginosa are a significant problem in human healthcare. This bacterial pathogen is the principle agent of sepsis in burn patients; of persistent lung infections and mortality in cystic fibrosis patients; of nosocomial infections in HIV and other immune-suppressed patients; and of the outbreak of deleterious multi-drug resistant infections in hospitals. The long-term goal of this proposal is to provide effective and selective therapies that reduce the incidence and complications of human P. aeruginosa infections. This study proposes this goal can be achieved by drugs that prevent or limit the activation of the MvfR/HAQ pathway, and the development of such anti-infective compounds is the immediate goal of this application. This proposal is based on the hypothesis that MvfR, a P. aeruginosa transcriptional regulator, is a candidate target for anti-infective drugs, as it plays a central role in modulating the expression of many QS-controlled virulence-associated factors; and its activation is mediated by its binding to a specific ligand, which is essential for its function. To identify MvfR-pathway inhibitors, and demonstrate their in vivo anti-infective activity, this study proposes three Specific Aims: 1) to confirm the identity of the MvfR ligand, identify its binding site, and determine its mechanism of action; 2) to identify compounds that inhibit the MvfR/HAQ pathway; and 3) to determine the in vivo efficacy and potential feasibility of these inhibitors to limit P. aeruginosa infection in mammals. These aims will be accomplished via three sets of experiments. First, biochemical, mass spectrometric, and molecular genetic analyses will confirm the identity of the P. aeruginosa MvfR-ligand; define the MvfR ligand binding domain; and determine the pqsA promoter sequence recognized and bound by MvfR and the MvfR-ligand complex. Second, biochemical and mass spectrometric analyses
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will identify compounds that prevent ligand-mediated MvfR activation by limiting the synthesis and/or binding of its ligand, and that are metabolically stable in P. aeruginosa. Third, each identified inhibitor will be tested in the Drosophila melanogaster, the mouse full-thickness skin thermal injury, and the mouse neonatal respiratory model, to determine their toxicity, their in vivo efficacy to limit P. aeruginosa infection; and their "immunity" to the development of bacterial resistance. Specific inhibition of a pathway that directly mediates virulence is less likely to generate selective pressure to develop resistance to the inhibitor, than for drugs, including most antibiotics, that reduce bacterial viability. Such targeted inhibitors could significantly enhance the long-term prognosis of burn, cystic fibrosis, and HIV patients. To this end, the results here should enable novel therapies to treat and/or prevent P. aeruginosahuman infections. •
Project Title: FUNDS TO ACQUIRE A JEOL JSM-7401F FESEM Principal Investigator & Institution: Apicella, Michael A.; Professor and Chairman; Microbiology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2007 Summary: (provided by applicant): This proposal requests funds for a JEOL JSM-7401F Field Emission Scanning Electron Microscope with embedded digital imaging, beam decelerating technology and high resolution backscattered electron imaging. The University of Iowa has one SEM (a Hitachi S-4000 acquired in 1989) to serve the entire campus. The current system cannot provide images of immunogold labeled samples at low accelerating voltages and a second system is critically needed because having only one system is severely limiting access by investigators. From February 1, 2004 to January 31, 2005, 87 investigators from 54 faculty labs in 22 departments and 6 colleges used the S-4000 SEM. 30 of the 54 faculty labs have NIH funded research grants totaling over $38,000,000.00 annually. To better support this research, it is critical to have ready access to state-of-the-art instrumentation. Heavy usage requires Investigators to reserve the Hitachi S-4000 SEM 2-3 weeks in advance. The system is made available 24 hrs a day to accommodate investigators. In addition, an average of 20 students a semester enroll in formal Microscopy Research classes. SEM short courses and workshops are also offered on a regular basis. Downtime for maintenance on the S-4000 has been nearly 25% and is due to the combination of very heavy use, difficulty in obtaining replacement parts and inexperienced service support. The new FESEM would be conveniently located in room 80 of the Eckstein Medical Research Building under the supervision of The University of Iowa Central Microscopy Research Facility (CMRF). Administration, maintenance as well as high-level technical assistance and training will be provided by experienced staff. Institutional commitment is strong, providing $39,000.00 in salary support for a Research Assistant and $14,000.00 towards the annual service contract on a continuing basis as well as $12,550.00 to upgrade a cryostage to be used on the JEOL JSM-7401 F. The five NIH funded faculty providing research descriptions are the heaviest users of the S-4000 SEM. Apicella will study human pathogenic bacteria. Welsh will investigate human airway epithelia cell biology in relation to Bardet- Biedl syndrome and other diseases. Grose is involved in determining the mechanism of human herpes virus infections. Wilson examines Leismania compromised human macrophages. Starner will study the relationship of Haemophilus biofilms to infection and inflammation in Cystic Fibrosis patients.
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Project Title: GENE AND PHARMACOLOGICAL THERAPIES FOR CYSTIC FIBROSIS Principal Investigator & Institution: Guggino, William B.; Professor of Physiology and Pediatrics; Physiology; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2005; Project Start 30-SEP-1993; Project End 31-MAR-2009 Summary: (provided by applicant): It is the overall goal of this Center to utilize the strengths of our current CF Research Group in basic and clinical research and patient care to develop gene and pharmacologic therapies for patients with CF. The specific aims are to develop adeno-associated viral vectors as gene therapy agents and to explore new pharmacologic therapies based upon altering expression and trafficking of mutant CFTR. Project by Guggino will develop a new AAV gene therapy vector based on the AAV5 serotype as a new therapy for CF. The aims will be to: assess the efficiency and distribution of vector DNA transfer and to determine the risk of immunologic reactions, alterations in pulmonary function, or spread in distant organs in monkeys. This will be followed by a clinical trial in adult CF patients. Project by Flotte: Adeno-associated virus vectors for CF gene therapy. The primary hypotheses to be tested is that: Aberrant down-regulation of certain anti-protease, anti-inflammatory, and glycosylation-related genes contribute to CF lung disease, and augmentation of these substances will ameliorate the CF lung disease phenotype. Project by Muzyczka will focus on the Biology of AAV. Finally, there are three cores, an Expression, a Vector Core, and an Administration Core.
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Project Title: GENERAL CLINICAL RESEARCH CENTER Principal Investigator & Institution: Horwitz, Ralph I.; Dean; None; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2005; Project Start 06-JAN-1997; Project End 31-MAR-2009 Summary: (provided by applicant) The purpose of this application to seek funding for the renewal of the General Clinical Research Center (GCRC) at Case Western Reserve University (CWRU) School of Medicine. The main GCRC is located at University Hospitals of Cleveland with a satellite at MetroHealth Medical Center (MHMC). In 2002, the GCRC supported 166 protocols for 90 principal investigators representing multiple schools, departments and divisions of CWRU, the Department of Cell Biology at the Cleveland Clinic Foundation, and the Department of Nutrition and Exercise Physiology at Cleveland State University. As a research institute, CWRU's School of Medicine has maintained a tradition of national leadership, including claim to 12 Nobel laureates among its alumni (5) and faculty (7). There are 1,493 full time faculty in the medical school. In 2001, CWRU researchers were funded over $174,000,000 by NIH. These awards include major funding for research in cancer, AIDS, diabetes, cystic fibrosis, hypertension, TB, skin diseases, Alzheimer's disease, cartilage regeneration, airway diseases, neonatal and adult metabolism, functional electric stimulation, perinatal medicine, and genetics defects of various types among others. Fifty-seven CWRU researchers were awarded more than $1 million in NIH support in 2002. In 2002, CWRU ranked 16th among the nations 126 medical schools in NIH support. Fifteen of the school's departments ranked in the top 20 of the corresponding departments. Compared to the last five year renewal, there has been a 17% increase in the number of GCRC investigators and 81% increase in number of protocols utilizing the GCRC which resulted in a 97% increase in the number of publications (from 201). The major areas of research include: 1. Biochemical and molecular enhancement of cancer chemotherapy. 2. Electronic restoration of movement in spinal cord injury and stroke. 3. Molecular
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biology and treatment of cystic fibrosis. 4. Carbohydrate and protein metabolism in pregnancy. 5. Epidemiology, genetics, and pathophysiology of sleep-disordered breathing. 6. Pathophysiology and renal outcomes of human hypertension. 7. Factors affecting feto-placental growth and development. 8. Pathophysiology and treatment of HIV diseases. •
Project Title: GENERATION OF A CF PIG BY SFHR AND NUCLEAR TRANSFER Principal Investigator & Institution: Gruenert, Dieter C.; Professor; California Pacific Med Ctr Res Institute 475 Brannan Street, Suite 220 San Francisco, Ca 94107 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: The development of transgenic mouse models for cystic fibrosis (CF) has been an important contribution to our understanding of CF and of CF transmembrane conductance regulator (CFTR) function. However, because of the dissimilarity between mouse and human anatomy and physiology, there are limitations in what can be discerned about CF pathology and in development of CF therapies. In this context, the advent of successful mammalian animal cloning by nuclear transfer has opened the door to a host of possibilities to develop large animal models for inherited diseases like CF. Recent studies investigating oligonucleotide-based genomic gene targeting suggest that some of these approaches might be effective for modifying somatic nuclei that act as the source of genetic material for nuclear transplantation. Thus it now appears possible to produce a more appropriate animal model of CF. A candidate as an alternative to the mouse model is the pig. The similarity between the human and the pig, both biochemically and physiologically, has been noted on numerous occasions and is at the heart of organ xenotransplantation. The recent sequencing of major portions of pig CFTR (pCFTR) gene has now provided the genetic information necessary to manipulate the pCFTR sequence and generate a transgenic CF animal. The small fragment homologous replacement (SFHR) gene targeting strategy is an oligonucleotide-based approach that has been previously used to modify both human and mouse CFTR by introducing the 3-bp deletion that gives rise to the AF508, CFTR mutation that predominates in the CF patient population. It is therefore well suited to generate transgenic cell lines that can be used for nuclear transplantation. This proposal will employ SFHR to modify pig fetal fibroblasts and introduce the AF508 mutation into the pCFTR. These transgenic donor cells will be clonally enriched by Fluorescence Activated Cell Sorting (FACS) and then be fused with enucleated pig oocytes that will ultimately be used for the generation of the CF pig. The transgenic donor cells will be initially screened by PCR and then evaluated by Southern blot hybridization. Transplanted oocytes will also be PCR screened and then tested in vitro for embryogenic potential. Those oocytes that have demonstrated embryogenic potential will be introduced into surrogate mothers. The development of such a transgenic CF pig will greatly enhance our ability to evaluate CF pathology and will facilitate development of new therapeutic regimens to improve the quality of life of CF patients.
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Project Title: GENERATION STRAINS(RMI)
OF
MEMBRANE
PROTEIN
PRODUCTION
Principal Investigator & Institution: Bowie, James U.; Professor; Chemistry and Biochemistry; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2005; Project Start 23-SEP-2005; Project End 31-JUL-2010 Summary: (provided by applicant): One of the primary barriers to the physical and structural characterization of membrane proteins is their often poor expression with
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standard methods. This project seeks to alleviate this bottleneck by creating E. coli strains that are more effective membrane protein producers. We plan to take a genetic approach, using a powerful selection for membrane protein expression that we have developed. By identifying and characterizing expression mutants we also plan learn more about the major barriers to expression. Our longer term goals are to apply the lessons learned here to other organisms, further broadening the range of membrane proteins that can be expressed at high levels. The specific aims are: Aim I. Find genes that (when over-expressed or mutated) can improve the production of poorly expressed membrane proteins and/or that redirect expression from inclusion bodies into membranes. Aim II. Identify the genes/mutations. Aim III. Employ targeted mutagenesis of the genes identified in Aim II to find even more effective expression mutants. Combine the most effective mutants to build a set of membrane protein expression strains. Aim IV. Characterize the effects of the expression mutants on the steps of membrane protein biogenesis. Relevance to Public Health: Membrane proteins play significant roles in diseases ranging from cystic fibrosis to cancer, and are the targets of the vast majority of drugs. Our understanding of these diseases and our ability to develop new drugs has been hampered by our inability to obtain sufficient quantities of many membrane proteins for detailed study. This project is an effort to reduce this problem by converting bacteria into membrane protein production factories. •
Project Title: GINSENG AS AN ANTI-BACTERIAL AGENT AGAINST P. AERUGINOSA Principal Investigator & Institution: Mathee, Kalai; Biological Sciences; Florida International University Office of Sponsored Research Administration Miami, Fl 33199 Timing: Fiscal Year 2005; Project Start 01-FEB-2005; Project End 31-JAN-2008 Summary: (provided by applicant): The main intention of this grant is to increase our understanding of the effect of ginseng as an anti-bacterial agent against Pseudomonas aeruginosa pathogenesis in chronic lung infection the most common cause of morbidity and mortality among patients with cystic fibrosis (CF). Although antibiotic therapy, mostly with a mixture of aminoglycoside and Beta-lactam antibiotics, is used to combat the infection, treatment often fails, owing to the emergence of alginate-producing P. aeruginosa isolates. The genetic and molecular mechanism of alginate overproduction has been elucidated in great detail. Yet, a possible therapeutic intervention has been elusive. Recent studies using animal models (described in detail later) have shown that ginseng might play a role in enhancing immune response and bacterial clearance. This research proposes to use genetic and molecular biological techniques to systematically analyze the effect of ginseng against Pseudomonas aeruginosa. Specifically this research will investigate the following: I. Analysis of the ginseng extracts. II. Determine whether ginseng modulates (down- or up-regulates) the alginate genes in vitro. III. Identify novel genes that are modulated by ginseng. Understanding the mechanism of ginseng action would be a key factor if we want to promote this alternative or supplementary therapy. This is vital to devising efficient antipseudomonal therapy and eradicating complications resulting from P. aeruginosa infections among patients with CF.
•
Project Title: HFH-4 EXPRESSION IN PULMONARY EPITHELIUM Principal Investigator & Institution: Brody, Steven L.; Associate Professor of Medicine; Internal Medicine; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2005; Project Start 01-JAN-1997; Project End 31-MAR-2007
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Summary: (provided by applicant): Airway epithelial cells are highly differentiated to perform critical functions for mucosal immunity and mucociliary clearance within the airway lumen. The unique morphology of ciliated and non-ciliated airway epithelial cells is characterized by a specialized set of receptors, channels, and anti-microbial proteins that must be localized in a polarized fashion to the apical or basolateral membranes. It is known that failure of differentiation or localization of apical proteins is the pathologic basis of lung disease in cystic fibrosis and other diseases. However, molecular pathways directing cell polarity are not well understood in airway epithelial cells. To further understand the regulation of epithelial cell differentiation, we previously cloned and initially characterized the forkhead transcription factor Foxj1 (HFH-4). We found that Foxj1 expression is restricted to ciliated epithelial cells, is temporally related to ciliogenesis, and that transgenic mice deficient in Foxj1 lack cilia. This proposal is based on a more detailed analysis of the Foxj1-/- mouse indicating the function of Foxj1 is broader than regulation of ciliogenesis and includes organization of the apical membrane of airway epithelial cells through regulation of cell membranecytoskeletal linker proteins. This hypothesis is based on our observations that Foxj1-/epithelial cells have a failure of apical localization of (1) ciliary basal bodies, (2) transmembrane ion channels, epidermal growth factor receptor, and B2 adrenergic receptor, (3) and importantly, apical membrane-cytoskeletal linker protein ezrin and associated PDZ-domain protein EBP5O. In contrast, basolateral proteins are normally localized. Thus, in the absence of Foxj1 there is a failure of the apical membrane scaffolding proteins to localize and establish apical airway epithelial cell organization required for epithelial cell function and maintenance of the airway mileu. Accordingly, we propose biochemical and genetic approaches for in vivo analysis of the following specific aims. First, we will characterize the relationship between Foxj1 expression and apical membrane cytoskeletal proteins by evaluation of expression, localization, and function of apical ezrin, and ezrin-associated cytoskeletal proteins. Second, we will determine the role of Foxj1 in regulation of the apical compartment by assessment of apical membrane-cytoskeletal linker protein activation in Foxj1 deficient cells, characterize the effect of ezrin disruption on the phenotype of airway epithelial cells, and evaluate role of intracellular trafficking genes to regulate the Foxj1 null phenotype. Completion of these aims will provide important information regarding proteins required for airway epithelial cell differentiation and maintenance of lung function. •
Project Title: HOMEOSTASIS OF THE ER IN DIFFERENTIATING B CELLS Principal Investigator & Institution: Brewer, Joseph W.; Associate Professor; Microbiology and Immunology; Loyola University Chicago 2160 S First Ave Maywood, Il 60153 Timing: Fiscal Year 2005; Project Start 01-JUN-2000; Project End 31-MAY-2009 Summary: (provided by applicant): The long-term goal of this research program is to delineate the molecular mechanisms that regulate homeostasis of the endoplasmic reticulum (ER) in B-lymphocytes. The ER is a specialized compartment for the maturation of membrane and secreted proteins. As such, the ER is the site where immunoglobulin chains fold and assemble into functional antibodies. When Blymphocytes differentiate into antibody-secreting plasma cells, the ER expands and adapts to accommodate high-rate antibody production. Therefore, the mechanisms that regulate ER homeostasis in differentiating B cells are critical for antibody-mediated immunity. An intracellular signaling pathway, termed the unfolded protein response (UPR), monitors the status of protein folding in the ER and transmits that information to mechanisms that modulate the ER environment. A key UPR transcriptional activator, XBP1(S), is required for plasma cell development. ER expansion includes increased
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Cystic Fibrosis
expression of many ER resident proteins and elevated synthesis of phospholipids necessary for membrane biosynthesis. Both of these events have been linked to XBP1(S). This project focuses on four specific aims. First, the protein and lipid composition of the ER will be characterized in differentiating B cells and in a fibroblast model in which ER expansion is induced by enforced expression of XBP1(S). Second, the ability of the expanded ER to support protein biosynthesis will be evaluated in these systems. Third, the mechanism by which phospholipid biosynthesis increases during ER expansion will be investigated. Finally, factors that regulate ER biogenesis will be identified using biochemical and genetic approaches. These studies will yield new information concerning UPR-regulated events that control plasma cell development, generate efficient antibody responses, and mediate ER homeostasis. Importantly, the UPR has been linked to a number of physiologically significant processes including pancreatic function, skeletal development, oxidative stress, and macrophage apoptosis in atherosclerotic lesions. In addition, a number of catastrophic disorders including lysosomal storage diseases, cystic fibrosis, and Alzheimer disease have been linked to protein maturation errors in the ER. A mechanistic understanding of ER homeostasis might lead to the development of novel therapeutics for these diseases. •
Project Title: HOMING AND DIFFERENTIATION OF ADULT STEM CELLS TO LUNG Principal Investigator & Institution: Prockop, Darwin J.; Professor and Director; Biochemistry; Tulane University of Louisiana 6823 St Charles Ave New Orleans, La 70118 Timing: Fiscal Year 2005; Project Start 18-JUL-2005; Project End 31-MAY-2010 Summary: (provided by applicant): This application is to foster collaborative research among four groups of investigators at two neighboring institutions that will develop definitive data about the potential usefulness of adult stem cells to treat important pulmonary diseases. The staff includes one group of investigators with expertise in the preparation and characterization of adult stem cells, two groups of investigators with expertise in animal models for diseases such as fibrosis and emphysema, and a fourth group with expertise in the development of viral vectors for correction of the genetic disease cystic fibrosis (CF). The research will focus on the special class of adult stem cells that can be isolated from a patient's own bone marrow and that are referred to as mesenchymal stem cells or marrow stromal cells (MSCs). The program project format will allow the investigators to advance the field by performing collaborative work that cannot be carried out with individual research grants. Three sub-populations of MSCs that are well characterized will be tested in an innovative co-culture system that assays quantitatively their potential for repairing damaged pulmonary cells. We will also explore the possibility that cell fusion may play a role in the repair of pulmonary cells by MSCs. In addition, it will use a new assay for competitive engraftment to determine which sub-population of MSCs engrafts most efficiently in lungs of immunodeficient mice. The three sub-populations of cells will be assayed for engraftment and differentiation in a model for lung damage by asbestos and in a tracheal explant model. The three sub-populations of cells will be tested for their effectiveness in repairing lung damage in an elastase model for emphysema. In addition, we will attempt to define the mechanisms by which MSCs engraft in lung. MSCs from patients with CF will be engineered to correct the gene defect and then tested to determine whether they can become functional ciliated epithelial cells. Of necessity, the investigators will have to quickly share data as their experiment progresses. For example, data will suggest which sub-populations of MSC should be tested in the other three projects. As another
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example, the experience developed with lentiviruses will make it possible to use viruses for tracking MSCs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HOST PATHOGENESIS
CELL
KILLING
BY
EPEC:
CENTRAL
ROLE
IN
Principal Investigator & Institution: Crane, John K.; Associate Professor of Clinical Medicine; Medicine; State University of New York at Buffalo Sponsored Projects Services Buffalo, Ny 14260 Timing: Fiscal Year 2005; Project Start 30-SEP-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Enteropathogenic E. coli (EPEC) is a common cause of severe, watery diarrhea in children in developing countries. EPEC is also the prototype of a group of attaching and effacing intestinal pathogens, including enterohemorrhagic E. coli (EHEC, such as O157:H7), Citrobacter rodentium, Hafnia alvei, and EPEC-like E. coli strains of domestic animals. Unlike many other E. coli strains that cause diarrhea, EPEC produces no known toxins, so the way it causes disease has been puzzling. Despite major advances in understanding how EPEC adhere, trigger cytoskeletal rearrangements in the host, and cause other host cell alterations, the mechanism by which EPEC causes diarrhea has been unclear. The discovery that EPEC triggers host cell death provided an important lead in how EPEC causes disease. The mode of cell death triggered by EPEC has features of both apoptosis (programmed cell death) and necrosis. One of the non-apoptotic features of EPEC-mediated killing is release of adenosine triphosphate (ATP) from the host cell. Once released, ATP is broken down to other adenine nucleotides and adenosine. Adenosine itself acts as a potent secretatagogue, i.e., a stimulator of intestinal fluid and electrolyte secretion, which may cause or contribute to watery diarrhea. The present application seeks to understand how EPEC triggers the ATP release from the host, with a particular focus on the role of the cystic fibrosis transmembrane regulator (CFTR). Other goals include determining the signaling pathways activated by adenosine which activate intestinal secretion, and the determining the extent of release of adenine nucleotides into the intestinal tract of rabbits infected with the EPEC-like pathogens rabbit diarrheagenic E. coli (RDEC-1) and rabbit EPEC (REPEC). •
Project Title: HOST FACTORS IN FUNGAL ALLERGY AND FIBROSIS Principal Investigator & Institution: Kolls, Jay K.; Professor; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 152132583 Timing: Fiscal Year 2006; Project Start 11-SEP-2006; Project End 31-JUL-2011 Summary: (provided by applicant): This program entitled "Host Factors in Fungal Asthma and Fibrosis" has its goal to translate our basic knowledge in antigen recognition, mechanisms of allergy and tolerance, and high throughput genomics and proteomics to 1) improve our understanding of allergjc and fibrotic lung diseases and 2) use this knowledge to design interventions to prevent or ameliorate these pathogenic processes. Towards this end, this SCCOR application proposes two closely linked clinical and basic science projects. One clinical and basic science project will investigate the role of beta-glucan and the beta-glucan receptor Dectin-1 in the development of allergy or tolerance to the ubiquitous fungus Aspergillus fumigatus. These studies will be conducted in the context of a cohort of patients with Cystic Fibrosis that have defined Aspergillus colonization with and without Allergic Bronchopulmonary Aspergillosis (ABPA) and a basic science project that uses a novel rodent model of
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Cystic Fibrosis
immune tolerance or allergy to define the role of the local pulmonary immune system and surfactant proteins in the development of allergy versus tolerance. Another clinical and basic science project will be focused on pulmonary fibrosis. The clinical project will use gene expression and protein expression profiling to better define subgroups of patients with idiopathic pulmonary fibrosis (IPF) as well as further define abnormalities in adaptive T -cell biology that occurs in these patients. A closely linked basic project will investigate the role of KGF and the ligands for CXCR3 (CXCL9, CXCL10, and CXCL11) in regulating the fibrotic response to bleomycin lung injury in rodents. The overall theme of this SCCOR is to define molecular pathways that regulate adaptive immunity to antigens and to improve our understanding of interactions between immune cells and parenchymal cells in the development of fibrosis or in the setting of allergy (or tolerance). These themes are in concert with the goals of the RFA to: characterize innate and adaptive immune responses, develop genomic and proteomic signatures of pulmonary pathways and conduct studies in humans that have direct diagnostic and potentially therapeutic application. The long-term objective of the SCCOR is to use the knowledge of the molecular pathways to improve diagnosis and treatment of patients suffering form chronic lung diseases particularly allergic and fibrotic lung diseases. End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1. Immune Tolerance and Inflammation in ABPA in Patients with Cystic Fibrosis (Kolls, Jay K.) (provided by applicant): Allergic bronchopulmonary aspergillosis (ABPA) is an allergic disease characterized clinically by wheezing, pulmonary infiltrates, bronchiectasis, and fibrosis that affects patients with asthma and cystic fibrosis (CF). In patients with ABPA, immunological responses to a variety of Aspergillus fumigatus (Af) antigens result in a heightened Th2 response and an elevated immunoglobulin E (IgE) level. At our CF Center ABPA affects 7% of the CF population however over 30% are colonized with Af. Preliminary data in our laboratory demonstrates that Dectin-1, a beta-glucan receptor expressed in dendritic cells and macrophages is required for recognition of swollen conidia; a form of Af that precedes hyphal development. Preliminary data suggest that Dectin-1 is also required for Th2 response in CF patients with ABPA. Additionally patients with Af colonization without ABPA have elevated antigen specific IL-10 responses which we propose is due the development of regulatory T-cell response in these patients. Based on these data, we hypothesize that CF patients with ABPA require monocyte/dendritic cell expression of dectin-1 for the presentation of specific Aspergillus antigens (namely swollen conidia) as well as for Th2 cytokine elaboration. Moreover, we hypothesize that a decreased in Treg cells is required for development of APBPA compared to CF patients colonized with Aspergillus but no evidence of ABPA. To test these hypotheses, we propose the following specific aims: Specific Aim 1: To test the hypothesis that CF patients with ABPA require Dectin-1 expression on peripheral blood monocytes/dendritic cells and that binding of A. fumigatus to Dectin-1 will produce a heightened inflammatory response in patients with ABPA compared to non-ABPA patients. Specific Aim 2: To test the hypothesis that T cells from CF patients with ABPA will have decreased adaptive Treg function. Specific Aim 3. To test the hypothesis that anti-fungals targeted against glucan synthetase block both proinflammatory and Th2 cytokine induction in peripheral blood of patients with CF with ABPA. Understanding these responses in ABPA will increase our knowledge regarding mechanisms of allergy vs. tolerance in human subjects. (End of Abstract) •
Project Title: HOST-PATHOGEN INTERACTIONS IN CYSTIC FIBROSIS Principal Investigator & Institution: Moskowitz, Samuel M.; Pediatrics; University of Washington Office of Sponsored Programs Seattle, Wa 98105
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Timing: Fiscal Year 2005; Project Start 05-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this application is to establish the independent research career of the candidate in the study of chronic lung disease, including that affecting individuals with cystic fibrosis (CF). The candidate is a pediatric pulmonary fellow with the career goal of developing an active program of disease-related basic research as a faculty member at a medical school. The training environments are the laboratory of the sponsor, Dr. Samuel Miller, at the University of Washington School of Medicine, and the CF Center at Children's Hospital and Regional Medical Center in Seattle, directed by the co-sponsor, Dr. Ronald Gibson. The proposed project seeks to clarify molecular mechanisms underlying chronic lung infection and inflammation in individuals with CF. The opportunistic pathogen Pseudomonas aeruginosa (PA) infects the lungs of most individuals with CF, frequently (but not invariably) causing severe progressive lung injury and premature death. Study of the interaction between PA and the CF lung is necessary to understand both the cellular processes that promote or permit CF lung infection, and the precise means by which PA interacts with lung cells to cause airway damage. The structure of lipopolysaccharide (LPS), the principal constituent of Gram-negative bacterial surfaces, appears to play a pivotal role in both microbial and human aspects of this interaction. The candidate's preliminary results indicate that resistance of laboratory and clinical isolates of PA to antimicrobial peptides (key components of host innate immunity) correlates with alterations in the structure of the lipid A moiety of LPS. Moreover, mutation of a PA locus that regulates LPS-modifying enzymes influences the antimicrobial peptide resistance phenotype. The microbiological phase of the project thus seeks to define PA genes necessary for this putative resistance mechanism, and to identify potential inhibitors using antimicrobial peptide-resistant strains. The human phase of the project builds on the clinical observation that some individuals with a severe CF genotype and chronic PA airway infection nevertheless have minimal lung disease. A case-control design will be utilized to test the hypothesis that polymorphisms in innate immune genes may limit CF lung disease. Those innate immune genes encoding the LPS receptor are leading candidates as CF modifier loci, based on the recent finding that CF-specific PA LPS structures have increased inflammatory activity. When prevalence of an LPS receptor variant differs in mild and severe CF lung disease, receptor function will be assayed in cell culture models of LPS signaling. Identifying innate immune genes as modifiers of the CF lung phenotype may suggest new avenues for treating the inflammatory consequences of CF airway infection. •
Project Title: INTERACTION MACROPHAGES
OF
P.
AERUGINOSA
WITH
ALVEOLAR
Principal Investigator & Institution: Worgall, Stefan; Genetic Medicine; Weill Medical College of Cornell Univ 1300 York Avenue New York, Ny 10021 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2007 Summary: (provided by applicant): Infection with Pseudomonas aeruginosa (Pa) is a hallmark of lung disease in cystic fibrosis (CF). Alveolar macrophages (AM) play an important part in the pulmonary inflammatory response. The analysis of transcript profiles in AM infected with Pa identified a variety of expected and novel factors related to inflammation and apoptosis. Although AM express the cystic fibrosis transmembrane regulator (CFTR), its function in AM is not known and there is evidence of a dysregulated inflammatory response of AM in CF. This proposal focuses on the role of CFTR expressed in AM in their response to Pa. Based on the difficulty to obtain unstimulated or uninfected AM from individuals with CF, CFTR-expression in AM will
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Cystic Fibrosis
be silenced using genetic modification with small interfering RNA (siRNA) delivered by an adenovirus (Ad) vector. The overall goal is to evaluate the role of CFTR in the response of AM to Pa. Two specific aims outline the studies to achieve this goal. Aim 1. To assess if silencing of CFTR in AM results in a proinflammatory phenotype. SiRNA constructs specific for the CFTR mRNA will be screened in epithelial cell lines. An Ad vector expressing the most effective siRNA-CFTR (AdsiRNA-CFTR) construct will be used to silence CFTR expression in AM. The expression of CFTR mRNA and protein will be monitored and the secretion of IL-8 following stimulation will be evaluated to assess if silencing of CFTR in AM results in a proinflammatory phenotype as known for epithelial cells. Two alternate controls will be evaluated to achieve decreased CFTR function: (1) An Ad vector expressing the CFTR R-domain and (2) the thiazilodine CFTR inhibitor CFTRinh-172.constructed to silence CFTR expression in human AM. Aim 2. To evaluate if AM with silenced CFTR expression display an altered response to Pa in vitro. To assess the hypothesis that CFTR expression in AM affects the response to Pa, human AM , genetically modified with AdsiRNA-CFTR will be infected with Pa or other control bacteria and evaluated for (1) Pa phagocytosis, cell death/apoptosis, and chemokine/cytokine release; and (2) the expression of genes related to inflammation and apoptosis, previously identified by transcript profiles of human AM exposed to Pa. •
Project Title: INTRACELLULAR IRON ACCUMULATION IN CYSTIC FIBROSIS Principal Investigator & Institution: Turi, Jennifer L.; Medicine; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2010 Summary: (provided by applicant): This proposal will enable the principal investigator to develop into an independent physician-scientist and gain new expertise in oxidative biology, gene regulation, and cystic fibrosis (CF). CF is a common, highly morbid, and ultimately fatal disease characterized by persistent pseudomonas lung infections and severe airways obstruction. It is also associated with markedly elevated concentrations of iron in the airway that may contribute to CF morbidity by generating oxidant injury, and supplying pseudomonas with an essential nutrient to exacerbate infection. Airway epithelial cells protect against these effects by transporting iron via natural resistanceassociated macrophage protein 2 (Nramp-2) into the cell where it is sequestered by ferritin. To prevent intracellular accumulation, iron is mobilized from lung cells via metal transport protein 1 (MTP1). We present data to support two potential mechanisms of intracellular iron accumulation in CF. First, inflammation appears to increase Nramp2 expression, decrease MTP1 expression, and elevate intracellular iron concentration. Second, basal expression of Nramp-2 and MTP1 appears elevated in unstimulated CF cells. This may be due to increased Na+ absorption via the epithelial channel (ENaC), that is typical in CF, given our data showing iron transport requires concurrent Na+ transport and ferritin is increased in airways of mice over-expressing ENaC. We will test the hypotheses that: 1) Inflammation increases Nramp-2 expression and decreases MTP1 expression in airway epithelial cells resulting in intracellular iron overload; 2) Increased intracellular iron, in the presence of inflammation, causes ROS generation and oxidant injury; and 3) In addition to and independently of inflammation, Nramp-2 and MTP1 expression are mediated by increased expression of ENaC in CF epithelial cells. Three Specific Aims will be tested: 1) Evaluate the extent to which LPS and proinflammatory cytokines IL-1B and TNF-a regulate iron transport proteins and increase cellular iron concentration in airway epithelial cells; 2) Evaluate whether elevated intracellular iron during inflammation stimulates ROS production and generates oxidative injury; 3) Investigate the role of increased ENaC expression in the regulation of Nramp-2 and MTP1 expression in CF in the presence and absence of inflammatory stimuli. These data
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will provide a scientific foundation to understand mechanisms of iron overload in CF and its role in the vulnerability of the airway to oxidative damage and cytotoxicity. (End of Abstract) •
Project Title: KRUPPEL LIKE FACTOR IN P. AERUGINOSA AIRWAY VIRULENCE Principal Investigator & Institution: Saavedra, Milene T.; Medicine; University of Colorado Denver/Hsc Aurora P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2005; Project Start 04-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Of the 2,500 children born every year with cystic fibrosis (CF) in the United States, 80% harbor P. aeruginosa by the time they reach 18 years of age. Recurrent Pseudomonas pulmonary infections are the major cause of morbidity and mortality in these patients. Airway structural damage is induced by excessive neutrophil populations in the airway, releasing large amounts of proteases which impair phagocytic killing of organisms. To date, the repertory of antiinflammatory therapies to limit excessive epithelial cell signaling to inflammatory mediators remains limited and imperfect, which may be partially due to a limited understanding of critical pathways to curb inflammation and their role in the pathogenesis of CF. Evidence suggests that the zinc finger protein, lung kruppel like factor (LKLF), described here for the first time as highly regulated by infection, plays a significant role in the regulation of the airway epithelial cell response to Pseudomonas infection. Based on preliminary data, Dr. Saavedra hypothesizes that a) the transcriptional activator LKLF is cytoprotective in normal airway cells, b) that it suppresses nuclear factor kappa B activation and c) that in cystic fibrosis, overexpression of LKLF is not protective due to alternate apoptotic/death pathway activation. These aims will be studied with an in vitro epithelial cell air liquid interface culture model system and the well characterized Pseudomonas strain PAO1. The approach will initially utilize functional genomics to define pathways activated by overexpression of this gene utilizing an LKLF plasmid construct. The true focus will be on elucidating gene function with apoptosis assays, luciferase reporter constructs, EMSA experiments and use of various constructs overexpressing genes involved in NFkappaB activation to ascertain target site of LKLF activity along that pathway. These experiments are designed to further understanding of how epithelial cells drive neutrophil recruitment, knowledge of which may contribute to development of new therapeutic interventions in inflammatory airways diseases such as CF. This project will allow Dr. Saavedra to become an independent investigator and expert in the realm of Pseudomonas and airway epithelial cell biology, via a multi-faceted approach of 75% dedicated laboratory time and didactic training with a special focus on mechanisms of microbial pathogenesis. Outside of the laboratory, 25% clinical time will be spent as an instructor in adult Pulmonary and Critical Care Medicine, taking care of both inpatients and outpatients with CF, with the ultimate goal of a closely knit research and clinical niche as a principal investigator and expert adult CF doctor.
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Project Title: LUNG EPITHELIAL CELL SURVIVAL SIGNALING IN OZONE IN CYSTIC FIBROSIS AND NORMALS Principal Investigator & Institution: White, Carl W.; Professor; National Jewish Medical & Res Ctr 1400 Jackson Street Denver, Co 80206 Timing: Fiscal Year 2005; Project Start 23-SEP-2005; Project End 31-JUL-2010 Summary: (provided by applicant): Oxidant air pollutants like ozone increase risk for exacerbation of cystic fibrosis, asthma, and COPD. Ultrafine particulates, which also
40
Cystic Fibrosis
can bear surface free radicals, can have such effects, alone or in synergy with ozone. Oxidant gases like supraphysiologic oxygen and ozone cause extracellular ATP release from lung cells, activating critical survival signals. Prompt, reversible ATP release due to ozone (50-200 ppb) occurs in tracheal, bronchial, small airway, and alveolar epithelial cells, appears due to calcium-, rho kinase-, and PI 3-kinase-dependent vesicular exocytosis, and, in polarized bronchial epithelium, is mainly from the apical surface. Acute ozone exposure also causes ATP release into lung epithelial lining fluid in mice within 15 min. In vitro, enzymatic removal of extracellular ATP increases cell death, while ATP, DTP, or a nonhydrolyzable ATP analog prevent ozone-induced apoptosis and necrosis. The protecting agonists, and their inhibition by P2 and P2Y receptorspecific antagonists, indicate a role for P2Y receptors. Extracellular ATP activates ERK 1/2 and Akt signaling. Besides epithelial injury, ozone causes release of cytokines like interleukin-8 (IL-8). IL-8 appears in CF airways even before bacterial infection, being the earliest identified pathologic event. We hypothesize that extracellular ATP preserves epithelial energy metabolism, airway cell survival and inhibits IL-8 release due to ozone in normals, that impaired ATP release in CF airways causes opposite effects, and that supplemental extracellular ATP or similar agonists will reverse these processes in CF and normals. Our specific aims are: (1) measure ATP release, IL-8 release, and cell death in CF and non-CF airway human epithelium in response to ozone, (2) quantitate ozonemediated ATP release, inflammatory cytokine release, and cell injury/death in airways of CFTR- mutant and non-mutant mice, (3) assess effects of ATP, DTP and ATP analog supplementation in CF and non-CF airway epithelium in ozone in vitro and in vivo, and determine activated signaling pathways and related metabolic effects. Polarized monolayers of primary and transformed CF-mutant and normal airway epithelium cultured on permeable supports with an air-liquid interface will be used. These studies will increase our understanding of lung oxidant injury and repair in CF and normals, and of normal defense mechanisms of airway epithelium. •
Project Title: MECHANISMS OF CUTANEOUS ACTIVE VASODILATION Principal Investigator & Institution: Kellogg, Dean L.; Associate Professor; Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2005; Project Start 15-SEP-2000; Project End 31-JUL-2009 Summary: (provided by applicant): Over 70 years ago the human cutaneous active vasodilator system (AVD) was first described; however, its mechanisms remain unclear today. The long-term goal of this project is to define the integrative physiological mechanisms that effect cutaneous active vasodilation during thermoregulatory reflex responses to hyperthermia. This will contribute to our understanding of the role of the cutaneous circulation in adaptation to hot environments and to understanding the increased morbidity and mortality of persons due to heat related illness in "heat waves". In addition to the specific benefits to be gained in understanding human thermoregulation, this project will add greatly to our understanding of how complex neural co-transmitter systems can control the cardiovascular system. Study of the AVD co-transmitter system that controls the cutaneous vasculature in humans can be used to gain insights into how co-transmitter neural control systems work. Gaining such knowledge directly from human beings in vivo could not be accomplished in any other human tissue, in vivo, without significant risk. The following specific aims will be explored: 1) To determine whether cutaneous AVD during heat stress is atropinesensitive in cystic fibrosis patients. 2) To determine whether activation of VPAC1 and/or PAC1 receptors mediate cutaneous active vasodilation during hyperthermia. 3) To resolve whether muscarinic receptor activation by endogenous acetylcholine release contributes to increased nitric oxide levels during cutaneous active vasodilation in heat
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stress. 4) To resolve whether the nitric oxide required for cutaneous active vasodilation is produced by endothelial nitric oxide synthase (eNOS) and/or by neuronal nitric oxide synthase (nNOS) during heat stress. 5) To define the role of cAMP in cutaneous active vasodilation during heat stress. 6) To define the role of cGMP in cutaneous active vasodilation during heat stress. Studies will be done in healthy humans and patients with cystic fibrosis. Intradermal microdialysis will be used to treat small areas of forearm skin with specific pharmacological agents to manipulate the cholinergic, neuropeptidergic, nitric oxide, and second messenger systems. Laser-Doppler flowmetry will monitor skin blood flow responses during normothermia and hyperthermia at both drug-treated, experimental sites, and at adjacent untreated, control sites. In addition, intradermal microdialysis will be combined with measurements of bioavailable NO by NO-selective amperometric electrode to define further how the NO system functions in cutaneous active vasodilation. •
Project Title: MECHANISMS OF NUCLEOTIDE BINDING AND REGULATION OF CFTR Principal Investigator & Institution: Berger, Allan L.; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2005; Project Start 01-MAY-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The goal of this application is to support the development of Dr. Allan Berger as a clinician scientist so that at the completion of the award he will be an independent researcher and an outstanding academic scientist and clinician. Dr. Michael J. Welsh will assume responsibility as mentor to ensure the success of the development plan. The heart of the proposal is an intensive training experience in the basic research laboratory. Cystic fibrosis (CF) is the most common lethal genetic disease in young Caucasians, and is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. ATP binding to the two nucleotide binding domains (NBD) of CFTR is required for normal channel function. In this proposal, Dr. Berger will explore the interactions between ATP and CFTR. Preliminary data suggest that certain novel missense mutations in CFTR selectively block ATP binding. There are three Specific Aims. 1) What are the biochemical and functional effects of mutations that block ATP binding to CFTR? 2) What are the effects of the Walker A lysine mutations K464A and K1250A on ATP binding? 3) What residues in CFTR contact the ATP base? Together these aims will determine the functional mechanisms underlying ATP regulation of the CFTR chloride channel and structural mechanisms of ATP binding. Dr. Berger will combine biochemical and functional assays to learn how ATP interacts with the NBDs to control channel activity. Dr. Berger will further develop his skills at using the scientific method to develop hypotheses that can be experimentally tested to yield unequivocal answers. In addition to basic research training, Dr. Berger will improve his skills of presenting data verbally and in writing. He will continue his training by participating in seminars and journal clubs, and will attend national meetings to present his own work and to learn from others. He will receive instruction in the responsible conduct of research. He will also receive instruction and critique in grant writing. In the latter stages of this training he will prepare grant applications for independent research funding. Both the mentor and the institution are highly committed to the applicant's scientific development and academic success.
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Cystic Fibrosis
Project Title: MECHANISMS UNDERLYING STEM CELL PLASTICITY Principal Investigator & Institution: Sharkis, Saul J.; Professor of Oncology and Medicine; Oncology; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2006; Project Start 01-JAN-2006; Project End 31-DEC-2010 Summary: (provided by applicant): We will establish the qualitative and quantitative potential of stem cells (SC) and committed progenitor cells of hematopoietic tissue (HSC) for the repair of damage to epithelial tissues. These studies are designed to examine the mechanisms responsible for tissue repair and regeneration. We believe in order to determine what regulates repair/regeneration we must show: a) What the factors are that induce conversion of hematopoietic stem cells into liver; b) what are the target cells responsible for the repair; c) how the cells can be delivered to the site of injury; d) how we can track the cells after transplantation; and e) what is the level of repair/regeneration over time. Our long term goals of these studies are to utilize SC from hematopoietic and non-hematopoietic tissue to offer treatment options for diseases such as Diabetes, Cystic Fibrosis, as well as liver or kidney failure. Our plan is to establish the mechanisms which allow adult SC to reprogram in response to specific injury signals. Thus our specific aims are: 1) we plan to determine the repair/regeneration potential of SC for repair of acutely or chronically injured liver. Further, we will examine the effect of injury signals on the conversion of HSC into functional cells of the injured tissue phenotype using a novel in vitro assay. Fusion is an additional mechanism which might be responsible for conversion. Therefore we will also study the consequences effusion if and when it occurs to understand this mechanism of cellular repair. Our in vitro studies will be complemented with in vivo transplant studies to determine the functional potential for SC therapy. Our aim 2) is to study which target cells can affect the repair of injured tissue. Is it possible that each tissue has its own reservoir of SC which can repair in particular circumstances? We will attempt to isolate SC from epithelial tissues by methods which we have already used to successfully isolated HSC and determine the potential for these cells to repair injured epithelial and hematopoietic tissue. Relevance: Our long term goals of these studies are to utilize SC from hematopoietic and non-hematopoietic tissue to offer treatment options for diseases such as Diabetes, Cystic Fibrosis, as well as liver or kidney failure. Our plan is to establish the mechanisms which allow adult SC to reprogram in response to specific injury signals.
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Project Title: MECHANISMS, STRUCTURE, AND REGULATION OF CFTR'S NBD'S Principal Investigator & Institution: Gadsby, David C.; Professor; Lab/Cardiac/Membrane Physiol; Rockefeller University 1230 York Avenue New York, Ny 100216399 Timing: Fiscal Year 2005; Project Start 30-SEP-1996; Project End 31-MAR-2010 Summary: (provided by applicant): CFTR (cystic fibrosis transmembrane conductance regulator), encoded by the gene mutated in CF patients, is one of approximately 50 human ATP-binding cassette (ABC) proteins, and belongs to subfamily ABC-C which also includes SUR (sulfonylurea receptor) and MRP (multidrug resistance related) proteins. Unlike other ABC proteins, CFTR is an ion channel; it allows the Cl- flow needed for transepithelial fluid movement. Opening and closing of the CFTR channel pore are controlled by ATP binding to CFTR's two nucleotide binding domains (NBDs) and by ATP hydrolysis. Transduction of these NBD events to the channel gates is regulated by phosphorylation, by cAMP-dependent protein kinase, of multiple serines
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in CFTR's regulatory (R) domain. The goal of the proposed research is to understand, in molecular detail, the mechanisms regulating NBD function and channel gating. Knowing the precise mechanisms that control CFTR channel opening and closing might help pharmacological rescue in CF patients of cells with inadequate ion flow due to expression of mutant CFTR channels; this includes mutants that reach the cell surface in inadequate numbers, those with diminished pore conductance, and those that spend an insufficient time open. The specific aims are essentially unchanged. The first addresses what the NBDs look like, how they function, how they interact, and how they control the channel's gates. The working hypothesis is that CFTR's two NBDs are structurally dissimilar (a characteristic of ABC-C family members), that upon ATP binding they form head-to-tail dimers that enclose two ATP molecules in composite catalytic sites within the dimer interface, that the dimerization drives channel opening, and that hydrolysis of the ATP at the NBD2 catalytic site prompts channel closing; ATP remains bound at the NBD1 catalytic site for several minutes without being hydrolyzed. The second aim addresses how phosphorylation (and at which site or sites) permits channel opening, and how additional phosphorylation promotes stabilization of the channel open state. Wild-type and mutant CFTR channels will be expressed in oocytes and mammalian cells, and their structure and function analyzed using biophysical, electrophysiological, and biochemical methods. Mutant cycle measurements of singlechannel gating kinetics will probe energetic interactions between residues and domains of CFTR. Photolabeling will probe nucleotide interactions with the NBDs. Structural analysis of prokaryotic NBD heterodimers, with an active and a dead catalytic site as in CFTR, will elucidate mechanisms in CFTR's NBDs. •
Project Title: MENTORED DEVELOPMENT AWARD
PATIENT-ORIENTED
RESEARCH
CAREER
Principal Investigator & Institution: Sagel, Scott D.; Pediatrics; University of Colorado Denver/Hsc Aurora P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2005; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): In children with cystic fibrosis (CF) proteolytic activity causes bronchiectasis, resulting in progressive lung disease and marked shortening of life expectancy. One of the long-term objectives for this proposal is to define proteolytic biomarkers that are predictive of future clinical course and disease progression in children with CF. By identifying those children with excessive and more aggressive proteolytic activity, it may be possible to intervene with anti-proteolytic treatments before irreversible airway damage occurs. The main hypothesis is that CF children with more pronounced proteolytic activity, as measured in induced sputum, would have a greater degree of structural and functional lung damage. This hypothesis will be tested through the following specific aims: 1) to determine changes in proteolytic activity by quantitating levels of neutrophil derived proteases (elastase, matrix metalloproteinase Types 2 and 9), lung antiproteases (alpha1antiprotease, secretory leukoprotease inhibitor, tissue inhibitors of metalloproteinase), and elastin breakdown products (desmosine, isodesmosine) in clinical specimens (induced sputum, urine) from CF children, during times of clinical stability, annually over three years; and 2) to correlate these changes in proteolytic activity with structural airway damage (assessed by severity and extent of bronchiectasis on annual high resolution computed tomography scans), functional airway impairment (as determined by annual pulmonary function testing), lower airway bacterial colonization status and bacterial burden, and related morbidities (rates of hospitalization, pulmonary exacerbations). These results will be crucial to evaluating emerging antiproteolytic treatments in children with CF. Another objective of this application is to enhance and strengthen Dr. Sagel's approach
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Cystic Fibrosis
to clinical investigation and patient-oriented research. Dr. Sagel will receive more formal training and education by completing his Ph.D. degree in the UC's Clinical Science Program. He will take courses in clinical epidemiology, bioethics, clinical trial design, pharmacokinetics, and human genetics, and complete a thesis about proteolytic activity in CF. In addition, he will actively participate and train in the Pediatric GCRC, and frequently interact with his sponsor, mentors, and collaborators. •
Project Title: MOLECULAR BASIS OF THE CYSTIC FIBROSIS PHENOTYPE Principal Investigator & Institution: Durie, Peter R.; Professor; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, on M5g 1X8 Timing: Fiscal Year 2004; Project Start 30-SEP-1994; Project End 31-MAY-2007 Summary: The goal of this SCOR application is to understand the clinical, biological and biochemical consequences of mutations in CFTR, the gene defective in cystic fibrosis (CF). The program brings together a group of basic scientists and clinician researchers with a broad range of expertise to the common task of analyzing the CF disease from different angles, through studying the CFTR molecular defects in patients, generating, mouse models, mapping of modifier genes, and using cell culture and in vitro systems for the protein. We combine our strengths in the area of CF patient documentation, human and mouse genetics, biochemistry and cell biology. The SCOR is organized into 4 Research Projects (RP), 3 Pilot Projects (PP) and 3 Core Units, grouped into 3 research areas, namely, clinical and genetic studies of patients, mouse models of identification of CF modifier genes, and direct characterization of CFTR. In the first area, RP1 will establish a comprehensive understanding of the spectrum of CF disease phenotype caused by or associated with the primary and secondary genetic determinants of the disease. In the second, RP2 will study the role of ClC-2 chloride channels in mediating epithelial chloride secretion in a mouse model and RP3 will dissect the physiologic and genetic aspects of lung disease in CF mice of a specific genetic background. In addition, a pilot project, PP3, is included to characterize the liver disease recently observed in one of the congenic CF mouse strains. These studies will discover new pathways through which alternative methods may be devised to treat CF. In the third area, RP4 will pursue a detailed analysis at the molecular, cellular and functional levels to establish the consequences of the missense mutations that occur in the first nucleotide binding domain (NBD1) of CFTR and mutations causing carboxyl terminal truncations will be used as probes for these studies. This will be complemented by the two pilot projects: PP1 which will explore a new fluorescence transfer technique for the study of transmembrane segment interactions and PP2 which will examine if purified CFTR an mediate energy-dependent transport of large organic anions such as glutamate and glutathione in a reconstituted system. In addition to the Administration Core, the Patient/Biostatistics Core, and the Mouse Core will serve to support the hove projects. The results from Score should yield novel insights into the molecular mechanisms of CF pathology and should lead to new improved therapeutic approaches.
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Project Title: MOLECULAR BIOPHYSICS OF CFTR CHLORIDE CHANNELS Principal Investigator & Institution: Bompadre, Silvia G.; Medical Pharmacology and Physiology; University of Missouri-Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2005; Project Start 01-FEB-2003; Project End 31-JAN-2006 Summary: (provided by applicant): CFTR (Cystic Fibrosis Transmembrane conductance Regulator) is a small conductance Cl channel that is regulated by phosphorylation and gated by ATP hydrolysis. Mutations in the gene coding for CFTR result in the genetic disease cystic fibrosis. Our long-term research goals are to investigate how mutations in
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CFTR cause its defective functions at the single molecule level and to examine how pharmacological interventions circumvent dysfunction of the mutant protein. The current proposal is aimed to explore the biophysical and biochemical mecanisms of the R domain in CFTR. The specific aims of this proposal are: Aim1. To investigate the mechanism of glibenclamide effect in CFTR-dR gating. Specifically we will investigate how the absence of the R domain reveals another binding site for glibenclamide. We will also test other sulphonylurea drugs. Aim 2. To investigate the role of the R domain in the functional defect of dF508, the most common mutation associated with cystic fibrosis disease. Specifically, we will investigate whether the deletion of the R domain can restore CFTR-dF508 channel function. We will combine electrophysiology methods with molecular biology methods to achieve these aims. Results from this work will not only shed light on the function of the R domain in CFTR, but will also provide invaluable information to help the understanding of the most commom disease associated mutation of the CFTR channel. •
Project Title: MOLECULAR MECHANISMS OF CFTR REGULATION Principal Investigator & Institution: Ladias, John Aa.; Assistant Professor; Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-regulated chloride channel that determines the rate of electrolyte and fluid transport in the apical membrane of epithelial cells. Abnormal CFTR function is associated with the pathogenesis of cystic fibrosis and secretory diarrhea. Our long-term objective is to understand the molecular mechanisms underlying the regulation of CFTR at the atomic level and develop novel strategies for modulating the activity of this channel and treating the CFTR-associated diseases. The CFTR topology consists of two membrane-spanning domains and five cytoplasmic domains: an N-terminal domain (NTD), two nucleotide-binding domains, a regulatory domain (R) and a C-terminal domain (CTD). The CFTR activity is modulated through phosphorylation of the R domain, ATP hydrolysis by the NBDs, and interactions of its NTD and CTD domains with syntaxin 1A and NHERF proteins, respectively. However the regulatory mechanisms remain unknown primarily because the three-dimensional structure of the CFTR domains and the structural basis of their interaction with intracellular regulatory proteins remain elusive. This proposal addresses these questions and focuses on the structural analysis of cytoplasmic CFTR domains and their complexes with regulatory proteins, using molecular biology techniques and X-ray crystallography. The specific aims are: 1. To dissect the structural basis of CFTR channel gating mediated through the interaction of the CFTR CTD with the NHERF PDZ1 and PDZ2 domains. 2. To elucidate the molecular mechanisms underlying the regulation of CFTR channel activity through the interaction of the CFTR NTD with syntaxin 1A. 3. To determine the three-dimensional atomic structures of the CFTR NBD1 and NBD2 domains. These studies will provide the first high-resolution three-dimensional structures of four cytoplasmic CFTR domains and the structural basis of CFTR regulation by proteins syntaxin 1A and NHERF. This information is an essential step towards elucidating the basic molecular mechanisms that control the CFTR channel gating. Importantly, the atomic coordinates of these complexes could be used for structure-based rational design of drugs that would modify selectively the CFTR activity with clinical applications in the treatment of cystic fibrosis and secretory diarrhea.
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Cystic Fibrosis
Project Title: MOLECULAR MECHANISMS OF ION TRANSPORT BY THE SMG Principal Investigator & Institution: Muallem, Shmuel; Professor; Physiology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2005; Project Start 01-SEP-1997; Project End 31-MAR-2007 Summary: Abnormal function of salivary gland occurs in radiation, drug therapies, Sjogren's syndrome and Cystic Fibrosis. Saliva is formed by secretion of proteins and fluid by acinar cells. The ductal system absorbs the Na+ and Cl- and secretes K+ and HCO3- to form the final saliva. Over the last few years, we came to appreciate the central role of CFTR-regulated HCO3- transport in epithelial fluid and electrolyte secretion, including that by salivary glands. CFTR supports Cl--dependent HCO3transport, and CF-causing mutations with normal C1- channel activity have aberrant HCO3- transport. In the preliminary data we show that SMG express several members of the new SLC26 family of Cl-/HCO3- exchangers-DRA, PDS, SMCBT-and BTR1, that function in HCO3- secretion. SMG also express splice variants on the NBCn1 family that function in HCO3- salvage. The proteins of both families are regulated by CFTR. Based on these findings, we developed a new hypothesis to propose that transcellular HCO3transport is central to salivary gland function and that CFTR coordinates HCO3transport at rest and during stimulation. The hypothesis will be tested by following four aims. In aim 1 we will study the reciprocal regulatory interaction between CFTR and mDRA. Preliminary data shows that CFTR markedly stimulates mDRA activity and that mDRA may affect anion selectivity of CFTR. We will use several CFTR and DRA mutants to a) characterize the mechanism by which CFTR activates mDRA b) study how mDRA affects CFTR channel properties and c) study the reciprocal regulation in vivo in WT and deltaF mice. In aim 2 we will probe interactions between CFTR and the SLC6 family members Pendrin and SLC26A6 that are expressed at high levels in SMG ducts. After basic characterization of SLC26A6 C1-/HCO3- exchange activity, we will probe whether CFTR regulates PDS and SMCBT in vitro and in vivo as it controls mDRA. In aim 3 we will study the role of BTR1 in SMG function. BTR1 is the first member of a new family of HCO3- transporters that is expressed in SMG duct and acinar cells. We propose to characterize Cl- and HCO3- transport by BTR1 as the potential HCO3transporter or channel in the LM of the SMG that generates the final 140 mM HCO3- in saliva. In aim 4 we will characterize regulation of the NBCn1 splice variants by CFTR and their role in HCO3- salvage by the SMG. We will characterize the activity of individual and combinations of NBCn1 isoforms and the mechanism of their inhibition by CFTR in vitro and in vivo using the deltaF mouse. Successful completion of the experiments should considerably clarify the role of CFTR in regulating HCO3homeostasis in the resting and stimulated states. The studies may also shift the emphasis from efforts to correct Cl- transport to efforts to correct Cl- and HCO3transport in diseases of secretory epithelia such as CF and Sjogren's syndrome.
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Project Title: MOLECULAR PATHOGENESIS OF CYSTIC FIBROSIS LIVER DISEASE Principal Investigator & Institution: Carey, Martin C.; Brigham and Women's Hospital Research Administration Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 15-SEP-2005; Project End 31-JUL-2008 Summary: (provided by applicant): The frequency of liver disease in humans with cystic fibrosis (CF) (focal biliary fibrosis leading to multilobular cirrhosis) ranges up to 43%, with prevalence increasing with age. Multilobular cirrhosis manifesting clinically with portal hypertension has become the third leading cause of morbidity and premature death in CF, and when pulmonary disease is controlled with or without lung
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transplantation, liver disease is the leading cause of death. The etiology, mechanisms and pathogenesis of CF liver disease are unknown, and currently ursodeoxycholic acid is prescribed without compelling evidence of its efficacy. Extending preliminary studies from this laboratory, the ?F508 and G551D murine models of CF and wild-type (WT) mice will be studied: 1) to explore the hepatobiliary secretory abnormalities of pH, bilirubins, electrolytes and biliary lipids utilizing biophysical, pathophysiological and physical-chemical approaches; 2) to determine the pathogenesis of enteric hyperbilirubinbilia and to correlate this with ileal pH abnormalities, bile salt malabsorption, hepatic bile pH and liver disease; 3) to elucidate the pathophysiology of bile salt malabsorption as a cause of induced enterohepatic cycling of unconjugated bilirubin (UCB), focusing on the ileal bile salt transporter and its response to less alkaline lumenal pH; in addition, to study intestinally hCFTR-rescued CF mice to verify the molecular nature of the intestinal defect; 4) to image and quantify age and genderrelated liver histology and ultrastructural studies to detect deposits of metal bilirubinates intraductally and in biliary epithelial cells using transmission and scanning electron microscopy coupled with atomic emission spectroscopy, and to quantify the pathobiology of UCB-induced periductal inflammation, fibrogenesis and obliterative cholangitis; 5) to prevent and treat chronic liver disease of CF mice by a) targeting the biliary tree with norUDCA to increase pH of hepatic bile, b) targeting UCB formation and absorption in the distal gut by non-absorbed polymers with covalently linked Dglucaro-1,4-lactone or cholic acid, and c) targeting bile salt malabsorption using colesevelam HCI to prevent solubility of UCB or by normalizing the lumenal pH using amiloride, a carbonic anhydrase agonist, or by upregulating ASBT activity with budesonide. The molecular insights from these hypothesis-driven specific aims should provide data, molecular understanding and agents that are translatable to humans with CF and lead to new modalities for prevention and treatment of CF liver disease. •
Project Title: MUC4 MUCIN AND AIRWAY EPITHELIAL REGENERATION IN COPD Principal Investigator & Institution: Voynow, Judith A.; Associate Professor; Pediatrics; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): In chronic obstructive pulmonary diseases such as chronic bronchitis, and in cystic fibrosis, the airway epithelium is constantly exposed to neutrophil elastase (NE), an inflammatory protease. The cellular response to NE dictates the balance between epithelial injury and repair. A critical factor in this balance is the activation of the epidermal growth factor receptor (EGFR), a member of the ErbB receptor tyrosine kinase family. Activation of EGFR requires homo- or heterodimerization of the receptor. A major EGFR heterodimerization partner in airway epithelial cells is ErbB2. To date, the only ligand known to activate ErbB2 is MUC4. MUC4 is a major membrane-tethered, respiratory tract mucin with epidermal growth factor (EGF)-like domains. We have made four key observations supporting a critical role for MUC4 in activating the airway epithelial response to NE: (1) NE acts on airway epithelial cells to enhance MUC4 mRNA stability and increase MUC4 protein levels. (2) NE induces tyrosine phosphorylation of EGFR. (3) NE stimulates proliferation of normal human bronchial epithelial cells in serum-free and EGF-free media. 4. MUC4, ErbB2 and EGFR colocalize in injured superficial airway epithelial cells in vivo. These observations support the hypotheses that NE triggers a molecular cascade of events in airway epithelial cells by inducing the production of MUC4, a key regulatory molecule in the cascade, activating ErbB2, and thereby promoting the heterodimerization/activation of EGFR. EGFR activation is a critical prerequisite for epithelial proliferation. The Specific
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Cystic Fibrosis
Aims to be tested in this proposal are: (1) To determine whether NE induces MUC4activation of the ErbB2/EGFR receptor tyrosine kinase cascade, resulting in epithelial cell proliferation. (2) To identify the RNA stability domains and RNA-binding proteins regulating NE-induced expression of MUC4, a key molecule in this signaling cascade. (3) To determine the relevance of these signaling pathways in mediating epithelial proliferation in vivo in chronic bronchitis and cystic fibrosis. Our ultimate goal is to use information from this project to identify new biologic targets for rational therapies to induce normal airway epithelial proliferation and differentiation following injury. •
Project Title: NHLBI SHARED MICROARRAY FACILITIES Principal Investigator & Institution: Casavant, Thomas L.; Professor and Director; Pediatrics; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2005; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The over riding goal of this proposal is to facilitate the application of microarray technology to fundamental, hypothesis-driven research for NHLBI funded investigators at the University of Iowa. The proposed Shared Microarray Facility has three components: (A) Microarray Hybridization Laboratory, (B) Informatics Core Laboratory, and (C) Statistics Core Laboratory. The Microarray Hybridization Laboratory will be responsible for the following activities: (a) array fabrication: PCR amplification/purification of cDNA inserts from non-redundant arrayed cDNA collections, slide printing and processing; (b) RNA purification, target preparation/labeling, hybridization and post-hybridization processes, (c) scanning/imaging capturing, processing and analysis. Our proposal contains six projects linked to the laboratories of NHLBI funded investigators in the areas of heart and lung diseases. There are approximately 130 NHLBI investigators at the University of Iowa in the areas of heart, lung, blood, and sleep that could benefit from these facilities. The Shared Microarray Facility will provide these scientists with a broad range of individualized support including assistance with study design, construction of libraries, slide printing, analysis of microarray hybridization results including bioinformatic and statistical support. The bioinformatics support will also make sure that results from these studies are promptly made available to the community. The six initial projects include: 1) Differential Gene Expression in Developing Heart, 2) Differential Gene Expression in Circumventricular Organs: Insights to the Maintenance of Cardiovascular Homeostasis, 3) Differential Gene Expression Profiling in a Rat Model of Hypertension 4) Differential Gene Expression in Resting and RSV-Infected Airway Epithelia 5) Dissecting Airway Epithelial Innate Immune Responses using Microarray Technology 6) Differential Gene Expression in CF and non-CF Airway Epithelia.
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Project Title: NONINVASIVE ALCOHOLICS
BREATH
CONDENSATE:
ARDS
RISK
IN
Principal Investigator & Institution: Brown, Lou Ann S.; Professor; Pediatrics; Emory University 1784 North Decatur Road, Suite 510 Atlanta, Ga 30322 Timing: Fiscal Year 2005; Project Start 01-JUN-2005; Project End 31-MAY-2007 Summary: (provided by applicant): Chronic alcohol abuse significantly increases the incidence of ARDS in critically ill patients at risk for the syndrome (relative risk of 3.7 to1). Approximately 50% of patients with sepsis-associated ARDS have a history of alcohol abuse. However, the absence of biomarkers means that it is difficult to assess at the time of admission a history of alcohol abuse and an increased risk of ARDS. In the alveolar lining fluid, glutathione (GSH) is essential for detoxification and protection against tissue injury during ARDS. In non-cirrhotics, we showed that the alveolar lining
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fluid GSH was decreased by 80% and shifted to an oxidized state as evidenced by increased GSSG and hydrogen peroxide. Assessment of this chronic oxidant stress in the alveolar space may identify those subjects with an increased risk of ARDS. We recently developed methods to analyze GSH in exhaled breath condensate (EBC), enabling us to monitor alveolar GSH homeostasis and oxidant stress non-invasively. The goal of this proposal is to develop and validate the use of chronic oxidative stress markers in the EBC as an noninvasive tool to predict which critically ill trauma patient has an increased risk for development of ARDS. The aims for this R21 are to determine if markers of oxidant stress (GSH, GSSG, H202, isoprostane or acidification) in the EBC (1) of otherwise healthy alcoholics is a valid non-invasive tool to monitor oxidant stress in the alveolar space, (2) of critically ill trauma patients with a history of alcohol abuse is a valid non-invasive tool to monitor oxidant stress in the alveolar space and (3) can noninvasively predict which critically ill trauma patients have a high risk of developing ARDS. Validation of the EBC technique could potentially be useful in other disease states where decreased alveolar GSH is associated with risk of infection and lung injury such as HIV, cystic fibrosis and interstitial lung disease as well as identify patients that would benefit from antioxidant replacement therapy. Whether it is decreases in GSH or changes in the other oxidant stress markers, we anticipate that from this non-invasive technique we will identify specific cutoff values in the EBC that will serve as a predictive tool to identify those subjects who have chronic oxidative stress in the alveoli (in the absence of lung injury) and have the greatest risk for development of ARDS. •
Project Title: NOVEL SMALL-MOLECULE THERAPIES FOR CF Principal Investigator & Institution: Verkman, Alan S.; Professor; Medicine; University of California San Francisco 3333 California St., Ste. 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2005; Project Start 15-SEP-2005; Project End 31-JUL-2010 Summary: This is a proposal to establish a Cystic Fibrosis (CF) Research and Translational Core Center at the University of California, San Francisco and collaborating institutions. The focus of the Core Center is to facilitate the discovery and evaluation of novel small-molecule therapies for CF. This proposal is the culmination of 5 years of work establishing a unique academic drug discovery program to identify and characterize inhibitors of CFTR and activators of CF-causing CFTR mutants. The proposed Core Center will fund 7 Cores that will support the activities of 2 Pilot Projects and at least a dozen ongoing CF-related projects. The Core directors and users are in most cases senior CF investigators with recognized expertise in their areas of investigation and a history of productive collaboration. The Cores include: highthroughput screening, clinical resources, cell models, animal models, organic/medicinal chemistry, CFTR biochemistry, and electrophysiology. The principal projects to utilize the Core include the discovery and evaluation of small-molecules: to activate CFcausing CFTR mutants such as deltaF508 and G551D (for treatment of the underlying defect in CF); to inhibit CFTR (for development of CF animal models), to enhance nonviral gene delivery (for CF gene therapy), to kill bacteria (for CF antimicrobial therapy), and to reduce airway surface fluid viscosity (for therapy of CF lung disease). The goal of the research to be enhanced by the Core Center is to develop new small-molecules therapies for CF that can be translated into the clinic.
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Project Title: OLIGONUCLEOTIDES AS TOOLS FOR CHEMOTHERAPY Principal Investigator & Institution: Zamecnik, Paul Charles.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 15-JUN-2004; Project End 31-MAY-2007
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Cystic Fibrosis
Summary: (provided by applicant): Completion of sequencing of the human and of bacterial genomes has made it possible to apply the principle of oligonucleotide hybridization competition to the inhibition of nefarious genic expression. We shall focus our efforts on three targets: l) M. tuberculosis, with its uniquely constructed mycocerosic outer cell wall; 2) Cystic Fibrosis, in which for our novel oligonucleotide insertion technique we must pin down the extent of insertion. Present estimates, as a result of over thousand sequencings, are that insertion occurs in 10-25 percent of delta508 mRNA molecules; 3) Huntington's Disease, requiring further studies to firm up our finding of inhibition of expression of Huntington protein in tissue cultures from patients with this disease, using derivatives of antisense oligonucleotides. •
Project Title: P. AERUGINOSA AS A SURROGATE MARKER OF CYSTIC FIBROSIS Principal Investigator & Institution: Miller, Samuel I.; Professor; Medicine; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 01-JUL-2004; Project End 31-MAY-2007 Summary: (provided by applicant): Chronic pulmonary infection significantly limits the span and quality of life of children and young adults with cystic fibrosis (CF). CF is the result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and individuals with CF have innate immune alterations, which in turn lead to chronic pulmonary infection, inflammation and, ultimately, airway destruction. The respiratory tracts of most patients with CF (>80% by age 15) are infected with the opportunistic gram-negative bacterium Pseudomonas aeruginosa, and such infection is clearly associated with poor outcome. The development of strategies to prevent P. aeruginosa colonization and eliminate chronic infection will require an understanding of the natural history of the bacterial component of CF. P. aeruginosa infection in CF involves colonization early in life. Over many years the bacteria adapt to the CF airway environment with an increased ability to replicate and stimulate inflammatory responses that are ineffective against the bacteria but damage airways. This grant proposes to define common characteristics of P. aeruginosa adaptation to the CF airway by analyzing bacteria isolated from the airways of children with CF as part of a natural history study. Common characteristics of bacteria airway adaptation will be defined using biochemical and phenotypic characterization as well as the most modern techniques in biological research including: DNA microarray analysis, genome sequencing, and quantitative proteomic analysis with mass spectrometry. This proposal will establish prevalence and clinical correlations for the characteristics associated with adaptation to the CF airway by performing cross-sectional and longitudinal studies on CF children with disease of varying severity. The data obtained will test the hypothesis: that characteristics of P. aeruginosa clinical isolates from children with CF can function as markers to predict clinical outcome and therapeutic response. Furthermore, the knowledge obtained from this proposal may direct the development of new therapeutic interventions for CF patients.
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Project Title: PANCREATITIS
PHARMACOGENETICS
OF
ASPARAGINASE-INDUCED
Principal Investigator & Institution: Silverman, Lewis B.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 07-JUL-2003; Project End 31-MAY-2008 Summary: (provided by applicant): We seek to determine whether there is a genetic predisposition for the development of asparaginase-related pancreatitis. Asparaginase is
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a highly effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL), but is associated with significant side effects in up to one-third of patients. Patients who are unable to receive all of their intended doses of asparaginase have a higher relapse rate than those who are able to tolerate all or nearly all of their doses, with a 5-year event-free survival rate of 73% for asparaginase-intolerant and 90% for asparaginase-tolerant patients (p<0.01). The most common cause of asparaginase intolerance is pancreatitis. The mechanism of asparaginase-induced pancreatitis is unknown. Recent studies suggest that genetic factors predispose to several types of pancreatitis, including chronic idiopathic and alcohol-induced pancreatitis. Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been associated with pancreatitis in people without cystic fibrosis. We hypothesize that children with ALL who have germline mutations of CFTR might be at increased risk for the development of asparaginase-related pancreatitis. The proposed investigations bring together two groups, one with expertise in asparaginase and the treatment of ALL and the other with expertise in the analysis of CFTR gene mutations/variations, in order to determine whether there is a pharmacogenetic relationship between CFTR gene mutations and the development of asparaginase-related pancreatitis. The frequency of CFTR gene mutations will be compared in children with ALL who had asparaginaserelated pancreatitis and similarly treated children who did not. The finding of an association between asparaginase-related pancreatitis and CFTR gene mutations would make an important contribution to the understanding of the pathophysiology of drugrelated pancreatitis. Additionally, because potential therapeutic interventions for CFTRmediated pancreatitis are becoming available, the finding of an association might also lead to effective therapy for this currently untreatable form of pancreatitis. Prevention or treatment of asparaginase-induced pancreatitis could result in more children receiving all of their intended doses of asparaginase, potentially both reducing toxicity and enhancing efficacy of treatment for children with ALL. •
Project Title: POLYPEPTIDE CONFORMATION AND INTERACTION WITH HSP70 Principal Investigator & Institution: Cavagnero, Silvia; Chemistry; University of Wisconsin Madison Suite 6401 Madison, Wi 537151218 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): The goal of this proposal is to elucidate the conformation of N-terminal polypeptides of increasing length (belonging to the sequence of an all-alpha-helical single domain model protein) in the presence of the cotranslationally active chaperone Hsp70. In order to obtain information at amino-acid specific resolution, multidimensional NMR in the presence of isotopically labeled peptide and unlabeled chaperone will be employed. Other biophysical methods such as isothermal titration calorimetry, size exclusion chromatography and fluorescence spectroscopy will also be used. The work focuses on elongating N-terminal polypeptides derived from apomyoglobin, a relatively small and extremely well characterized system which serves as an excellent model for all-alpha-helical proteins. The proposed investigations will explore whether Hsp70 merely prevents interchain aggregation by holding a statistical coil status, or it also acts by inducing specific polypeptide conformations. This study is not intended to directly mimic intracellular cotranslational and immediately posttranslational folding events. On the other hand, it aims at providing a first order in vitro approximation to how Hsp70 is able to affect the conformational space of elongating polypeptides. The expected influence of specific cellrelated effects such as polypeptide tethering (to the ribosome exit channel) and molecular crowding are discussed in the proposal and will be addressed by separate
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additional experiments. Very little is known about the mechanisms by which Hsp70, the main cotranslationally active chaperone, influences the course of protein folding. Yet, progress is urgently needed in this area since defective action (or insufficient bioavailable amount) of cotranslational chaperones has been linked to the formation of incorrectly folded self-associated species such as those involved in a number of deadly diseases. These include cystic fibrosis, inflammatory heart disease, Crohn disease, P53related cancers, and several neurodegenerative disorders such as Huntington's and Alzheimer's disease. Experiments to be carried out include (a) high resolution secondary structure mapping of isotopically labeled polypeptides by NMR in the presence of unlabeled Hsp70 chaperone; (b) hydrogen/deuterium exchange pulse labeling kinetic experiments to detect the mechanisms of structure formation in the presence of Hsp70; (c) additional studies in the presence of the Hsp40 and Hsp70-nucleotide exchange factor cochaperones. •
Project Title: PPG-GENE THERAPY FOR CYSTIC FIBROSIS LUNG DISEASE Principal Investigator & Institution: Welsh, Michael J.; Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2005; Project Start 01-SEP-1997; Project End 31-MAR-2009 Summary: (provided by applicant): Gene transfer to the airways of patients with cystic fibrosis (CF) could represent a major therapeutic advance for this lethal disease. Although previous work in vitro, in animals and in people with CF has established the feasibility of gene transfer, it has also revealed the limitations of current approaches. The two greatest barriers are limited efficiency of gene transfer from the apical surface of differentiated airway epithelia and limited persistence of expression. The projects in this program utilize novel approaches and models to overcome these barriers. Recent work showed that adeno-associated viruses-5 (AAV5) vectors target the apical surface of differentiated airway epithelia, which makes them an attractive vector. Project by Welsh (subproject 0001) focuses on overcoming the limited packaging capacity of AAV vectors and will test the long-term potential of AAV5 vectors to correct the CF C1- transport defect. In Project by Zabner (subproject 0004), the investigators will study how AAV5 interacts with its apical membrane receptors, sialic acid and PDGF-receptor. They combine this with a structural analysis of the virus and its receptor. Project by McCray (subproject 0005) takes a related approach to achieving apical targeting and long-lasting expression by developing LCMV-pseudotyped lentivirus vectors. They investigate the virus:receptor interactions and will test the ability to achieve persistent expression in airway epithelia. Our ability to answer several crucial questions about gene transfer has been hampered by the lack of an animal model that faithfully reproduces the lung disease found in humans with CF. Project by Welsh (subproject 0006) addresses this problem by developing a porcine model of CF. The PPG benefits from outstanding support by the In Vitro Models and Cell Culture Core, the Gene Transfer Vector Core, and the Administrative Core. These studies will take us closer to our long-term goal of developing new therapies for people who suffer from CF.
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Project Title: PRECLINICAL DEVELOPMENT OF INO-4995 FOR CYSTIC FIBROSIS Principal Investigator & Institution: Traynor-Kaplan, Alexis E.; Inologic, Inc. 225 108Th Ave Ne, Ste 570 Bellevue, Wa 98004 Timing: Fiscal Year 2005; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Inositol signaling molecules (ISMs) have been linked to regulation of ion channels. Evidence indicates that an lnsP4, myo-inositol 3,4,5,6tetrakisphosphate [lns(3,4,5,6)P4] and its analogs regulate CI- channels in multiple
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epithelia. While inositol polyphosphates are highly charged, making them unlikely to cross membranes, we have developed membrane permeant forms that enable intracellular delivery recapitulating the activity of endogenous inositol polyphosphates. These activities suggest that derivatives of inositol polyphosphates may be therapeutic in cystic fibrosis (CF) and other diseases characterized by abnormal ion flux. In contrast to extracellularly acting agents directed against the extracellular domain of ion channel pores, membrane-permeant inositol polyphosphate analogs modulate ion channel activities from inside the cell. We have identified an lnsP4 derivative, INO-4995, as a potential treatment for CF and have initiated development toward the filing of an IND. INO-4995 is selective for CF epithelial tissue as compared to non-CF tissue. The goal of the current study is to predict how INO-4995 functions in CF tissue and in different genetic backgrounds. This will aid in identifying and treating an optimal patient population most likely to benefit from the compound's therapeutic effects. The specific aims include: Aim 1: Assess the in-vitro cellular metabolism and the in-vivo pharmacokinetics of radiolabeled INO-4995. Aim 2: Assess the bioavailability and safety of INO-4995 using an epithelial airway tissue culture system. Aim 3: Determine the effects of INO-4995 on nasal transepithelial voltage of CF and non-CF mice under a variety of conditions, including genetic background, age, and gender. To date, work has been performed with tissue from deltaF508 homozygous CF patients. We will extend this work to assess the electrophysiological effects of the compound on tissue with other mutations or in tissue that is heterozygous for deltaF508. We will also compare the effect of the compound in deltaF508 homozygous mice on different genetic backgrounds. The broader aim of this study is to further characterize the biological responses to INO-4995, and in conjunction with the ongoing preclinical and clinical development program for CF, would offer further validation for the therapeutic utility of an inositol polyphosphate signaling molecule derivative. This work will help delineate the mechanism of action of INO-4995, will assess the bioavailability and safety, and will help define dosing/regimen protocols, and could expedite regulatory and clinical planning during the development process. •
Project Title: PSEUDOMONAS AERUGINOSA LIPID A Principal Investigator & Institution: Ernst, Robert K.; Medicine; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2006; Project Start 01-JUL-2000; Project End 31-JUL-2011 Summary: (provided by applicant): Patients with cystic fibrosis, (CF) suffer from chronic airway infections with the opportunistic pathogen Pseudomonas aeruginosa (PA), and experience worsening, irreversible lung injury leading to premature death. This injury is mediated by an inflammatory process that results, at least in part, from stimulation of the innate immune system by PA lipid A, the bioactive component of lipopolysaccharide (IPS). PA isolates from CF patients constitutively synthesize lipid A with unique structural modifications. The synthesis of these structures may be essential for CF lung disease pathogenesis. PA with unique lipid A could contribute to CF lung disease in two ways: by increasing host inflammatory responses, and by increasing bacterial resistance to elements of host innate immunity, such as cationic antimicrobial peptides (CAMPs) or antibiotics. We therefore propose to identify the relevance and regulation of these lipid A structural modifications to CF pulmonary disease by identifying genes involved in their synthesis, constructing isogenic PA mutant strains unable to synthesize specific lipid A structures, and testing PA with these specific lipid A structures in models of lung inflammation and their susceptibility to CAMPs. These studies will provide insight into bacterial mechanisms that contribute to CF lung disease, including the role of lipid A modifying enzymes. Such enzymes may provide
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novel targets for the development of drugs to treat PA lung infections and their inflammatory consequences. The focus of this proposal is to further define enzymes required for the synthesis and regulation of cystic fibrosis-specific lipid A, the bioactive component of lipopolysaccharide in a variety of Pseudomonas aeruginosa clinical isolate backgrounds. P. aeruginosa isolates from patients with cystic fibrosis constitutively synthesize lipid A with unique structural modifications. In addition, the role of specific lipid A structures in modulation of the host the innate immune system and inflammatory responses will be determined. These studies could lead to the identification of candidate protein targets that block the synthesis of CF-specific lipid A structures and render P. aeruginosa more susceptible to host cell killing and/or conventional antibiotic intervention. •
Project Title: MUCOIDY
PSEUDOMONAS
IN
CYSTIC
FIBROSIS-REGULATION
OF
Principal Investigator & Institution: Deretic, Vojo P.; Professor; Molecular Genetics & Microbiol; University of New Mexico Albuquerque Health Sciences Ctr, Financial Srvs Div. Albuquerque, Nm 87131 Timing: Fiscal Year 2005; Project Start 01-FEB-1992; Project End 31-JUL-2007 Summary: (provided by applicant): Pseudomonas aeruginosa is the major cause of chronic respiratory infections in cystic fibrosis (CF) leading to persistent inflammation, lung tissue damage and high morbidity and mortality in this most common inheritable disease in Caucasians. The initially invading strains of P. aeruginosa are nonmucoid, but concomitantly with the establishment of a chronic infection, mucoid mutants overproducing the exopolysaccharide alginate emerge. The chronic infection, and additional host and bacterial factors that are not fully understood, lead to increased inflammation and irreversible tissue damage. This laboratory has previously described the mechanism of conversion to mucoidy which occurs via muc mutations that lead to the activation of the alternative sigma factor AIgU, the P. aeruginosa ortholog of the bacterial extreme stress sigma factor sigma-E. While alginate overproduction plays a role in reducing pulmonary clearance, we hypothesize that additional factors, coexpressed with alginate upon activation of AlgU, may contribute to pathogenesis in CF, since sigma factors normally direct transcription of a large number of gene subsets. So far, we have identified 10 additional genes controlled by A1gU that are activated in muc mutants. Importantly, a significant portion of these genes encode lipoproteins. Since lipoproteins play a role in innate proinflammatory signaling, we additionally hypothesize that P. aeruginosa products co-expressed with mucoidy contribute to inflammation in CF via pattern recognition receptors. Here we propose to: 1.further identify P. aeruginosa genes whose expression is activated in mucoid cells using conventional methods and techniques of global expression profiling; 2.analyze P. aeruginosa proinflammatory products associated with conversion to mucoidy; 3. analyze the role of pattern recognition receptors and signaling pathways involved in innate host response to P. aeruginosa products; and 4. study proinflammatory signaling in CF in combination with altered responses in CF cells. The specific alms of this proposal are to: 1) Identify P. aeruginosa genes that are activated or otherwise affected during conversion to mucoidy. 2) Determine how products of mucoid P. aeruginosa contribute to inflammation in CF. 3) Examine how proinflammatory products of mucoid P. aeruginosa synergize with the basic defect in CF and its downstream physiological effects, leading to exacerbation of pulmonary disease. These studies are expected to improve our understanding of respiratory pathogenesis in CF, and lead to new treatments of presently incurable lung infections associated with this disease.
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Project Title: PULMONARY BENEFITS OF CYSTIC FIBROSIS NEONATAL SCREENING Principal Investigator & Institution: Farrell, Philip M.; Pediatrics; University of Wisconsin Madison Suite 6401 Madison, Wi 537151218 Timing: Fiscal Year 2005; Project Start 01-AUG-1985; Project End 31-MAR-2007 Summary: 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 initiation of treatment. Advances of the past two decades have made CF screening feasible using routinely collected neonatal blood specimens and determining trypsinogen levels and CF mutations by DNA analyses. Our overall goal is to address the following hypothesis: Early diagnosis of CF through neonatal screening will be medically beneficial without major risks. "Medically beneficial" refers to better nutritional and/or pulmonary status, whereas "risks" include laboratory errors, potential iatrogenic medical sequelae, 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 delineation of the characteristic epidemiologic features of CF. A comprehensive, randomized clinical trial emphasizing early diagnosis as the key variable has been underway since 1985. Nutritional status has been assessed by anthropometric and biochemical methods, and the results have demonstrated significant benefits in the screened group. Answering the important questions about pulmonary outcome will require five more years of follow-up evaluation focused on lung function measures and quantitative chest radiology, including high resolution computerized tomography. If the questions underlying this study are answered favorably, it is likely that neonatal screening using a combination of trypsinogen and DNA tests will become the routine method for identifying new cases of CF and that diagnosis in early infancy will allow prevention of many clinically-significant problems such as malnutrition. If CF neonatal screening is implemented nationally, however, several epidemiologic gaps must be closed, and this will require more precise data on the course of this disease and determination of risk factors for pulmonary infections with Pseudomonas aeruginosa. This project will generate that important information, as well as essential data on the quality of life and cognitive function of children with CF who experience early or delayed diagnosis. We will also clarify the risks of screening and delineate for the first time the costs of diagnosis and treatment of CF throughout childhood as well as the cost-effectiveness of screening.
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Project Title: QUALITY OF LIFE IN ADVANCED CF IN A TRANSPLANTATION ERA Principal Investigator & Institution: Robinson, Walter M.; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2005; Project Start 04-JUN-2003; Project End 31-MAY-2006 Summary: (provided by investigator): Cystic fibrosis (CF), the most common lethal inherited illness among Caucasians in North America, is undergoing a revolution. The advent of lung transplantation, while offering a chance at extended life for many patients, has undone the previous consensus on the appropriate treatment of end-stage symptoms, the use of assisted ventilation, and the management of psychosocial suffering. In order to answer the call of the Institute of Medicine for the integration of palliative care into chronic and ultimately fatal illnesses, a comprehensive study of the care of patients with end-stage cystic fibrosis is proposed. The purpose of the proposed study is to gather empirical data on the experiences of CF patients, their families, and
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caregivers during the final years of life. The specific aim is to understand the quality of life and the social and logistical needs of CF patients and their families, and to understand how the these factors may differ depending on the patient's end-of-life trajectory. The approach for addressing these questions will be a three-year longitudinal panel study of adult CF patients with advanced disease. Ten CF centers from across the United States will enroll adult patients with a predicted life expectancy of two to three years; these patients will be followed in a prospective manner for 36 months. The study will employ three methods of data collection: (1) self-administered surveys of patients, (2) telephone interviews with patients, family members of patients who die, and clinicians, and (3) medical record abstraction. Expected outcomes from this research will be decreased suffering and enhanced quality of life for CF patients, guidelines for the appropriate use of technological interventions for patients both on and off the transplant list, new care models that can accommodate both the goals of transplantation and the goals of palliative care, better systems of care for the families of seriously ill CF patients, and increased understanding of the role of palliative care and technological intervention in other chronic, ultimately fatal illnesses. •
Project Title: QUANTITATIVE TRANSPORTERS
STRUCTURE
&
FUNCTION
OF
ABC
Principal Investigator & Institution: Zou, Xiaoqin; Dalton Cardiovascular Research Center; University of Missouri-Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2005; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant) The ATP-binding cassette (ABC) superfamily is one of the largest and most highly conserved class of integral membrane proteins and is involved in the ATP-dependent transport of solutes across cellular membranes. Prominent members in this family include P-glycoprotein linked to multidrug resistance to chemotherapy for cancers and the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a chloride channel whose malfunction causes cystic fibrosis, the most common lethal genetic disease in Caucasians. One unique feature of CFTR is that it has two distinct nucleotide binding domains (NBDs) that play critical roles in the gating of CFTR channels. Our understanding of the molecular basis of the regulation mechanisms, however, remains primitive. Unresolved questions include: What is the functional role of the individual NBD? Which NBD opens the channel, and which NBD closes the channel? How do the two NBDs interact with each other? Do they form a dimeric structure? If yes, does this dimeric structure depend on the state of the channel? These are the fundamental questions that interest a broad spectrum of biologists. A quantitative, multi-disciplinary approach will be used to tackle the molecular mechanisms whereby CFTR gating is regulated. It is a combination of structural modeling, energetic studies, patch-clamp recordings, biochemical assays and chemical synthesis. We plan to investigate quantitatively the functional roles of NBDs in the gating of CFTR channels. The two parallel aims in this project are: Aim 1. To engineer the nucleotide-binding pockets of CFTR to distinguish the functional roles of the NBDs. Aim 2. To investigate the hetero-dimeric structure of the NBD complex. A clear understanding of the quantitative mechanisms of the functions of CFTR is essential to future therapeutic design for CFTR-related diseases such as cystic fibrosis and secretory diarrhea. The methods as well as the results are directly applicable; to quantitative structure-function studies on other ABC transporter proteins.
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Project Title: REGULATING MICROBIAL BIOFILM FORMATION: A NOVEL PROKARYOTIC MULTI-PROTEIN COMPLEX Principal Investigator & Institution: Urbauer, Jeffrey L.; Associate Professor; Biochem and Molecular Biology; University of Georgia (Uga) Office of Sponsored Programs Athens, Ga 306027411 Timing: Fiscal Year 2006; Project Start 01-JUN-2006; Project End 31-MAY-2008 Summary: (provided by applicant): The long term goals of the research are to identify and understand the details of the elaborate regulatory mechanisms utilized by Pseudomonas aeruginosa that result in biofilm formation and chronic infections of compromised individuals. Pseudomonas aeruginosa is the quintessential opportunistic pathogen. Chronic Pseudomonas aeruginosa infections of the lung are the most common cause of death in cystic fibrosis patients, underscoring the notoriety of Pseudomonas aeruginosa as a pathogen. There are many keys to the ability of this bacterium to colonize and survive in environments such as the cystic fibrosis lung and to thwart antibiotic regimes and circumvent the body's immune responses. These include the ability to form biofilms, to produce the exomucopolysaccharide alginate - a natural barrier and virulence factor, the ability to act as a community to coordinate biological responses via multiple quorum sensing systems, and the ability to sense and adapt to conditions of high oxidative stress, iron limitation, and available carbon sources. Not surprisingly, these attributes are tightly intertwined, and together reflect the complexity and elegance of the regulatory network in Pseudomonas aeruginosa. We have discovered a novel multi-protein complex in Pseudomonas aeruginosa that includes proteins integral to quorum sensing, alginate biosynthesis regulation, the oxidative stress response and the response to environmental iron and carbon, including the novel protein AlgH whose function is not understood. Based on the identities of the proteins in the complex, and based on fact that these responses are integral to biofilm formation and colonization and survival in the cystic fibrosis lung, it functions to integrate the responses to a variety of key biological signals and is essential for survival in the cystic fibrosis lung. Furthermore, because these systems (the quorum sensing system(s), the alginate biosynthesis regulatory system, etc.) are good targets for controlling Pseudomonas aeruginosa infections, targeting this novel protein complex pharmaceutically should be quite advantageous as multiple systems will simultaneously be disrupted. Our overall hypothesis is that the intricate regulatory and adaptive mechanisms used by Pseudomonas aeruginosa to survive and thrive in the cystic fibrosis lung as biofilms can be disrupted and controlled by regulating the formation/functions) of this multi-protein complex. To begin to address this broad hypothesis, we propose to; 1) Establish the requirements for formation of the multiprotein complex, 2) Identify the interprotein interactions in the multi-protein complex and determine the structural topology of the complex, 3) Solve the structures of component proteins of the multi-protein complex at high resolution, and 4) Initiate functional studies of the complex. The results of the research should provide important new strategies for prevention and treatment of infections by bacteria that form biofilms.
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Project Title: REGULATION OF AIRWAY LACTOPEROXIDASE HOST DEFENSE Principal Investigator & Institution: Conner, Gregory E.; Associate Professor; Cell Biology and Anatomy; University of Miami-Medical School 1507 Levante Avenue Coral Gables, Fl 33124 Timing: Fiscal Year 2006; Project Start 01-MAR-2001; Project End 31-MAR-2010 Summary: (provided by applicant): The lactoperoxidase (LPO) system is a significant contributor to airway host defense against bacteria, viruses and fungi and also is a major
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consumer of airway H2O2 that in turn is associated with airway inflammation. A loss of LPO activity may lead to increased airway infection, while any increase in LPO could have injurious consequences. This application will test the hypothesis that all components of the LPO system, including LPO enzyme expression and secretion, SCN~ transport across the epithelium and H2O2 production, are coordinately regulated and that an absence of the LPO substrate, SCN~, in cystic fibrosis (CF) may contribute to pathogenesis. This hypothesis is supported by a computational model of LPO system activity in airway surface liquid that predicts any unbalance in the components will render the system inadequate for host defense. The hypothesis and model are supported by preliminary data showing: a) CF airway epithelia lack normal transport of LPO's substrate, SCN~, to the apical surface that may contribute to airway infections and inflammation; b) airway epithelia produce H2O2 through Duox, an NADPH oxidase that may be regulated by intracellular [Ca2+]; c) reactive oxygen species (ROS) increase expression of LPO; and d) Duox and LPO mRNAs are up-regulated in CF airway epithelia. Specific Aim 1 will address regulation of Duox H2O2 production in normal and CF airway epithelial cells by changes in [Ca2+]i, cAMP, SCN~ or proinflammatory and infection related stimuli. Specific Aim 2 will test the hypothesis that defective SCN~ transport in CF airway epithelia results in decreased SCN~ in CF airway secretions in vivo that then may compromise host defense. SCN~ and peroxidase endproducts will be determined in exhaled breath condensate using liquid chromatography in tandem with electrospray ionization-mass spectrometry. Specific Aim 3 will test the hypothesis that ROS and/or SCN~ increases LPO mRNA expression in normal and CF airway epithelia by using turnover studies and nuclear runoff assays. The 5' end of LPO mRNA will be mapped by RACE and promoter elements in upstream sequences identified. Specific Aim 4 will test the hypothesis that depressed CF airway SCN~ levels contribute to neutrophil-mediated oxidative damage and to the phenotype of colonizing bacteria observed in CF airways. Lay Summary: These experiments will provide new information about physiological defects in cystic fibrosis patients that may lead to new therapeutic approaches to treating this disease. •
Project Title: REGULATION OF DROSOPHILA EPITHELIAL POLARITY Principal Investigator & Institution: Bilder, David; Molecular and Cell Biology (Mcb); University of California Berkeley 2150 Shattuck Avenue, Room 313 Berkeley, Ca 947045940 Timing: Fiscal Year 2005; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Epithelial cells have a distinct architecture, including an apico-basally polarized plasma membrane that is critical for their proper function in embryonic development and adult physiology. Defects in epithelial polarity contribute to many human diseases, including congestive heart failure and cystic fibrosis, and have been implicated in the transition between benign and malignant carcinomas. The long-term goal of this project is to understand the cellular and molecular mechanisms that generate epithelial polarity. While studies in cell culture have identified surface cues responsible for initiating epithelial polarization, the identity and mechanism of proteins that regulate the internal cellular machinery, such as the cytoskeleton and protein trafficking pathways, to execute polarity are not known. To identify such regulators we have used genetic screens in Drosophila to search for proteins required for epithelial architecture of the embryonic, larval, or adult stages. Our screens have identified a cell junction-localized protein called Scribble (Scrib) that is essential for the polarity of epithelia at all three stages of development. Scrib also acts as a tumor suppressor, revealing that Scrib links polarity and proliferation control in Drosophila. Scrib encodes a protein with four PDZ protein-protein interaction domains,
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suggesting that it acts as a scaffolding protein. PDZ domains are found in many proteins implicated in cell polarity, but the mechanism of PDZ-mediated polarization is not known. The experiments in this proposal are designed to uncover the mechanism of Scrib polarizing activity by isolating the proteins with which Scrib interacts to mediate polarity. The aims are: 1) Determine the Scrib interaction domains required for polarity regulation; 2) Biochemically isolate new members of the Scrib complex, and characterize their functions in epithelia; and 3) Genetically identify additional genes in the Scrib pathway as modifiers of Scrib activity. Given the strong conservation of Scrib structure, function, and localization across phylogeny, it is likely that our results will provide new insight into the mechanisms of epithelial polarity in all animals, and inform our understanding of how loss of epithelial cytoarchitecture may contribute to human tumor progression. •
Project Title: REGULATION OF SECRETORY ION CHANNELS IN COLONIC CRYPTS Principal Investigator & Institution: Halm, Dan R.; Associate Professor; Physiology and Biophysics; Wright State University Dayton, Oh 45435 Timing: Fiscal Year 2005; Project Start 15-MAY-2005; Project End 31-MAR-2010 Summary: (provided by applicant): The central objective of this project is to determine the mechanisms regulating Cl- and K+ channels involved in active Cl- and K+ secretion across the mammalian colonic epithelium, since these channels are key elements in stimulating these distinct modes of ion secretion; Mucosal secretory responses are a balance between activator and repressor pathways. Secretory diarrhea can result from a pathophysiologic stimulation of crypt epithelial cells, which actively secrete Cl- and K+ in response to increased intracellular cAMP. Conditions such as inflammatory bowel disease and cystic fibrosis also lead to altered ion and water transport via actions at these secretory epithelial cells. Inappropriate inhibitions of repressor pathways, in particular, are a likely source of secretory diarrhea for patients with ulcerative colitis. The working model is that active secretory processes for Cl- and K+ occur in columnar cells of the colonic crypt epithelium, such that these cells are a locus of dysfunction in many gastrointestinal diseases. Ion channels involved in Cl- and K+ secretion will be examined using patch-clamp electrophysiologic techniques to record membrane ionic currents. Recordings from isolated crypts allow study of both apical and basolateral membrane channels as well as the second messengers controlling ion channel activity. Fluorescent probes will be used to monitor involvement of cell Ca++ and pH as second messengers controlling ion channels. The specific aims are to determine regulatory mechanisms for the basolateral membrane K+ channels, the Cl- basolateral membrane channels and the apical membrane K+ and Cl- channels involved in fluid secretion. The long-term objective is to determine the regulatory mechanisms acting on the multiple secretory functions of intestinal epithelial cells during physiologic stimulation. These distinct modes of ion channel control are the basis for excessive and impaired secretory functions that occur in secretory diarrhea, ulcerative colitis and cystic fibrosis. The close relationship between prostaglandin stimulation of secretion and inflammatory responses provides an opportunity to develop pharmaceutical agents that differentially target the prostanoid receptor subtypes involved. Differences in the ion channel types supporting each mode of secretion also can be exploited to develop further agents for selective clinical intervention, without producing deleterious side effects. Thus, this project will lead to greater insight into the regulatory control of colonic fluid secretion and likely to therapeutic interventions for patients with life-threatening secretory activity.
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Project Title: ROLE OF OXYR IN P. AERUGINOSA BIOFILM RESISTANCE TO H202 Principal Investigator & Institution: Hassett, Daniel J.; Associate Professor; Molecular Genetics, Biochemistry & Microbiology; University of Cincinnati Sponsored Research Services Cincinnati, Oh 45221 Timing: Fiscal Year 2005; Project Start 01-AUG-2004; Project End 31-JUL-2008 Summary: (provided by applicant): In cystic fibrosis (CF) airway disease, there is compelling evidence for two distinct clinical stages, an oxidative phase (early-stage CF) and an anaerobic phase (chronic, late-stage CF). Within the thick mucus lining the CF airways, the bacteria grow as a "biofilm," a form of development that affords organisms the luxury of enhanced resistance to antibiotics and biocides. The early oxidative phase is based upon a rapid and dramatic influx of neutrophils to the upper airways, an event triggered by bacterial infection. When stimulated, these professional phagocytes mount a potent "respiratory burst," an antimicrobial product from which is hydrogen peroxide (H202). In fact, neutrophils can generate millimolar levels of H202 within the phagolysomal vacuole. In contrast, H202 levels in blood are nearly 1000-fold lower. Surprisingly, a mutant of the major CF pathogen, Pseudomonas aeruginosa, lacking the H202-responsive transactivator, OxyR, is exquisitely sensitive to H202 and the bacteria perish even in the presence of blood H202 levels (micromolar range). Were OxyR to be compromised during human infection, bacteria would be unable to elicit a systemic infection because they would die via H202-mediated killing. Therefore, the goal of this proposal is to determine if OxyR of P. aeruginosa could serve as a drug target during various P. aeruginosa infections. The goals of this proposal are to (i) define a role for OxyR in animal virulence and resistance to human neutrophils, (ii) define the lesions that evoke exquisite sensitivity to H202 in the OxyR mutant and what OxyR-controlled gene products contribute to maximal or minimal protection, and (iii) determine whether OxyR is critical for survival of biofilm bacteria to H202 and aminoglycosides.
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Project Title: SERINE-PROTEASE EFFECTS ON THE EPITHELIAL SODIUM CHANNEL Principal Investigator & Institution: Caldwell, Ray A.; Cystic Fibrosis/Pulmonary Research & Treatment Center; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2005; Project Start 15-SEP-2004; Project End 31-JUL-2007 Summary: (provided by applicant): Dr. Ray A. Caldwell is proposing original research for understanding the physiological regulation of the epithelial sodium channel (ENaC) by serine proteases (SPs). The recent discovery of endogenous epithelial SPs and their effects on ENaC reveal a novel and potentially important pathway for epithelial Na+transport. The candidate probes the effects of SPs on ENaC at the most basic level, the single channel, and provides direct evidence for an elusive subset (i.e. silent) of ENaCs that exhibit a robust increase in channel open probability (Po) when acted on by low concentrations of SP. To elucidate the mechanism(s) by which SPs increase ENaCmediated currents, Dr. Caldwell will test the following hypothesis: SPs increase EnaC Po through proteolytic cleavage of an extracellular gating regulatory domain. To achieve this objective, he will use the patch-clamp technique to address 3 specific aims: 1) to determine the mechanism of action by characterizing the effect(s) of SPs on ENaC, 2) to elucidate the putative ENaC gating domain by engineering mutations in the extracellular loop of the protein that renders the channel insensitive to SPs, and 3) to test the role of these protease-sensitive gating domains in epithelial models of ENaC function. Experimental results from these studies are anticipated to have an immediate
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impact on existing models of ENaC regulation. For instance, Dr. Caldwell's recently published work challenges the view that ENaC, residing at the cell surface membrane, is constitutively active, and regulated only through endo/exocytosis. Results from the experiments described will be used to provide a more comprehensive model of epithelial Na+transport as well as potentially novel therapeutic approaches to diseases involving ENaC, such as cystic fibrosis and hypertension. The KO1 award will provide the foundation for Dr. Caldwell to pursue his career goals of establishing scientific funding and continued publication of research results in peer-reviewed journals. Collectively, these components will be vital for him to emerge as an independent investigator •
Project Title: SILVER CARBENE COMPLEXES AS TREATMENT OF CF LUNG DISEASE Principal Investigator & Institution: Cannon, Carolyn Louise.; Pediatrics; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2009 Summary: (provided by applicant): The long-term goal of these studies is to explore the utility of silver carbene complexes as antimicrobial agents in the treatment of pulmonary infections with emphasis on treatment of the chronic infections of the cystic fibrosis (CF) lung. Silver N-heterocyclic carbene complexes have antimicrobial activity against all bacterial species tested to date including the CF lung pathogens Pseudomonas aeruginosa and Burkholderia cepacia complex (Bcc) organisms. The silver carbene complexes are water soluble, and hence amenable to nebulization for drug delivery. Silver complexes have a long history of safe use for topical applications; however, the use of silver compounds to treat pulmonary infections has not been explored. In addition to in vitro and in vivo toxicity studies aimed at determining the effects of silver complexes on the respiratory epithelium, we will establish the efficacy of these compounds for treatment of the primary CF pathogen P. aeruginosa, as well as the less common Bcc organisms, particularly B. dolosa, the causative agent of a recent epidemic. The B. dolosa strains are the most antibiotic resistant among the Bcc organisms. Virtually nothing is known about the pathogenesis of the lung infections caused by B. dolosa, and no effective therapy currently exists for these patients. We aim to characterize a novel murine model of B. dolosa infection and use this model, as well as more established models of P. aeruginosa lung infections, to test the in vivo properties of these newly developed silver-based antimicrobial agents. Specifically, we aim to 1) synthesize silver carbene complexes as candidate antimicrobial agents; 2) determine the antimicrobial properties and toxicity profiles of the silver carbene compounds with the most promising physical properties, as well as the mechanisms of epithelial cell-silver toxicity or detoxification; and 3) develop murine models of chronic pulmonary infection with resistant CF pathogens and use these models to determine the in vivo efficacy of the leading silver carbene compounds for treatment of pulmonary infections.
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Project Title: STRUCTURAL STUDIES OF BACTERIAL QUORUM SENSING REGULATOR Principal Investigator & Institution: Churchill, Mair E.; Associate Professor; Pharmacology; University of Colorado Denver/Hsc Aurora P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2005; Project Start 01-JUL-2001; Project End 31-MAY-2007 Summary: (provided by applicant): Persistent bacterial infections are a major cause of death in cystic fibrosis patients and immune-compromised individuals. A number of
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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. •
Project Title: STRUCTURE AND MECHANISM OF THE ABC MALTOSE TRANSPORTER Principal Investigator & Institution: Chen, Jue; Biological Sciences; Purdue University West Lafayette 302 Wood St West Lafayette, in 479072108 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): ATP-binding cassette (ABC) transporters are ubiquitous transmembrane protein complexes that couple ATP binding and hydrolysis to the movement of substances across the membrane. More than a dozen human diseases have been traced to ABC proteins including cystic fibrosis, Startgardt disease and Tangier disease. Over-expression of some ABC transporters in tumor cells confers drug resistance by pumping the drugs out of the cells, a phenomenon that becomes one of the major barriers to effective treatment of cancer. We propose to study the molecular mechanism underlying the active transport process mediated by ABC proteins, using the E coli maltose transporter (MalFGK2) as a model system. Specifically, we plan to: (1) determine the crystal structures of the ATPase subunit, MalK, in different catalytic stages of the ATP hydrolysis; (2) to study biochemically and physically the mechanism underlying inducer exclusion, in which Enzyme IIAglc binds to MalK and inhibits maltose transport when glucose is present in the medium; (3) to reveal the molecular interface between MalK and the transmembrane subunits using various biochemical and physical methods; and (4) to determine the crystal structure of the entire transport complex in a transition-state-like intermediate form. At the completion of the proposed studies, we expect that we will have gained new knowledge on how the ATPase activity of the transporter is regulated, how ATPase subunits interact with the transmembrane subunits, and what happens during the maltose transport cycle. Because all members of ABC transporter family share a common domain organization and high degree of
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sequence similarity, the knowledge of the E. coli maltose transport mechanism will advance our understanding of how conformational changes of ABC transporters facilitate the transport processes. •
Project Title: THE CYSTIC FIBROSIS GENE AND CHRONIC PANCREATITIS Principal Investigator & Institution: Cohn, Jonathan A.; Professor; Medicine; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2005; Project Start 15-SEP-2005; Project End 31-JUL-2010 Summary: (provided by applicant): This project's general hypothesis is that genetic factors influence individual susceptibility to chronic pancreatitis (CP). Past work from this lab associated idiopathic CP (ICP) with mutations of CFTR, the cystic fibrosis gene. Specifically, 15-20% of Caucasian ICP patients were found to have two CFTR mutations, abnormal nasal CFTR-mediated ion transport, and extra pancreatic findings consistent with reduced CFTR function. This proposal follow s up on these findings by addressing two aims: AIM #1 will test a series of ICP patients for CFTR mutations and for CFTR function. This effort is designed to identify the CFTR genotypes causing highest susceptibility to ICP and to measure how much these genotypes influence ICP risk. Caucasian and African-American ICP patients will be compared wit h controls (without pancreatitis) by comprehensively testing the CFTR gene. CFTR functional testing will then be used to confirm the impact of these genotypes on CFTR-mediated ion transport and to identify patients wit h CFTR-related ICP in whom reduced CFTR function would not have been predicted by DNA testing (e.g., due to polymorphism s or splice variants).Additional studies will test the prediction that the N34S PSTI mutation independently increases ICP risk in individuals with CFTR mutations. AIM 2 will study the role of CFTR in alcoholic CP (ACP). Data from several groups argues against a major role for CFTR in determine in g ACP risk in most cases. Nonetheless, we found an excess of CFTR mutation s in a pilot study of ACP patients who had early-onset disease (p <0.005). We therefore will compare the frequency of CFTR mutation s in patients with early-onset ACP (by age 36, first quartile) versus control subjects. Additional studies will explore the relationship between abnormal CFTR genotypes and CFTR-mediated nasal ion transport in ACP. CP affects over 300,000Americans. This study is expected to clarify the genetic basis for roughly 40,000 of these cases. It also is expected to develop improved CFTR gene testing methods that will identify an additional 160,000asymptomatic individual s who are highly susceptible to developing CP (roughly 200 times normal). Finally, this data will provide a foundation for further studies testing whether CP-associated abnormal CFTR genotypes affect pancreatic ductal secretion in vivo in susceptible individuals who have not yet developed CP. Thus, this project's general goals are to develop methods to identify health y individuals who are highly susceptible to CP and CP, and to work towards developing preventative therapy for these individuals.
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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 Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; 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
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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 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. •
Project Title: TRAFFICKING AND REGULATION OF THE EPITHELIAL NA+ CHANNEL Principal Investigator & Institution: Johnson, John P.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2005; Project Start 01-FEB-2002; Project End 31-JAN-2006 Summary: (provided by applicant): Maintenance of extracellular fluid volume homeostasis is essential for hemodynamic stability, and abnormalities of renal sodium handling have been linked to cardiovascular disease and hypertension. Ultimate regulation of sodium excretion in the kidney occurs in the distal nephron via conductive transport through the amiloride sensitive epithelial Na+ channel (ENaC). ENaC expression and activity in the apical membrane of epithelial cells is the rate limiting step in Na+ reabsorption not only in kidney collecting duct, but in airway epithelia and colon as well. Abnormalities of ENaC function have been demonstrated in hereditary forms of hypertension, renal salt wasting, and cystic fibrosis. The long term goal of this research is to understand the factors that regulate ENaC expression in the apical membrane of epithelial cells and the mechanisms by which hormones, physiologic conditions and other channels (such as the cystic fibrosis transmembrane regulator, CFTR) control ENaC function. Experiments will define the synthesis, apical expression, endocytosis, recycling and degradation of ENaC subunits in well polarized kidney cells. We will then examine a novel paradigm to explain the non-coordinate regulation of ENaC subunits under basal and hormonally-stimulated conditions that we and other investigators have observed.
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Project Title: TRAFFICKING PATHWAYS TO THE CELL SURFACE IN YEAST Principal Investigator & Institution: Chang, Amy Y.; Molecular and Integrative Physiology; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; Project Start 01-MAY-1999; Project End 31-MAR-2009 Summary: (provided by applicant): We propose to study two major mechanisms that regulate the structure and function of the plasma membrane: ER quality control and lipid rafts. We have used mutants of PMA1 encoding the yeast plasma membrane H+ATPase as tools to understand normal membrane biogenesis as well as the molecular mechanisms of regulation at the ER and at the plasma membrane. The dominant negative Pma1-D378N mutant is recognized and targeted for destruction by the ERassociated degradation (ERAD) pathway, whereas the temperature-sensitive Pma1-10 mutant fails to associate with lipid rafts and is removed from the plasma membrane for vacuolar degradation. Each pma1 mutant has been used as the basis for genetic selection leading to identification of Eps1, a novel component of the ERAD pathway, and Yvh1, a dual-specificity phosphatase, which may play a role in quality control at the cell surface. This proposal integrates biochemical, cell biological and genetic approaches to study the molecular mechanisms of these novel proteins. Specific Aim I addresses a proposed role for Eps1, a member of the protein disulfide isomerase family, in substrate recognition during ERAD. In addition, the ERAD substrate, Pma1-D378N, will be analyzed in detail because it represents a major resource for studying ERAD. Specific Aim II uses the pma1-10 mutant and its suppressor yvh1 to study the relationship between protein phosphorylation, ubiquitination, association with lipid rafts, and protein stability. Our studies have important implications for understanding human diseases caused by misfolding and ERAD of important molecules, including cystic fibrosis. Our results on lipid rafts will have significance for understanding the immune response (during which signaling occurs in rafts), AIzheimer's disease (in which protein processing is raftbased), and lipid storage diseases (in which raft lipids are abnormally accumulated in lysosomes).
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Project Title: AERUGINOSA
TRANSCRIPTION
REGULATION
IN
PSEUDOMONAS
Principal Investigator & Institution: Dove, Simon L.; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2006; Project Start 01-JAN-2006; Project End 31-DEC-2010 Summary: (provided by applicant): Pseudomonas aeruginosa is an important opportunistic pathogen of humans that is notorious for being the principal cause of morbidity and mortality in Cystic Fibrosis (CF) patients; chronic colonization of the CF lung by P. aeruginosa typically leads to progressive lung damage, and eventually respiratory failure and death. The proposed work will elucidate the function and mechanism of action of Tex, a putative transcription factor from P. aeruginosa that is required for infection of the host lung in a chronic disease model. Tex is highly conserved amongst bacteria, and is a homolog of the eukaryotic transcription elongation factor Spt6. The underlying hypothesis for the proposed study is that Tex plays an important role in P. aeruginosa pathogenesis by influencing the expression of virulence genes that are themselves important for infection of, or survival within, the host. In support of this idea, preliminary experiments indicate that Tex associates with RNA polymerase (RNAP), the central enzyme of gene expression, and that Tex can influence the expression of a subset of genes in P. aeruginosa. Furthermore these experiments reveal that Tex associates not only with RNAP but also with components of a putative
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multi-subunit complex, termed the RNA degradosome: a ribonuclease-containing complex first described in E. coli that is predicted to be primarily involved in the degradation of mRNA. These findings raise the possibility that the transcription machinery may be operationally linked to the RNA degradation machinery in P. aeruginosa. Such a link could conceivably facilitate any requisite processing or degradation of a particular transcript and may represent a novel mechanism for eliciting gene control. The proposed studies will identify genes whose expression is influenced by Tex, identify RNAs that co-purify with Tex, and test specific models for how Tex might influence gene expression. With a high-resolution crystal structure of Tex as a guide, we will explore which structural features of Tex are important for its function. Moreover, we will investigate further the nature of those protein complexes that contain Tex and investigate the interactions of Tex with both RNAP and components of the putative degradosome in P. aeruginosa. The proposed experiments should not only shed light on the molecular basis for the importance of Tex in pathogenesis, but may also facilitate the development of novel therapeutic agents that can be used to combat P. aeruginosa infection in the CF lung. •
Project Title: VIRTUAL LUNG PROJECT: INTEGRATED MODELING OF EPITHELIAL Principal Investigator & Institution: Superfine, Richard; Bowman and Gordon Gray Professor; Physics and Astronomy; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2011 Summary: (provided by applicant): The flow of liquid on mucosal surfaces is ubiquitous in human physiology. The failure of cilia and airflow induced liquid flow in the lungs (mucus clearance), as in Cystic Fibrosis, primary cilia dyskinesis, and environmentally damaged lungs, leads to severe health problems as the lung tissue will be destroyed by infections that cannot be cleared. Significant progress has been made in recent years in identifying the key genetic mutation responsible for Cystic Fibrosis, studying the hydrodynamics and biochemistry of airway mucus and beginning to develop effective treatments. In parallel, theory and simulation have begun to tackle issues such as the basis for force production in biological molecules, the rheology of biological fluids and hydrodynamics of viscous, complex flows. We stand at a critical time when an understanding of biological systems assembled into a unified simulation is essential for making breakthroughs in the science of microbiological hydrodynamics. The approach of this project is to develop sophisticated physics-based models of polymer dynamics and viscoelastic hydrodynamics in close coordination with experiments in human bronchial epithelial cell cultures. Through a combination of established and advanced techniques, the project will develop an integrated view of the biophysics of the mucus clearance system from the molecular scale seen by signaling molecules and viruses, up to the millimeter scales that control flow. By combining a team of researchers from Applied Mathematics, Chemistry, Physics and Astronomy, Biochemistry and Biophysics, and the Cystic Fibrosis Center, the long term goal is to develop an integrated computational model that will be able to predict and evaluate truly effective therapeutic strategies. The challenge in developing this comprehensive approach is to proceed through a series of research goals that accomplish short range impact.
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NTIS (National Technical Information Service) The NTIS (www.ntis.gov), a service of the U.S. Department of Commerce, has published the following information on sponsored studies related to cystic fibrosis: •
"Carrier Screening, Cystic fibrosis, and Stigma. - Draft rept," published in June 1992. Sponsored by: Office of Technology Assessment, Washington, DC. Written by: A. Asch. Abstract: A group of contractor documents were prepared for the OTA assessment entitled Cystic fibrosis and DNA Tests: Implications of Carrier Screening. They are being made available because they contain much useful information beyond that used in the OTA report. However, they are not endorsed by OTA, nor have they been reviewed by the Technology Assessment Board. The documents include: (1) Carrier Screening, Cystic fibrosis, and Stigma; (2) Cystic fibrosis, Genetic Screening, and Insurance: Summary of OTA Workshop Proceedings; (3) CORN Report on Funding of State Genetic Services Programs in the United States; (4) Genetics, Ethics, and Health Insurance; (5) The Cost Effectiveness of Population Carrier Screening for Cystic fibrosis: Draft Final Report; (6) The Cost Effectiveness of Population Carrier Screening for Cystic fibrosis: Final Report; (7) The Cost Effectiveness of Population Carrier Screening for Cystic fibrosis: Appendix to Final Report; and (8) Ethical Implications of Population Screening for Cystic fibrosis: The Concept of Harm and Claims of Wrongful Life.
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"Emerging Infectious Diseases, Volume 7, No. 1, Jan-Feb 2001. A Peer-Reviewed Journal Tracking and Analyzing Disease Trends," published in February 2001. Abstract: Contents: Emerging Chagas Disease: Trophic Network and Cycle of Transmission of Trypanosoma cruzi from Palm Trees in the Amazon; Persistence and Variability of Stenotrophomonas Maltophilia in Cystic fibrosis Patients, Madrid, 19911998; Hospital Control and Multidrug-Resistant Pulmonary Tuberculosis in Female Patients, Lima, Peru; Outbreak of West Nile Infection, Volgograd Region, Russia, 1999; Rapid Identification of Corynebacterium diphtheria Epidemic, Russian Federation; Shigella spp. Surveillance in Indonesia: The Emergence or Reemergence of S. dysenteriae; Tracking Cryptosporidium parvum by Sequence Analysis of Small DoubleStranded RNA; Pathologic Studies of Fatal Cases in Outbreak of Hand, Foot, and Mouth Disease, Taiwan; Disseminated Neocosmospora vasinfecta Infection in a Patient with Acute Nonlymphocytic Leukemia; Summary of the 5th International Conference on Legionella, Sept. 26-29, 2000; Announcement of the 4th Annual Conference on Vaccine Research, April 23-25, 2001; and Erratum, Vol. 6 No. 4.
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"Evaluation of Innovative Sweat-Based Drug Testing Techniques for Use in Criminal Justice Drug Testing. Final Report," published in July 2004. Sponsored by: Utah Univ., Salt Lake City. Center for Human Toxicology.; National Inst. of Standards and Technology (NEL), Gaithersburg, MD. Law Enforcement Standards Lab. Written by: R. F. Cook, D. C. Dove, D. J. Crouch and J. Baudys. Abstract: To improve the practice of drug testing in the criminal justice system, the National Institute of Justice (NIJ) funds research into new methods. The NIJ also evaluates the potential of alternative techniques. Research areas include the use of hair, saliva, and sweat as alternatives to urinalysis for drug testing. Types of investigation include evaluation of available collection devices, possible adaptation of such devices for use in the criminal justice system, development of quality assurance programs and standard reference materials, and improved methods for interpreting test results. This
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project assessed the feasibility for adapting a device originally designed to collect liquid perspiration from infants to test for Cystic fibrosis (the Macroduct(trademark))(star) for use in criminal justice settings to test for drug use (as an alternative to urinalysis and the sweat patch). The primary focus of this report is a comparison of liquid perspiration test results to urinalysis and sweat patch results, and an assessment of participant's perceptions of the different collection methods. Results from both a pilot study and subsequent field study are reported. •
"MEMS-based miniature DNA analysis system," published in April 1995. Sponsored by: Lawrence Livermore National Lab., CA.; Department of Energy, Washington, DC. Written by: M. A. Northrup, C. Gonzalez and D. Hadley. Abstract: We detail the design and development of a miniature thermal cycling instrument for performing the polymerase chain reaction (PCR) that uses microfabricated, silicon-based reaction chambers. The MEMS-based, battery-operated instrument shows significant improvements over commercial thermal cycling instrumentation. Several different biological systems have been amplified and verified with the miniature PCR instrument including the Human Immunodeficiency Virus; both cloned and genomic DNA templates of (beta) globin; and the genetic disease, Cystic fibrosis from human DNA. The miniaturization of a PCR thermal cycler is the initial module of a fully-integrated portable, low-power, rapid, and highly efficient bioanalytical instrument.
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"Newborn Screening for Cystic fibrosis: A Paradigm for Public Health Genetics Policy Development. Proceedings of a Workshop. Held in Atlanta, Georgia in January 1997. Morbidity and Mortality Weekly Report, Vol. 46, No. RR-16, December 12, 1997," published in December 1997. Sponsored by: Centers for Disease Control and Prevention, Atlanta, GA. Written by: J. Cono, N. L. Qualls, M. J. Khoury, W. H. Hannon and P. M. Farrell. Abstract: Cystic fibrosis (CF) is a genetic disease that can be detected in newborn infants by immunotrypsinogen testing. The sensitivity and specificity of such testing can now be improved as a result of the recent discovery of the Cystic fibrosis Transmembrane Conductance Regulatory (CFTR) gene. Although limited CF screening for newborns has been used since the 1980s, the clinical, social, and economic outcomes of population-based screening are controversial. During January 1997, a workshop was convened at CDC in Atlanta, Georgia to discuss the benefits and risks associated with screening newborns for CF and to develop public health policy concerning such screening. The workshop planning committee comprised representatives from CDC, the Cystic fibrosis Foundation, the National Institutes of Health, and the University of Wisconsin. Experts in the fields of CF, public health, the screening of newborns, and economics also contributed to discussions.
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 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
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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 cystic fibrosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type cystic fibrosis (or synonyms) into the search box, and click Go. The following is the type of output you can expect from PubMed for cystic fibrosis (hyperlinks lead to article summaries): •
A case of metoclopramide-induced oculogyric crisis in a 16-year-old girl with cystic fibrosis. Author(s): Lou E, Abou-Zeid N. Source: Southern Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17195428&query_hl=25&itool=pubmed_docsum
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A new insertion/deletion of the cystic fibrosis transmembrane conductance regulator gene accounts for 3.4% of cystic fibrosis mutations in Sardinia: implications for population screening. Author(s): Faa V, Bettoli PP, Demurtas M, Zanda M, Ferri V, Cao A, Rosatelli MC. Source: The Journal of Molecular Diagnostics : Jmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16931591&query_hl=25&itool=pubmed_docsum
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A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms. Author(s): Matsui H, Wagner VE, Hill DB, Schwab UE, Rogers TD, Button B, Taylor RM 2nd, Superfine R, Rubinstein M, Iglewski BH, Boucher RC. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17116883&query_hl=25&itool=pubmed_docsum
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A regulatory role of polycystin-1 on cystic fibrosis transmembrane conductance regulator plasma membrane expression. Author(s): Ikeda M, Fong P, Cheng J, Boletta A, Qian F, Zhang XM, Cai H, Germino GG, Guggino WB. Source: Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16914886&query_hl=25&itool=pubmed_docsum
with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A survey of palivizumab for infants with cystic fibrosis in the UK. Author(s): McCormick J, Southern KW. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17185451&query_hl=25&itool=pubmed_docsum
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Abdominal manifestations of cystic fibrosis in older children and adults. Author(s): Fields TM, Michel SJ, Butler CL, Kriss VM, Albers SL. Source: Ajr. American Journal of Roentgenology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17056906&query_hl=25&itool=pubmed_docsum
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Absence of cochleotoxicity measured by standard and high-frequency pure tone audiometry in a trial of once- versus three-times-daily tobramycin in cystic fibrosis patients. Author(s): Mulheran M, Hyman-Taylor P, Tan KH, Lewis S, Stableforth D, Knox A, Smyth A. Source: Antimicrobial Agents and Chemotherapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16801404&query_hl=25&itool=pubmed_docsum
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ACOG Committee Opinion. Number 325, December 2005. Update on carrier screening for cystic fibrosis. Author(s): Committee on Genetics, American College of Obstetricians and Gynecologists. Source: Obstetrics and Gynecology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16319281&query_hl=25&itool=pubmed_docsum
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Aerosolized VEGF in combination with intravenous magnetically targeted delivery of DNA-nanoparticle complex may increase efficiency of cystic fibrosis gene therapy. Author(s): Babincova M, Babinec P. Source: Medical Hypotheses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16797874&query_hl=25&itool=pubmed_docsum
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Airway surface liquid volume regulates ENaC by altering the serine proteaseprotease inhibitor balance: a mechanism for sodium hyperabsorption in cystic fibrosis. Author(s): Myerburg MM, Butterworth MB, McKenna EE, Peters KW, Frizzell RA, Kleyman TR, Pilewski JM. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16873367&query_hl=25&itool=pubmed_docsum
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Allergic bronchopulmonary aspergillosis in a patient with cystic fibrosis: diagnostic criteria when the IgE level is less than 500 IU/mL. Author(s): Knutsen AP, Noyes B, Warrier MR, Consolino J. Source: Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16312174&query_hl=25&itool=pubmed_docsum
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Alteration of bone mineral density in cystic fibrosis adults. Author(s): Neri AS, Lori I, Taccetti G, Festini F, de Martino M, Masi L, Brandi ML. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17167027&query_hl=25&itool=pubmed_docsum
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An enteric-coated high-buffered pancrelipase reduces steatorrhea in patients with cystic fibrosis: a prospective, randomized study. Author(s): Brady MS, Garson JL, Krug SK, Kaul A, Rickard KA, Caffrey HH, Fineberg N, Balistreri WF, Stevens JC. Source: Journal of the American Dietetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16863712&query_hl=25&itool=pubmed_docsum
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Analysis of bone mineral density and turnover in patients with cystic fibrosis: associations between the IGF system and inflammatory cytokines. Author(s): Street ME, Spaggiari C, Ziveri MA, Volta C, Federico G, Baroncelli GI, Bernasconi S, Saggese G. Source: Hormone Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16804317&query_hl=25&itool=pubmed_docsum
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Anti-inflammatory cytokines in cystic fibrosis lung disease. Author(s): Starosta V, Ratjen F, Rietschel E, Paul K, Griese M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16807263&query_hl=25&itool=pubmed_docsum
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Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells. Author(s): Cigana C, Nicolis E, Pasetto M, Assael BM, Melotti P. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17045242&query_hl=25&itool=pubmed_docsum
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Approaches to the synthesis of immunolides: selective immunomodulatory macrolides for cystic fibrosis. Author(s): Fecik RA, Nguyen PL, Venkatraman L. Source: Curr Opin Drug Discov Devel. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16312149&query_hl=25&itool=pubmed_docsum
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Association between mannan-binding lectin and impaired lung function in cystic fibrosis may be age-dependent. Author(s): Muhlebach MS, MacDonald SL, Button B, Hubbard JJ, Turner ML, Boucher RC, Kilpatrick DC. Source: Clinical and Experimental Immunology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16879250&query_hl=25&itool=pubmed_docsum
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Association of the cystic fibrosis transmembrane regulator with CAL: structural features and molecular dynamics. Author(s): Piserchio A, Fellows A, Madden DR, Mierke DF. Source: Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16331976&query_hl=25&itool=pubmed_docsum
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Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis. Author(s): Xu N, Glockner JF, Rossetti S, Babovich-Vuksanovic D, Harris PC, Torres VE. Source: Journal of Nephrology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17048214&query_hl=25&itool=pubmed_docsum
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Balancing benefits and risks for cystic fibrosis newborn screening: implications for policy decisions. Author(s): Wilfond BS, Parad RB, Fost N. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16202773&query_hl=25&itool=pubmed_docsum
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Barriers to treatment adherence for children with cystic fibrosis and asthma: what gets in the way? Author(s): Modi AC, Quittner AL. Source: Journal of Pediatric Psychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16401680&query_hl=25&itool=pubmed_docsum
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Behavioral and nutritional treatment to improve energy intake and growth in toddlers and preschool-aged children with cystic fibrosis. Author(s): Rowland M, Broderick A, Bourke B. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16818595&query_hl=25&itool=pubmed_docsum
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Behavioral aspects of nutrition in children with cystic fibrosis. Author(s): Stark LJ, Powers SW. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16217182&query_hl=25&itool=pubmed_docsum
Studies
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Benefits of an education programme on the self-management of aerosol and airway clearance treatments for children with cystic fibrosis. Author(s): Downs JA, Roberts CM, Blackmore AM, Le Souef PN, Jenkins SC. Source: Chron Respir Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16509174&query_hl=25&itool=pubmed_docsum
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Beta-cell autoantibodies and diabetes mellitus family history in cystic fibrosis. Author(s): Minicucci L, Cotellessa M, Pittaluga L, Minuto N, d'Annunzio G, Avanzini MA, Lorini R. Source: J Pediatr Endocrinol Metab. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16200841&query_hl=25&itool=pubmed_docsum
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Betterland: an interactive cd-rom guide for children with cystic fibrosis. Author(s): Duff A, Ball R, Wolfe S, Blyth H, Brownlee K. Source: Paediatric Nursing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16986754&query_hl=25&itool=pubmed_docsum
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Biliary liver cirrhosis secondary to cystic fibrosis: a rare indication for liver transplantation. Author(s): Sanko-Resmer J, Paczek L, Wyzgal J, Ziolkowski J, Ciszek M, Alsharabi A, Grzelak I, Paluszkiewicz R, Patkowski W, Krawczyk M. Source: Transplantation Proceedings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16504705&query_hl=25&itool=pubmed_docsum
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Biomarkers of neutrophilic inflammation in exhaled air of cystic fibrosis children with bacterial airway infections. Author(s): Bodini A, D'Orazio C, Peroni D, Corradi M, Folesani G, Baraldi E, Assael BM, Boner A, Piacentini GL. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16229003&query_hl=25&itool=pubmed_docsum
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Birth prevalence and survival in cystic fibrosis: a national cohort study in the Netherlands. Author(s): Slieker MG, Uiterwaal CS, Sinaasappel M, Heijerman HG, van der Laag J, van der Ent CK. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16236889&query_hl=25&itool=pubmed_docsum
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BMD and body composition in children and young patients affected by cystic fibrosis. Author(s): Bianchi ML, Romano G, Saraifoger S, Costantini D, Limonta C, Colombo C. Source: Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16491286&query_hl=25&itool=pubmed_docsum
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Body composition and adiponectin serum concentrations in adult patients with cystic fibrosis. Author(s): Moriconi N, Kraenzlin M, Muller B, Keller U, Nusbaumer CP, Stohr S, Tamm M, Puder JJ. Source: The Journal of Clinical Endocrinology and Metabolism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16464949&query_hl=25&itool=pubmed_docsum
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Body composition assessment in adults with cystic fibrosis: comparison of dualenergy X-ray absorptiometry with skinfolds and bioelectrical impedance analysis. Author(s): King S, Wilson J, Kotsimbos T, Bailey M, Nyulasi I. Source: Nutrition (Burbank, Los Angeles County, Calif.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16183254&query_hl=25&itool=pubmed_docsum
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Breast-feeding in a woman with cystic fibrosis undergoing antibiotic intravenous treatment. Author(s): Festini F, Ciuti R, Taccetti G, Repetto T, Campana S, De Martino M. Source: The Journal of Maternal-Fetal & Neonatal Medicine : the Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16801316&query_hl=25&itool=pubmed_docsum
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Breath sulfides and pulmonary function in cystic fibrosis. Author(s): Kamboures MA, Blake DR, Cooper DM, Newcomb RL, Barker M, Larson JK, Meinardi S, Nussbaum E, Rowland FS. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16247007&query_hl=25&itool=pubmed_docsum
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Bronchial artery embolization in adults with cystic fibrosis: impact on the clinical course and survival. Author(s): Vidal V, Therasse E, Berthiaume Y, Bommart S, Giroux MF, Oliva VL, Abrahamowicz M, du Berger R, Jeanneret A, Soulez G. Source: Journal of Vascular and Interventional Radiology : Jvir. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16778227&query_hl=25&itool=pubmed_docsum
Studies
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Burkholderia respiratory tract infections in Italian patients with cystic fibrosis: molecular characterization. Author(s): Allice T, Scutera S, Chirillo MG, Savoia D. Source: The Journal of Infection. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16375971&query_hl=25&itool=pubmed_docsum
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Candida albicans infection in adults with cystic fibrosis. Author(s): Webb AK, Woolnough E. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16927951&query_hl=25&itool=pubmed_docsum
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Case study: providing evidence-based behavioral and nutrition treatment to a toddler with cystic fibrosis and multiple food allergies via telehealth. Author(s): Piazza-Waggoner C, Ferguson KS, Daines C, Acton JD, Powers SW. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16871593&query_hl=25&itool=pubmed_docsum
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CFTR Expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Author(s): Painter RG, Valentine VG, Lanson NA Jr, Leidal K, Zhang Q, Lombard G, Thompson C, Viswanathan A, Nauseef WM, Wang G, Wang G. Source: Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16922501&query_hl=25&itool=pubmed_docsum
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CFTR genotype as a predictor of prognosis in cystic fibrosis. Author(s): McKone EF, Goss CH, Aitken ML. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17099022&query_hl=25&itool=pubmed_docsum
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Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils. Author(s): Hays SR, Fahy JV. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16917116&query_hl=25&itool=pubmed_docsum
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Chest x ray and high-resolution computed tomography in cystic fibrosis. Author(s): Kollamparambil TG, Padua K, Fairhurst J, Connett G. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17119092&query_hl=25&itool=pubmed_docsum
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Classification of nutritional status in cystic fibrosis. Author(s): Lai HJ. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053492&query_hl=25&itool=pubmed_docsum
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Clinical Year in Review IV: Interstitial lung disease, cystic fibrosis, pulmonary infections, and mycobacterial disease. Author(s): Tino G. Source: Proc Am Thorac Soc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17065369&query_hl=25&itool=pubmed_docsum
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Clonal analysis of Inquilinus limosus isolates from six cystic fibrosis patients and specific serum antibody response. Author(s): Schmoldt S, Latzin P, Heesemann J, Griese M, Imhof A, Hogardt M. Source: Journal of Medical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17005793&query_hl=25&itool=pubmed_docsum
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Cochrane systematic reviews in cystic fibrosis. Author(s): Smyth R, Jahnke N. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16927950&query_hl=25&itool=pubmed_docsum
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Cognitive behavioural therapy in cystic fibrosis. Author(s): Heslop K. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16927954&query_hl=25&itool=pubmed_docsum
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Consequences of combining cystic fibrosis- and non-cystic fibrosis-derived Pseudomonas aeruginosa antibiotic susceptibility results in hospital antibiograms. Author(s): Bosso JA, Mauldin PD, Steed LL. Source: The Annals of Pharmacotherapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17018687&query_hl=25&itool=pubmed_docsum
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Cost of home and hospital care for patients with cystic fibrosis followed up in two reference medical centers in France. Author(s): Horvais V, Touzet S, Francois S, Bourdy S, Bellon G, Colin C, Durieu I. Source: International Journal of Technology Assessment in Health Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16984688&query_hl=25&itool=pubmed_docsum
Studies
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Cough frequency and patterns of cough in cystic fibrosis. Author(s): Smith JA. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16927952&query_hl=25&itool=pubmed_docsum
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CR5/20--Acute renal failure in a child with cystic fibrosis awaiting lung transplantation--a good outcome after all. Author(s): Benden C. Source: Paediatric Respiratory Reviews. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17036408&query_hl=25&itool=pubmed_docsum
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Cross-infection with Pseudomonas aeruginosa among patients with cystic fibrosis. Author(s): Agarwal G, Kapil A, Kabra SK, Das BK. Source: Natl Med J India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17103494&query_hl=25&itool=pubmed_docsum
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Current prospects for gene therapy of cystic fibrosis. Author(s): Ziady AG, Davis PB. Source: Current Opinion in Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16890018&query_hl=25&itool=pubmed_docsum
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Cystic fibrosis presenting with haematological abnormalities. Author(s): Minasian CC, Sriskandan S, Balfour-Lynn IM, Bush A. Source: Clinical and Laboratory Haematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17105498&query_hl=25&itool=pubmed_docsum
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Cystic fibrosis. Pseudomonas aeruginosa infection. Author(s): Chang AL. Source: Ceylon Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16898036&query_hl=25&itool=pubmed_docsum
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Cystic fibrosis: hope remains for a 'miracle cure'. Author(s): Dick M. Source: Biotechnol J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17086624&query_hl=25&itool=pubmed_docsum
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De novo biosynthetic profiling of high abundance proteins in cystic fibrosis lung epithelial cells. Author(s): Pollard HB, Eidelman O, Jozwik C, Huang W, Srivastava M, Ji XD, McGowan B, Norris CF, Todo T, Darling T, Mogayzel PJ, Zeitlin PL, Wright J, Guggino WB, Metcalf E, Driscoll WJ, Mueller G, Paweletz C, Jacobowitz DM. Source: Molecular & Cellular Proteomics : Mcp. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16829594&query_hl=25&itool=pubmed_docsum
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Decreased coenzyme Q10 concentration in plasma of children with cystic fibrosis. Author(s): Oudshoorn JH, Lecluse AL, van den Berg R, Vaes WH, van der Laag J, Houwen RH. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17130743&query_hl=25&itool=pubmed_docsum
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Decreased lung function in female but not male subjects with established cystic fibrosis-related diabetes. Author(s): Sims EJ, Green MW, Mehta A. Source: Diabetes Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15983304&query_hl=25&itool=pubmed_docsum
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Delayed diagnosis of females with respiratory presentation of cystic fibrosis did not segregate with poorer clinical outcome. Author(s): McCormick J, Sims EJ, Mehta A. Source: Journal of Clinical Epidemiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16488363&query_hl=25&itool=pubmed_docsum
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Delayed gastric emptying scintigraphy in cystic fibrosis patients before and after lung transplantation. Author(s): Bodet-Milin C, Querellou S, Oudoux A, Haloun A, Horeau-Llanglard D, Carlier T, Bizais Y, Couturier O. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16962469&query_hl=25&itool=pubmed_docsum
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Detecting early lung disease in cystic fibrosis: are current techniques sufficient? Author(s): Sly PD, Brennan S. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15563695&query_hl=25&itool=pubmed_docsum
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Development of a diagnostic test for the Midlands 1 cystic fibrosis epidemic strain of Pseudomonas aeruginosa. Author(s): Smart CH, Scott FW, Wright EA, Walshaw MJ, Hart CA, Pitt TL, Winstanley C. Source: Journal of Medical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16849729&query_hl=25&itool=pubmed_docsum
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Diagnosing and managing cystic fibrosis in the developing world. Author(s): Kabra SK, Kabra M, Shastri S, Lodha R. Source: Paediatric Respiratory Reviews. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16798545&query_hl=25&itool=pubmed_docsum
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Diagnosing cystic fibrosis in South Africa. Author(s): Westwood T, Henderson B, Ramsay M; Medical and Scientific Advisory Committee of the South African Cystic Fibrosis Association. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16670800&query_hl=25&itool=pubmed_docsum
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Did Lady Windermere have cystic fibrosis? Author(s): Rubin BK. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17035420&query_hl=25&itool=pubmed_docsum
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Differential sensitivity of the cystic fibrosis (CF)-associated mutants G551D and G1349D to potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Author(s): Cai Z, Taddei A, Sheppard DN. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16311240&query_hl=25&itool=pubmed_docsum
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Disease modifying genes in cystic fibrosis. Author(s): Slieker MG, Sanders EA, Rijkers GT, Ruven HJ, van der Ent CK. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15996905&query_hl=25&itool=pubmed_docsum
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Disseminated herpes simplex infection with cystic fibrosis: a case report. Author(s): Goyal R, Nada R, Das A, Marwaha RK. Source: Indian J Pathol Microbiol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17183874&query_hl=25&itool=pubmed_docsum
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Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient after double-lung transplantation. Author(s): Symoens F, Knoop C, Schrooyen M, Denis O, Estenne M, Nolard N, Jacobs F. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16678041&query_hl=25&itool=pubmed_docsum
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Does splenectomy in cystic fibrosis related liver disease improve lung function and nutritional status? A case series. Author(s): Linnane B, Oliver MR, Robinson PJ. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16737995&query_hl=25&itool=pubmed_docsum
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Dornase alpha and exhaled NO in cystic fibrosis. Author(s): Grasemann H, Lax H, Treseler JW, Colin AA. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15390350&query_hl=25&itool=pubmed_docsum
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Drug evaluation: PTC-124--a potential treatment of cystic fibrosis and Duchenne muscular dystrophy. Author(s): Hamed SA. Source: Idrugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17096300&query_hl=25&itool=pubmed_docsum
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Dysregulated interleukin-8 secretion and NF-kappaB activity in human cystic fibrosis nasal epithelial cells. Author(s): Carrabino S, Carpani D, Livraghi A, Di Cicco M, Costantini D, Copreni E, Colombo C, Conese M. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16481223&query_hl=25&itool=pubmed_docsum
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Early pulmonary manifestation of cystic fibrosis in children with the DeltaF508/R117H-7T genotype. Author(s): O'Sullivan BP, Zwerdling RG, Dorkin HL, Comeau AM, Parad R. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16951024&query_hl=25&itool=pubmed_docsum
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Effect of aerosolized colistin on multidrug-resistant Pseudomonas aeruginosa in bronchial secretions of patients without cystic fibrosis. Author(s): Horianopoulou M, Lambropoulos S, Papafragas E, Falagas ME. Source: J Chemother. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16323443&query_hl=25&itool=pubmed_docsum
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Effect of allergic bronchopulmonary aspergillosis on lung function in children with cystic fibrosis. Author(s): Kraemer R, Delosea N, Ballinari P, Gallati S, Crameri R. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16959918&query_hl=25&itool=pubmed_docsum
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Effect of disease-related pain on the health-related quality of life of children and adolescents with cystic fibrosis. Author(s): Palermo TM, Harrison D, Koh JL. Source: The Clinical Journal of Pain. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16788339&query_hl=25&itool=pubmed_docsum
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Effect of high-frequency chest wall oscillation on the central and peripheral distribution of aerosolized diethylene triamine penta-acetic acid as compared to standard chest physiotherapy in cystic fibrosis. Author(s): Stites SW, Perry GV, Peddicord T, Cox G, McMillan C, Becker B. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16537872&query_hl=25&itool=pubmed_docsum
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Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease. Author(s): Montgomery GS, Sagel SD, Taylor AL, Abman SH. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16479610&query_hl=25&itool=pubmed_docsum
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Elastic contributions dominate the viscoelastic properties of sputum from cystic fibrosis patients. Author(s): Nielsen H, Hvidt S, Sheils CA, Janmey PA. Source: Biophysical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15572248&query_hl=25&itool=pubmed_docsum
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Electroconvulsive therapy for treatment of refractory depression in a patient with cystic fibrosis. Author(s): Fogg-Waberski JH, Szarek BL, Knauft RF. Source: The Journal of Ect. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16633213&query_hl=25&itool=pubmed_docsum
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Cystic Fibrosis
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Energy balance and the accuracy of reported energy intake in preadolescent children with cystic fibrosis. Author(s): Trabulsi J, Schall JI, Ittenbach RF, Olsen IE, Yudkoff M, Daikhin Y, Zemel BS, Stallings VA. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16960165&query_hl=25&itool=pubmed_docsum
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Energy balance in cystic fibrosis when stable and during a respiratory exacerbation. Author(s): Mc Closkey M, Redmond AO, Mc Cabe C, Pyper S, Westerterp KR, Elborn SJ. Source: Clinical Nutrition (Edinburgh, Lothian). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15556263&query_hl=25&itool=pubmed_docsum
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Enteric-coated pancreatic enzyme with bicarbonate is equal to standard enteric-coated enzyme in treating malabsorption in cystic fibrosis. Author(s): Kalnins D, Ellis L, Corey M, Pencharz PB, Stewart C, Tullis E, Durie PR. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16540792&query_hl=25&itool=pubmed_docsum
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Epidemiology of liver disease in cystic fibrosis: a longitudinal study. Author(s): Lamireau T, Monnereau S, Martin S, Marcotte JE, Winnock M, Alvarez F. Source: Journal of Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15582124&query_hl=25&itool=pubmed_docsum
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EPI-hNE4, a proteolysis-resistant inhibitor of human neutrophil elastase and potential anti-inflammatory drug for treating cystic fibrosis. Author(s): Attucci S, Gauthier A, Korkmaz B, Delepine P, Martino MF, Saudubray F, Diot P, Gauthier F. Source: The Journal of Pharmacology and Experimental Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16627747&query_hl=25&itool=pubmed_docsum
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Evaluating the "Leeds criteria" for Pseudomonas aeruginosa infection in a cystic fibrosis centre. Author(s): Proesmans M, Balinska-Miskiewicz W, Dupont L, Bossuyt X, Verhaegen J, Hoiby N, de Boeck K. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16707392&query_hl=25&itool=pubmed_docsum
Studies
83
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Evidence of choline depletion and reduced betaine and dimethylglycine with increased homocysteine in plasma of children with cystic fibrosis. Author(s): Innis SM, Hasman D. Source: The Journal of Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16857845&query_hl=25&itool=pubmed_docsum
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Evidence of coinfection with distinct strains of Burkholderia multivorans in a cystic fibrosis patient. Author(s): Wellinghausen N, Kothe J. Source: Infection. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17033756&query_hl=25&itool=pubmed_docsum
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Evolving stealth: genetic adaptation of Pseudomonas aeruginosa during cystic fibrosis infections. Author(s): Nguyen D, Singh PK. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16717189&query_hl=25&itool=pubmed_docsum
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Expression and antimicrobial function of bactericidal permeability-increasing protein in cystic fibrosis patients. Author(s): Aichele D, Schnare M, Saake M, Rollinghoff M, Gessner A. Source: Infection and Immunity. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16861658&query_hl=25&itool=pubmed_docsum
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Extracorporeal membrane oxygenation support post-arterial switch procedure for a child with cystic fibrosis: case report. Author(s): Baslaim GM, Jamjoom AA. Source: Journal of Cardiac Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16846427&query_hl=25&itool=pubmed_docsum
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Factors associated with infection by Pseudomonas aeruginosa in adult cystic fibrosis. Author(s): Chambers D, Scott F, Bangur R, Davies R, Lim A, Walters S, Smith G, Pitt T, Stableforth D, Honeybourne D. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16204596&query_hl=25&itool=pubmed_docsum
84
Cystic Fibrosis
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Factors associated with reduced FEV1 in adult patients with cystic fibrosis in a relatively affluent area. Author(s): Jarad NA, Higgs S, Jeffcote T, Giles K. Source: Chron Respir Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16281436&query_hl=25&itool=pubmed_docsum
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Faecal elastase-1 test is superior to faecal lipase test in the assessment of exocrine pancreatic function in cystic fibrosis. Author(s): Walkowiak J, Lisowska A, Przyslawski J, Grzymislawski M, Krawczynski M, Herzig KH. Source: Acta Paediatrica (Oslo, Norway : 1992). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15456193&query_hl=25&itool=pubmed_docsum
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False-positive results in neonatal screening for cystic fibrosis based on a three-stage protocol (IRT/DNA/IRT): Should we adjust IRT cut-off to ethnic origin? Author(s): Cheillan D, Vercherat M, Chevalier-Porst F, Charcosset M, Rolland MO, Dorche C. Source: Journal of Inherited Metabolic Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16435172&query_hl=25&itool=pubmed_docsum
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Family structure and mothers' caregiving of children with cystic fibrosis. Author(s): Gayer D, Ganong L. Source: J Fam Nurs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17099117&query_hl=25&itool=pubmed_docsum
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Fecal elastase: pancreatic status verification and influence on nutritional status in children with cystic fibrosis. Author(s): Cohen JR, Schall JI, Ittenbach RF, Zemel BS, Stallings VA. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15795591&query_hl=25&itool=pubmed_docsum
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Fecal elastase-1: utility in pancreatic function in cystic fibrosis. Author(s): Daftary A, Acton J, Heubi J, Amin R. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16603421&query_hl=25&itool=pubmed_docsum
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Fibrosing colonopathy in a man with cystic fibrosis on pancreatic enzyme supplements. Author(s): Jain S, Subramony C, Blanchard K, Petro M, Minocha A. Source: Indian J Gastroenterol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16424618&query_hl=25&itool=pubmed_docsum
Studies
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Fibrosing colonopathy in an adult cystic fibrosis patient after discontinuing pancreatic enzyme therapy. Author(s): Mack EH, Brett AS, Brown D. Source: Southern Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15455984&query_hl=25&itool=pubmed_docsum
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Fifty-year perspective of "cystic fibrosis of the pancreas". Author(s): Spock A. Source: Pediatric Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15940390&query_hl=25&itool=pubmed_docsum
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Finding genetic modifiers of cystic fibrosis. Author(s): Haston CK, Hudson TJ. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16207854&query_hl=25&itool=pubmed_docsum
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First bacterial infection as an alternative clinical end point for regulatory approval of agents targeting the primary cystic fibrosis defect. Author(s): VanDevanter DR. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16182671&query_hl=25&itool=pubmed_docsum
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Fluorescence in situ hybridization for rapid identification of Achromobacter xylosoxidans and Alcaligenes faecalis recovered from cystic fibrosis patients. Author(s): Wellinghausen N, Wirths B, Poppert S. Source: Journal of Clinical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16954289&query_hl=25&itool=pubmed_docsum
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Free radicals in exhaled breath condensate in cystic fibrosis and healthy subjects. Author(s): Rosias PP, Den Hartog GJ, Robroeks CM, Bast A, Donckerwolcke RA, Heynens JW, Suykerbuyk J, Hendriks HJ, Jobsis Q, Dompeling E. Source: Free Radical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17015269&query_hl=25&itool=pubmed_docsum
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Frequency of ASCA seropositivity in children with cystic fibrosis. Author(s): Condino AA, Hoffenberg EJ, Accurso F, Penvari C, Anthony M, Gralla J, O'Connor JA. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15990625&query_hl=25&itool=pubmed_docsum
86
Cystic Fibrosis
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Frequency of the deltaF508 mutation in 108 cystic fibrosis patients in Sao Paulo: comparison with reported Brazilian data. Author(s): Okay TS, Oliveira WP, Raiz-Junior R, Rodrigues JC, Del Negro GM. Source: Clinics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15880249&query_hl=25&itool=pubmed_docsum
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Functional genomic responses to cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR(delta508) in the lung. Author(s): Xu Y, Liu C, Clark JC, Whitsett JA. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16455659&query_hl=25&itool=pubmed_docsum
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Gastroesophageal reflux (symptomatic and silent): a potentially significant problem in patients with cystic fibrosis before and after lung transplantation. Author(s): Button BM, Roberts S, Kotsimbos TC, Levvey BJ, Williams TJ, Bailey M, Snell GI, Wilson JW. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16210125&query_hl=25&itool=pubmed_docsum
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Gender affects self-evaluation in children with cystic fibrosis and their healthy siblings. Author(s): Wennstrom IL, Berg U, Kornfalt R, Ryden O. Source: Acta Paediatrica (Oslo, Norway : 1992). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16278999&query_hl=25&itool=pubmed_docsum
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Gene therapy for children with cystic fibrosis--who has the right to choose? Author(s): Jaffe A, Prasad SA, Larcher V, Hart S. Source: Journal of Medical Ethics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16731738&query_hl=25&itool=pubmed_docsum
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Gene therapy for cystic fibrosis airway disease- is clinical success imminent? Author(s): Anson DS, Smith GJ, Parsons DW. Source: Current Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16611040&query_hl=25&itool=pubmed_docsum
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Gene therapy for cystic fibrosis lung disease: current status and future perspectives. Author(s): Rosenecker J, Huth S, Rudolph C. Source: Curr Opin Mol Ther. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17078386&query_hl=25&itool=pubmed_docsum
Studies
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Gene therapy for cystic fibrosis: an example for lung gene therapy. Author(s): Griesenbach U, Geddes DM, Alton EW. Source: Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15454956&query_hl=25&itool=pubmed_docsum
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Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Author(s): Smith EE, Buckley DG, Wu Z, Saenphimmachak C, Hoffman LR, D'Argenio DA, Miller SI, Ramsey BW, Speert DP, Moskowitz SM, Burns JL, Kaul R, Olson MV. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16687478&query_hl=25&itool=pubmed_docsum
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Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening. Author(s): Sontag MK, Corey M, Hokanson JE, Marshall JA, Sommer SS, Zerbe GO, Accurso FJ. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17095337&query_hl=25&itool=pubmed_docsum
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Genetic modifiers in cystic fibrosis. Author(s): Rossi G, Rossi V. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16395827&query_hl=25&itool=pubmed_docsum
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Genetic modifiers in cystic fibrosis. Author(s): Stanke F, Tummler B, Becker T. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16394309&query_hl=25&itool=pubmed_docsum
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Genetically engineered bacteria may be useful for delivery of mucolytics into cystic fibrosis lungs. Author(s): Babinec P, Babincova M. Source: Medical Hypotheses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16675156&query_hl=25&itool=pubmed_docsum
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Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Author(s): de Gracia J, Mata F, Alvarez A, Casals T, Gatner S, Vendrell M, de la Rosa D, Guarner L, Hermosilla E. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15994263&query_hl=25&itool=pubmed_docsum
88
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Giant inflammatory polyposis coli as a manifestation of Crohn's disease in patients with coexistent cystic fibrosis. Author(s): Banville N, Broderick A, Fitzgerald R, Drumm B, McDermott M. Source: Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16808638&query_hl=25&itool=pubmed_docsum
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Gross genomic rearrangements involving deletions in the CFTR gene: characterization of six new events from a large cohort of hitherto unidentified cystic fibrosis chromosomes and meta-analysis of the underlying mechanisms. Author(s): Ferec C, Casals T, Chuzhanova N, Macek M Jr, Bienvenu T, Holubova A, King C, McDevitt T, Castellani C, Farrell PM, Sheridan M, Pantaleo SJ, Loumi O, Messaoud T, Cuppens H, Torricelli F, Cutting GR, Williamson R, Ramos MJ, Pignatti PF, Raguenes O, Cooper DN, Audrezet MP, Chen JM. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16493442&query_hl=25&itool=pubmed_docsum
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Growing up and growing older with cystic fibrosis. Author(s): Madge S. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16927953&query_hl=25&itool=pubmed_docsum
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Growth hormone normalizes pubertal onset in children with cystic fibrosis. Author(s): Vanderwel M, Hardin DS. Source: J Pediatr Endocrinol Metab. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16607924&query_hl=25&itool=pubmed_docsum
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Growth hormone treatment improves growth and clinical status in prepubertal children with cystic fibrosis: results of a multicenter randomized controlled trial. Author(s): Hardin DS, Adams-Huet B, Brown D, Chatfield B, Dyson M, Ferkol T, Howenstine M, Prestidge C, Royce F, Rice J, Seilheimer DK, Steelman J, Shepherds R. Source: The Journal of Clinical Endocrinology and Metabolism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17018651&query_hl=25&itool=pubmed_docsum
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Haemophilus influenzae forms biofilms on airway epithelia: implications in cystic fibrosis. Author(s): Starner TD, Zhang N, Kim G, Apicella MA, McCray PB Jr. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16675778&query_hl=25&itool=pubmed_docsum
Studies
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Haplotype distribution of and linkage disequilibrium between four polymorphic markers near the CFTR locus in Brazilian cystic fibrosis patients. Author(s): Cabello GM, Cabello PH, Lopez-Camelo JS, Llerena JC Jr, Fernandes O. Source: Human Biology; an International Record of Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16715841&query_hl=25&itool=pubmed_docsum
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Heterogeneity of biofilms formed by nonmucoid Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Author(s): Lee B, Haagensen JA, Ciofu O, Andersen JB, Hoiby N, Molin S. Source: Journal of Clinical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16207991&query_hl=25&itool=pubmed_docsum
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High incidence of gastric bezoars in cystic fibrosis patients after lung transplantation. Author(s): Dellon ES, Morgan DR, Mohanty SP, Davis K, Aris RM. Source: Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16641599&query_hl=25&itool=pubmed_docsum
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High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Author(s): Tirouvanziam R, Conrad CK, Bottiglieri T, Herzenberg LA, Moss RB, Herzenberg LA. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16537378&query_hl=25&itool=pubmed_docsum
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High-resolution computed tomography (HRCT) should not be considered as a routine assessment method in cystic fibrosis lung disease. Author(s): Cooper P, MacLean J. Source: Paediatric Respiratory Reviews. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16938642&query_hl=25&itool=pubmed_docsum
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Home versus hospital intravenous antibiotic therapy for acute pulmonary exacerbations in children with cystic fibrosis. Author(s): Nazer D, Abdulhamid I, Thomas R, Pendleton S. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16779852&query_hl=25&itool=pubmed_docsum
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Hospitalisation costs of cystic fibrosis. Author(s): Schreyogg J, Hollmeyer H, Bluemel M, Staab D, Busse R. Source: Pharmacoeconomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17002482&query_hl=25&itool=pubmed_docsum
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Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Author(s): Wang X, Venable J, LaPointe P, Hutt DM, Koulov AV, Coppinger J, Gurkan C, Kellner W, Matteson J, Plutner H, Riordan JR, Kelly JW, Yates JR 3rd, Balch WE. Source: Cell. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17110338&query_hl=25&itool=pubmed_docsum
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Human-specific cystic fibrosis transmembrane conductance regulator antibodies detect in vivo gene transfer to ovine airways. Author(s): Davidson H, McLachlan G, Wilson A, Boyd AC, Doherty A, MacGregor G, Davies L, Painter HA, Coles R, Hyde SC, Gill DR, Amaral MD, Collie DD, Porteous DJ, Penque D. Source: American Journal of Respiratory Cell and Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16498081&query_hl=25&itool=pubmed_docsum
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Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis. Author(s): Song Y, Salinas D, Nielson DW, Verkman AS. Source: American Journal of Physiology. Cell Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16207791&query_hl=25&itool=pubmed_docsum
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Hyperglycaemia and insulinopenia in a neonate with cystic fibrosis. Author(s): Siahanidou T, Mandyla H, Doudounakis S, Anagnostakis D. Source: Acta Paediatrica (Oslo, Norway : 1992). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16421050&query_hl=25&itool=pubmed_docsum
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Hyperpolarized HHe 3 MRI of the lung in cystic fibrosis: assessment at baseline and after bronchodilator and airway clearance treatment. Author(s): Mentore K, Froh DK, de Lange EE, Brookeman JR, Paget-Brown AO, Altes TA. Source: Academic Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16253854&query_hl=25&itool=pubmed_docsum
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Hypertonic saline for cystic fibrosis. Author(s): Kuver R, Lee SP. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16642591&query_hl=25&itool=pubmed_docsum
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Hypertonic saline for cystic fibrosis. Author(s): Zarogiannis S, Hatzoglou C, Gourgoulianis K. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16642590&query_hl=25&itool=pubmed_docsum
Studies
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Hypertonic saline for cystic fibrosis. Author(s): Aziz I, Kastelik JA. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16641405&query_hl=25&itool=pubmed_docsum
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Hypertonic saline therapy in cystic fibrosis: Evidence against the proposed mechanism involving aquaporins. Author(s): Levin MH, Sullivan S, Nielson D, Yang B, Finkbeiner WE, Verkman AS. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16829520&query_hl=25&itool=pubmed_docsum
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Hyponatremic dehydration as a presentation of cystic fibrosis. Author(s): Ballestero Y, Hernandez MI, Rojo P, Manzanares J, Nebreda V, Carbajosa H, Infante E, Baro M. Source: Pediatric Emergency Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17110865&query_hl=25&itool=pubmed_docsum
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Hyposecretion, not hyperabsorption, is the basic defect of cystic fibrosis airway glands. Author(s): Joo NS, Irokawa T, Robbins RC, Wine JJ. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16410244&query_hl=25&itool=pubmed_docsum
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Identification of the 5T-12TG allele of the cystic fibrosis transmembrane conductance regulator gene in hypertrypsinaemic newborns. Author(s): Padoan R, Corbetta C, Bassotti A, Seia M. Source: Acta Paediatrica (Oslo, Norway : 1992). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16801189&query_hl=25&itool=pubmed_docsum
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Identification of the commonest cystic fibrosis transmembrane regulator gene DeltaF508 mutation: evaluation of PCR--single-strand conformational polymorphism and polyacrylamide gel electrophoresis. Author(s): Kakavas KV, Noulas AV, Kanakis I, Bonanou S, Karamanos NK. Source: Biomedical Chromatography : Bmc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16708396&query_hl=25&itool=pubmed_docsum
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Immunoreactive trypsin/DNA newborn screening for cystic fibrosis: should the R117H variant be included in CFTR mutation panels? Author(s): Scotet V, Audrezet MP, Roussey M, Rault G, Dirou-Prigent A, Journel H, Moisan-Petit V, Storni V, Ferec C. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17015492&query_hl=25&itool=pubmed_docsum
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Cystic Fibrosis
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Improvement of cystic fibrosis during treatment with isotretinoin. Author(s): Buckley JL, Chastain MA, Rietschel RL. Source: Skinmed. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16957442&query_hl=25&itool=pubmed_docsum
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Incidence and prevalence of diabetes mellitus in patients with cystic fibrosis undergoing lung transplantation before and after lung transplantation. Author(s): Hadjiliadis D, Madill J, Chaparro C, Tsang A, Waddell TK, Singer LG, Hutcheon MA, Keshavjee S, Elizabeth Tullis D. Source: Clinical Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16313324&query_hl=25&itool=pubmed_docsum
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Increased NaCl-induced interleukin-8 production by human bronchial epithelial cells is enhanced by the DeltaF508/W1282X mutation of the cystic fibrosis transmembrane conductance regulator gene. Author(s): Chan MM, Chmura K, Chan ED. Source: Cytokine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16647268&query_hl=25&itool=pubmed_docsum
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Individualised unsupervised exercise training in adults with cystic fibrosis: a 1 year randomised controlled trial. Author(s): Moorcroft AJ, Dodd ME, Morris J, Webb AK. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15563708&query_hl=25&itool=pubmed_docsum
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Inhaled hypertonic saline as a therapy for cystic fibrosis. Author(s): Elkins MR, Bye PT. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053496&query_hl=25&itool=pubmed_docsum
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Inhibition by TNF-alpha and IL-4 of cationic lipid mediated gene transfer in cystic fibrosis tracheal gland cells. Author(s): Bastonero S, Gargouri M, Ortiou S, Gueant JL, Merten MD. Source: The Journal of Gene Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16001392&query_hl=25&itool=pubmed_docsum
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Inhibition of p38 mitogen activated protein kinase controls airway inflammation in cystic fibrosis. Author(s): Raia V, Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Auricchio S, Cimmino M, Cavaliere M, Nardone M, Cesaro A, Malcolm J, Quaratino S, Londei M. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15994249&query_hl=25&itool=pubmed_docsum
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Interactions between impermeant blocking ions in the cystic fibrosis transmembrane conductance regulator chloride channel pore: evidence for anion-induced conformational changes. Author(s): Ge N, Linsdell P. Source: The Journal of Membrane Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16794779&query_hl=25&itool=pubmed_docsum
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Interleukin-8 in whole blood and clinical status in cystic fibrosis. Author(s): Schmitt-Grohe S, Naujoks C, Bargon J, Wagner TO, Schubert R, Hippe V, Zielen S. Source: Cytokine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15579374&query_hl=25&itool=pubmed_docsum
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Intra- and interpatient variability of the hsp65 and 16S-23S intergenic gene region in Mycobacterium abscessus strains from patients with cystic fibrosis. Author(s): Konig B, Tammer I, Sollich V, Konig W. Source: Journal of Clinical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16000490&query_hl=25&itool=pubmed_docsum
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Intracellular trafficking and replication of Burkholderia cenocepacia in human cystic fibrosis airway epithelial cells. Author(s): Sajjan US, Yang JH, Hershenson MB, LiPuma JJ. Source: Cellular Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16922864&query_hl=25&itool=pubmed_docsum
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Intravenous injection of pharmaceutical tablets presenting as multiple pulmonary nodules and declining pulmonary function in an adolescent with cystic fibrosis. Author(s): Smith KJ, Elidemir O, Dishop MK, Eldin KW, Tatevian N, Moore RH. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16923925&query_hl=25&itool=pubmed_docsum
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Ion and fluid transport properties of small airways in cystic fibrosis. Author(s): Blouquit S, Regnier A, Dannhoffer L, Fermanian C, Naline E, Boucher R, Chinet T. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16645176&query_hl=25&itool=pubmed_docsum
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Is it go or NO go for S-nitrosylation modification-based therapies of cystic fibrosis transmembrane regulator trafficking? Author(s): Zeitlin PL. Source: Molecular Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16877677&query_hl=25&itool=pubmed_docsum
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Is limited computed tomography the future for imaging the lungs of children with cystic fibrosis? Author(s): Langton Hewer SC. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16632660&query_hl=25&itool=pubmed_docsum
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Is testing for cytomegalovirus and cystic fibrosis indicated in members of a nonwhite pregnant population in whom the fetus has an echogenic bowel? Author(s): Aboujaoude R, Alvarez J, Ganesh V, Apuzzio J. Source: American Journal of Perinatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16799919&query_hl=25&itool=pubmed_docsum
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Is there value in susceptibility testing of Pseudomonas aeruginosa causing chronic infection in patients with cystic fibrosis? Author(s): Gilligan PH. Source: Expert Rev Anti Infect Ther. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17140346&query_hl=25&itool=pubmed_docsum
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Just what are the mucous secretions of cystic fibrosis? Author(s): Dwyer TM. Source: American Journal of Respiratory Cell and Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15713816&query_hl=25&itool=pubmed_docsum
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Lentivirus-mediated gene transfer to the respiratory epithelium: a promising approach to gene therapy of cystic fibrosis. Author(s): Copreni E, Penzo M, Carrabino S, Conese M. Source: Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15454960&query_hl=25&itool=pubmed_docsum
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Linguistic validation of cystic fibrosis quality of life questionnaires. Author(s): Rozov T, Cunha MT, Nascimento O, Quittner AL, Jardim JR. Source: Jornal De Pediatria. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16614771&query_hl=25&itool=pubmed_docsum
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Liver disease in cystic fibrosis. Author(s): Colombo C, Russo MC, Zazzeron L, Romano G. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16819402&query_hl=25&itool=pubmed_docsum
Studies
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Liver disease in cystic fibrosis. Author(s): Flora KD, Benner KG. Source: Clinics in Liver Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15560045&query_hl=25&itool=pubmed_docsum
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Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry. Author(s): Melzi ML, Kelly DA, Colombo C, Jara P, Manzanares J, Colledan M, Strazzabosco M, DeLorenzo P, Valsecchi MG, Adam R, Gridelli B, Assael BM; EGSLTCF; European Liver Transplant Association (ELTA); European Cystic Fibrosis Society (ECFS). Source: Transplant International : Official Journal of the European Society for Organ Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16918533&query_hl=25&itool=pubmed_docsum
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Liver transplantation for cirrhosis in cystic fibrosis. Author(s): Lamireau T, Martin S, Lallier M, Marcotte JE, Alvarez F. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16858500&query_hl=25&itool=pubmed_docsum
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Living in limbo--patients with cystic fibrosis waiting for transplant. Author(s): Macdonald K. Source: British Journal of Nursing (Mark Allen Publishing). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16835554&query_hl=25&itool=pubmed_docsum
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Long term effects of azithromycin in patients with cystic fibrosis: A double blind, placebo controlled trial. Author(s): Clement A, Tamalet A, Leroux E, Ravilly S, Fauroux B, Jais JP. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16809416&query_hl=25&itool=pubmed_docsum
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Long term nutritional rehabilitation by gastrostomy in Israeli patients with cystic fibrosis: clinical outcome in advanced pulmonary disease. Author(s): Efrati O, Mei-Zahav M, Rivlin J, Kerem E, Blau H, Barak A, Bujanover Y, Augarten A, Cochavi B, Yahav Y, Modan-Moses D. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16456419&query_hl=25&itool=pubmed_docsum
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Longitudinal pulmonary function of childhood bronchiectasis and comparison with cystic fibrosis. Author(s): Twiss J, Stewart AW, Byrnes CA. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16467074&query_hl=25&itool=pubmed_docsum
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Lung transplantation for cystic fibrosis. Author(s): Liou TG, Woo MS, Cahill BC. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053498&query_hl=25&itool=pubmed_docsum
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Lung transplantation in patients with cystic fibrosis: the Israeli experience. Author(s): Prais D, Raviv Y, Shitrit D, Yellin A, Sahar G, Bendayan D, Yahav Y, Efrati O, Reichart N, Blau H, Bakal I, Buchman G, Saute M, Vidne B, Kramer MR. Source: Isr Med Assoc J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16833168&query_hl=25&itool=pubmed_docsum
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Management of recurrent sinus disease in children with cystic fibrosis: a combined approach. Author(s): Shatz A. Source: Otolaryngology and Head and Neck Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16890077&query_hl=25&itool=pubmed_docsum
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Meal patterns, dietary fat intake and pancreatic enzyme use in preadolescent children with cystic fibrosis. Author(s): Schall JI, Bentley T, Stallings VA. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17130744&query_hl=25&itool=pubmed_docsum
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Mealtime behaviors in families of infants and toddlers with cystic fibrosis. Author(s): Powers SW, Mitchell MJ, Patton SR, Byars KC, Jelalian E, Mulvihill MM, Hovell MF, Stark LJ. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15982934&query_hl=25&itool=pubmed_docsum
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Measurement of tobramycin and gentamicin in saliva is not suitable for therapeutic drug monitoring of patients with cystic fibrosis. Author(s): Spencer H, Kozlowska W, Davies JC, Webber P, Chadwick M, Kerr J, Makhecha S. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15994133&query_hl=25&itool=pubmed_docsum
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Multidrug-resistant organisms in cystic fibrosis: management and infection-control issues. Author(s): Waters V, Ratjen F. Source: Expert Rev Anti Infect Ther. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17140357&query_hl=25&itool=pubmed_docsum
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Multidrug-resistant pulmonary infection in cystic fibrosis--what does 'resistant' mean? Author(s): Govan JR. Source: Journal of Medical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17108262&query_hl=25&itool=pubmed_docsum
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Mycobacterium abscessus chest wall and pulmonary infection in a cystic fibrosis lung transplant recipient. Author(s): Taylor JL, Palmer SM. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16890122&query_hl=25&itool=pubmed_docsum
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Myeloperoxidase promoter polymorphism -463G is associated with more severe clinical expression of cystic fibrosis pulmonary disease. Author(s): Reynolds WF, Sermet-Gaudelus I, Gausson V, Feuillet MN, Bonnefont JP, Lenoir G, Descamps-Latscha B, Witko-Sarsat V. Source: Mediators of Inflammation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16883063&query_hl=25&itool=pubmed_docsum
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Nebulizer use and maintenance by cystic fibrosis patients: a survey study. Author(s): Lester MK, Flume PA, Gray SL, Anderson D, Bowman CM. Source: Respiratory Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15571641&query_hl=25&itool=pubmed_docsum
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Neonatal screening for cystic fibrosis does not affect time to first infection with Pseudomonas aeruginosa. Author(s): Baussano I, Tardivo I, Bellezza-Fontana R, Forneris MP, Lezo A, Anfossi L, Castello M, Aleksandar V, Bignamini E. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16950978&query_hl=25&itool=pubmed_docsum
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Neutrophil glutamine deficiency in relation to genotype in children with cystic fibrosis. Author(s): D'Eufemia P, Finocchiaro R, Celli M, Tote J, Ferrucci V, Zambrano A, Troiani P, Quattrucci S. Source: Pediatric Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16327011&query_hl=25&itool=pubmed_docsum
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New insights into cystic fibrosis: molecular switches that regulate CFTR. Author(s): Guggino WB, Stanton BA. Source: Nature Reviews. Molecular Cell Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16723978&query_hl=25&itool=pubmed_docsum
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New insights into pulmonary inflammation in cystic fibrosis. Author(s): Rao S, Grigg J. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16923862&query_hl=25&itool=pubmed_docsum
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New tests for cystic fibrosis. Author(s): Davies JC. Source: Paediatric Respiratory Reviews. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16798543&query_hl=25&itool=pubmed_docsum
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Newborn screening for cystic fibrosis. Author(s): Wallace J, Stein Q. Source: S D Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17124920&query_hl=25&itool=pubmed_docsum
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Newborn screening for cystic fibrosis: parents' preferences regarding counseling at the time of infants' sweat test. Author(s): Tluczek A, Koscik RL, Modaff P, Pfeil D, Rock MJ, Farrell PM, Lifchez C, Freeman ME, Gershan W, Zaleski C, Sullivan B. Source: Journal of Genetic Counseling. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16865559&query_hl=25&itool=pubmed_docsum
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Non cystic fibrosis bronchiectasis. Author(s): Byrnes C. Source: Paediatric Respiratory Reviews. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16798584&query_hl=25&itool=pubmed_docsum
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Nonmucoid Pseudomonas aeruginosa expresses alginate in the lungs of patients with cystic fibrosis and in a mouse model. Author(s): Bragonzi A, Worlitzsch D, Pier GB, Timpert P, Ulrich M, Hentzer M, Andersen JB, Givskov M, Conese M, Doring G. Source: The Journal of Infectious Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15995954&query_hl=25&itool=pubmed_docsum
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Objective measurement of cough during pulmonary exacerbations in adults with cystic fibrosis. Author(s): Smith JA, Owen EC, Jones AM, Dodd ME, Webb AK, Woodcock A. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16449266&query_hl=25&itool=pubmed_docsum
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Obstructive sleep apnea syndrome: a potential cause of lower airway obstruction in cystic fibrosis. Author(s): Hayes D Jr. Source: Sleep Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16309963&query_hl=25&itool=pubmed_docsum
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On the complexity of the pulmonary microbiology in cystic fibrosis: thoughts of a clinician. Author(s): Katznelson D. Source: Isr Med Assoc J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16450753&query_hl=25&itool=pubmed_docsum
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Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development? Author(s): Burkhardt O, Lehmann C, Madabushi R, Kumar V, Derendorf H, Welte T. Source: The Journal of Antimicrobial Chemotherapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16885180&query_hl=25&itool=pubmed_docsum
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Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Author(s): Smyth AR, Tan KH. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16855982&query_hl=25&itool=pubmed_docsum
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Osteoclastogenesis during infective exacerbations in patients with cystic fibrosis. Author(s): Shead EF, Haworth CS, Gunn E, Bilton D, Scott MA, Compston JE. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16675777&query_hl=25&itool=pubmed_docsum
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Outcome of total splenectomy with portosystemic shunt for massive splenomegaly and variceal bleeding in cystic fibrosis. Author(s): Robberecht E, Van Biervliet S, Vanrentergem K, Kerremans I. Source: Journal of Pediatric Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16952592&query_hl=25&itool=pubmed_docsum
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Oxidative changes of bronchoalveolar proteins in cystic fibrosis. Author(s): Starosta V, Rietschel E, Paul K, Baumann U, Griese M. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16478863&query_hl=25&itool=pubmed_docsum
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Oxygen, cyanide and energy generation in the cystic fibrosis pathogen Pseudomonas aeruginosa. Author(s): Williams HD, Zlosnik JE, Ryall B. Source: Adv Microb Physiol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17027370&query_hl=25&itool=pubmed_docsum
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Pancreatic cancer in cystic fibrosis after bilateral lung transplantation. Author(s): Petrowsky H, Schuster H, Irani S, Schafer M, Jochum W, Schmid C, Boehler A, Clavien PA. Source: Pancreas. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17079951&query_hl=25&itool=pubmed_docsum
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Parental attitudes to the identification of their infants as carriers of cystic fibrosis by newborn screening. Author(s): Lewis S, Curnow L, Ross M, Massie J. Source: Journal of Paediatrics and Child Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16925540&query_hl=25&itool=pubmed_docsum
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Pathogenesis of bone disease in cystic fibrosis: the role of bone size and sarcopenia. Author(s): Mughal Z, Sood M, Ward KA, Adams JE. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16927949&query_hl=25&itool=pubmed_docsum
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Peptide microarray analysis of substrate specificity of the transmembrane Ser/Thr kinase KPI-2 reveals reactivity with cystic fibrosis transmembrane conductance regulator and phosphorylase. Author(s): Wang H, Brautigan DL. Source: Molecular & Cellular Proteomics : Mcp. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16887929&query_hl=25&itool=pubmed_docsum
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Peroxisome proliferator-activated receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes. Author(s): Reynders V, Loitsch S, Steinhauer C, Wagner T, Steinhilber D, Bargon J. Source: Respiratory Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16875506&query_hl=25&itool=pubmed_docsum
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Practical management of cystic fibrosis. Author(s): Elborn JS. Source: Chron Respir Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16916010&query_hl=25&itool=pubmed_docsum
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Prevalence of vertebral fractures in adults with cystic fibrosis and their relationship to bone mineral density. Author(s): Stephenson A, Jamal S, Dowdell T, Pearce D, Corey M, Tullis E. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16899856&query_hl=25&itool=pubmed_docsum
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Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis. Author(s): Kraemer R, Baldwin DN, Ammann RA, Frey U, Gallati S. Source: Respiratory Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17137500&query_hl=25&itool=pubmed_docsum
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Protease IV production in Pseudomonas aeruginosa from the lungs of adults with cystic fibrosis. Author(s): Smith L, Rose B, Tingpej P, Zhu H, Conibear T, Manos J, Bye P, Elkins M, Willcox M, Bell S, Wainwright C, Harbour C. Source: Journal of Medical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17108265&query_hl=25&itool=pubmed_docsum
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Pulmonary abnormalities on high-resolution CT demonstrate more rapid decline than FEV1 in adults with cystic fibrosis. Author(s): Judge EP, Dodd JD, Masterson JB, Gallagher CG. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17099020&query_hl=25&itool=pubmed_docsum
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Quality of life in cystic fibrosis: the impact of gender, general health perceptions and disease severity. Author(s): Gee L, Abbott J, Conway SP, Etherington C, Webb AK. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15463875&query_hl=25&itool=pubmed_docsum
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Quality of life of children with cystic fibrosis. Author(s): Koscik RL, Douglas JA, Zaremba K, Rock MJ, Splaingard ML, Laxova A, Farrell PM. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16202786&query_hl=25&itool=pubmed_docsum
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Quality-of-life in children and adolescents with cystic fibrosis managed in both regional outreach and cystic fibrosis center settings in Queensland. Author(s): Thomas C, Mitchell P, O'Rourke P, Wainwright C. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16647415&query_hl=25&itool=pubmed_docsum
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Quantifying pulmonary inflammation in cystic fibrosis with positron emission tomography. Author(s): Chen DL, Ferkol TW, Mintun MA, Pittman JE, Rosenbluth DB, Schuster DP. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16543553&query_hl=25&itool=pubmed_docsum
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Quantitative air-trapping analysis in children with mild cystic fibrosis lung disease. Author(s): Bonnel AS, Song SM, Kesavarju K, Newaskar M, Paxton CJ, Bloch DA, Moss RB, Robinson TE. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15390349&query_hl=25&itool=pubmed_docsum
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Quantitative analysis of regional airways obstruction using dynamic hyperpolarized 3He MRI-preliminary results in children with cystic fibrosis. Author(s): Koumellis P, van Beek EJ, Woodhouse N, Fichele S, Swift AJ, Paley MN, Hill C, Taylor CJ, Wild JM. Source: Journal of Magnetic Resonance Imaging : Jmri. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16104046&query_hl=25&itool=pubmed_docsum
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Randomized clinical trial of behavioral and nutrition treatment to improve energy intake and growth in toddlers and preschoolers with cystic fibrosis. Author(s): Powers SW, Jones JS, Ferguson KS, Piazza-Waggoner C, Daines C, Acton JD. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16322169&query_hl=25&itool=pubmed_docsum
Studies
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Randomized, double-blind, placebo-controlled, dose-escalating study of aerosolized interferon gamma-1b in patients with mild to moderate cystic fibrosis lung disease. Author(s): Moss RB, Mayer-Hamblett N, Wagener J, Daines C, Hale K, Ahrens R, Gibson RL, Anderson P, Retsch-Bogart G, Nasr SZ, Noth I, Waltz D, Zeitlin P, Ramsey B, Starko K. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15573395&query_hl=25&itool=pubmed_docsum
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Rapid detection of cystic fibrosis transmembrane conductance regulator gene IVS8 5T variant by real-time PCR. Author(s): Kamory E, Csokay B, Hollo Z. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15388663&query_hl=25&itool=pubmed_docsum
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Re: Antibiotic renal failure and cystic fibrosis. Author(s): Coulthard K, Smith C, Martin J. Source: Journal of Paediatrics and Child Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16487396&query_hl=25&itool=pubmed_docsum
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Reduced number of CFTR molecules in erythrocyte plasma membrane of cystic fibrosis patients. Author(s): Lange T, Jungmann P, Haberle J, Falk S, Duebbers A, Bruns R, Ebner A, Hinterdorfer P, Oberleithner H, Schillers H. Source: Molecular Membrane Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16923725&query_hl=25&itool=pubmed_docsum
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Relationships between cystic fibrosis transmembrane conductance regulator, extracellular nucleotides and cystic fibrosis. Author(s): Marcet B, Boeynaems JM. Source: Pharmacology & Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16828872&query_hl=25&itool=pubmed_docsum
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Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis. Author(s): Blackman SM, Deering-Brose R, McWilliams R, Naughton K, Coleman B, Lai T, Algire M, Beck S, Hoover-Fong J, Hamosh A, Fallin MD, West K, Arking DE, Chakravarti A, Cutler DJ, Cutting GR. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17030173&query_hl=25&itool=pubmed_docsum
104
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Report of a Korean patient with cystic fibrosis, carrying Q98R and Q220X mutations in the CFTR gene. Author(s): Koh WJ, Ki CS, Kim JW, Kim JH, Lim SY. Source: Journal of Korean Medical Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16778407&query_hl=25&itool=pubmed_docsum
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Review of the abdominal manifestations of cystic fibrosis in the adult patient. Author(s): Robertson MB, Choe KA, Joseph PM. Source: Radiographics : a Review Publication of the Radiological Society of North America, Inc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16702447&query_hl=25&itool=pubmed_docsum
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Role of magnesium in the failure of rhDNase therapy in patients with cystic fibrosis. Author(s): Sanders NN, Franckx H, De Boeck K, Haustraete J, De Smedt SC, Demeester J. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17071834&query_hl=25&itool=pubmed_docsum
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Sequence diversity of the mucABD locus in Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Author(s): Bragonzi A, Wiehlmann L, Klockgether J, Cramer N, Worlitzsch D, Doring G, Tummler B. Source: Microbiology (Reading, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17074897&query_hl=25&itool=pubmed_docsum
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Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Author(s): Younger JM, Chen L, Ren HY, Rosser MF, Turnbull EL, Fan CY, Patterson C, Cyr DM. Source: Cell. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16901789&query_hl=25&itool=pubmed_docsum
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Serum leptin and cytokines in whole blood in relation to clinical and nutritional status in cystic fibrosis. Author(s): Schmitt-Grohe S, Hippe V, Igel M, von Bergmann K, Posselt HG, Krahl A, Smaczny C, Wagner TO, Nikolaizik W, Lentze MJ, Zielen S. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16877990&query_hl=25&itool=pubmed_docsum
Studies
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Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3- secretion: relevance to cystic fibrosis. Author(s): Wang Y, Soyombo AA, Shcheynikov N, Zeng W, Dorwart M, Marino CR, Thomas PJ, Muallem S. Source: The Embo Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053783&query_hl=25&itool=pubmed_docsum
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Small-cell lung carcinoma of recipient origin after bilateral lung transplantation for cystic fibrosis. Author(s): Picard C, Grenet D, Copie-Bergman C, Martin N, Longchampt E, Zemoura L, Stern M. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16890121&query_hl=25&itool=pubmed_docsum
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S-nitrosylating agents: a novel class of compounds that increase cystic fibrosis transmembrane conductance regulator expression and maturation in epithelial cells. Author(s): Zaman K, Carraro S, Doherty J, Henderson EM, Lendermon E, Liu L, Verghese G, Zigler M, Ross M, Park E, Palmer LA, Doctor A, Stamler JS, Gaston B. Source: Molecular Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16857740&query_hl=25&itool=pubmed_docsum
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Socialization of children and adolescents with cystic fibrosis: Support for nursing care. Author(s): Pizzignacco TM, de Lima RA. Source: Revista Latino-Americana De Enfermagem. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16967164&query_hl=25&itool=pubmed_docsum
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Sodium channel blockers for cystic fibrosis. Author(s): Burrows E, Southern KW, Noone P. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16856076&query_hl=25&itool=pubmed_docsum
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Study of a novel pancreatic enzyme replacement therapy in pancreatic insufficient subjects with cystic fibrosis. Author(s): Borowitz D, Goss CH, Limauro S, Konstan MW, Blake K, Casey S, Quittner AL, Murray FT. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17095338&query_hl=25&itool=pubmed_docsum
106
Cystic Fibrosis
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Targeted therapy for cystic fibrosis: cystic fibrosis transmembrane conductance regulator mutation-specific pharmacologic strategies. Author(s): Rubenstein RC. Source: Mol Diagn Ther. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17022692&query_hl=25&itool=pubmed_docsum
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The AlgT-dependent transcriptional regulator AmrZ (AlgZ) inhibits flagellum biosynthesis in mucoid, nonmotile Pseudomonas aeruginosa cystic fibrosis isolates. Author(s): Tart AH, Blanks MJ, Wozniak DJ. Source: Journal of Bacteriology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16952938&query_hl=25&itool=pubmed_docsum
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The CF-CIRC study: a French collaborative study to assess the accuracy of cystic fibrosis diagnosis in neonatal screening. Author(s): Sermet-Gaudelus I, Roussel D, Bui S, Deneuville E, Huet F, Reix P, Bellon G, Lenoir G, Edelman A. Source: Bmc Pediatrics [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17018149&query_hl=25&itool=pubmed_docsum
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The evaluation of a novel conductometric device for the diagnosis of cystic fibrosis. Author(s): Losty HC, Wheatley H, Doull I. Source: Annals of Clinical Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17022880&query_hl=25&itool=pubmed_docsum
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The mannan-binding lectin pathway and lung disease in cystic fibrosis--disfunction of mannan-binding lectin-associated serine protease 2 (MASP-2) may be a major modifier. Author(s): Olesen HV, Jensenius JC, Steffensen R, Thiel S, Schiotz PO. Source: Clinical Immunology (Orlando, Fla.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17045845&query_hl=25&itool=pubmed_docsum
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The prospects of pharmacotherapy for cystic fibrosis. Author(s): Cuthbert AW. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16927955&query_hl=25&itool=pubmed_docsum
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Thymosin beta4 sequesters actin in cystic fibrosis sputum and decreases sputum cohesivity in vitro. Author(s): Rubin BK, Kater AP, Goldstein AL. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17099021&query_hl=25&itool=pubmed_docsum
Studies
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Transitioning families to adult cystic fibrosis care. Author(s): Hink H, Schellhase D. Source: Journal for Specialists in Pediatric Nursing : Jspn. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16999750&query_hl=25&itool=pubmed_docsum
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Treatment of bronchomalacia in cystic fibrosis by silicone stent. Author(s): Herlitz GN, Sternberg DI, Palazzo R, Arcasoy S, Sonett JR. Source: The Annals of Thoracic Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17126148&query_hl=25&itool=pubmed_docsum
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Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis. Author(s): Ratjen F. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053493&query_hl=25&itool=pubmed_docsum
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Understanding genetic disease in a socio-historical context: a case study of cystic fibrosis. Author(s): Kerr A. Source: Sociology of Health & Illness. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16313521&query_hl=25&itool=pubmed_docsum
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Update in cystic fibrosis 2005. Author(s): Accurso FJ. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16632633&query_hl=25&itool=pubmed_docsum
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Update on maintaining bone health in cystic fibrosis. Author(s): Boyle MP. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053497&query_hl=25&itool=pubmed_docsum
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Update on the application of chest computed tomography scanning to cystic fibrosis. Author(s): Tiddens HA, de Jong PA. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053494&query_hl=25&itool=pubmed_docsum
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Update on treatment of pulmonary exacerbations in cystic fibrosis. Author(s): Smyth A. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053495&query_hl=25&itool=pubmed_docsum
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Up-regulation of AMP-activated kinase by dysfunctional cystic fibrosis transmembrane conductance regulator in cystic fibrosis airway epithelial cells mitigates excessive inflammation. Author(s): Hallows KR, Fitch AC, Richardson CA, Reynolds PR, Clancy JP, Dagher PC, Witters LA, Kolls JK, Pilewski JM. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16361706&query_hl=25&itool=pubmed_docsum
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Upregulation of COX-1 and COX-2 in nasal polyps in cystic fibrosis. Author(s): Roca-Ferrer J, Pujols L, Gartner S, Moreno A, Pumarola F, Mullol J, Cobos N, Picado C. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16517580&query_hl=25&itool=pubmed_docsum
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Use of 16S rRNA gene profiling by terminal restriction fragment length polymorphism analysis to compare bacterial communities in sputum and mouthwash samples from patients with cystic fibrosis. Author(s): Rogers GB, Carroll MP, Serisier DJ, Hockey PM, Jones G, Kehagia V, Connett GJ, Bruce KD. Source: Journal of Clinical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16825392&query_hl=25&itool=pubmed_docsum
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Use of PCR analyses to define the distribution of Ralstonia species recovered from patients with cystic fibrosis. Author(s): Coenye T, Spilker T, Reik R, Vandamme P, Lipuma JJ. Source: Journal of Clinical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16000479&query_hl=25&itool=pubmed_docsum
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Use of suppression subtractive hybridization to examine the accessory genome of the Liverpool cystic fibrosis epidemic strain of Pseudomonas aeruginosa. Author(s): Smart CH, Walshaw MJ, Hart CA, Winstanley C. Source: Journal of Medical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16687584&query_hl=25&itool=pubmed_docsum
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Vaginal delivery of a patient with severe cystic fibrosis. Author(s): Faden Y, Gruslin A. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16202413&query_hl=25&itool=pubmed_docsum
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Value of the chlorhexidine decontamination method for recovery of nontuberculous mycobacteria from sputum samples of patients with cystic fibrosis. Author(s): Ferroni A, Vu-Thien H, Lanotte P, Le Bourgeois M, Sermet-Gaudelus I, Fauroux B, Marchand S, Varaigne F, Berche P, Gaillard JL, Offredo C. Source: Journal of Clinical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16757627&query_hl=25&itool=pubmed_docsum
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Variable reactivity of an engineered cysteine at position 338 in cystic fibrosis transmembrane conductance regulator reflects different chemical states of the thiol. Author(s): Liu X, Alexander C, Serrano J, Borg E, Dawson DC. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16436375&query_hl=25&itool=pubmed_docsum
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Variants in the glutamate-cysteine-ligase gene are associated with cystic fibrosis lung disease. Author(s): McKone EF, Shao J, Frangolias DD, Keener CL, Shephard CA, Farin FM, Tonelli MR, Pare PD, Sandford AJ, Aitken ML, Kavanagh TJ. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16690975&query_hl=25&itool=pubmed_docsum
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Variceal hemorrhage and cystic fibrosis: outcomes and implications for liver transplantation. Author(s): Gooding I, Dondos V, Gyi KM, Hodson M, Westaby D. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16258952&query_hl=25&itool=pubmed_docsum
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Ventilation inhomogeneities in patients with cystic fibrosis: inappropriate reference data and errors? Author(s): Ranganathan SC, Robertson CF. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16120722&query_hl=25&itool=pubmed_docsum
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Vitamin A and E deficiency and lung disease in infants with cystic fibrosis. Author(s): Bines JE, Truby HD, Armstrong DS, Carzino R, Grimwood K. Source: Journal of Paediatrics and Child Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16398871&query_hl=25&itool=pubmed_docsum
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Voriconazole therapy in children with cystic fibrosis. Author(s): Hilliard T, Edwards S, Buchdahl R, Francis J, Rosenthal M, Balfour-Lynn I, Bush A, Davies J. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16243008&query_hl=25&itool=pubmed_docsum
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Weight and energy: parents' and children's perspectives on managing cystic fibrosis diet. Author(s): Savage E, Callery P. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15723908&query_hl=25&itool=pubmed_docsum
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What are the calorie requirements for patients with cystic fibrosis? Author(s): Marcason W. Source: Journal of the American Dietetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15800573&query_hl=25&itool=pubmed_docsum
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What are the cancer risks from using chest computed tomography to manage cystic fibrosis? Author(s): Berrington de Gonzalez A, Samet JM. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16391301&query_hl=25&itool=pubmed_docsum
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What follows newborn screening? An evaluation of a residential education program for parents of infants with newly diagnosed cystic fibrosis. Author(s): Sawyer SM, Glazner JA. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15286224&query_hl=25&itool=pubmed_docsum
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What is the incidence of cystic fibrosis in Italy? Data from the National Registry (1988-2001). Author(s): Bossi A, Casazza G, Padoan R, Milani S; Assemblea Dei Direttori Dei Centri. Source: Human Biology; an International Record of Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15481678&query_hl=25&itool=pubmed_docsum
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Widespread clone of Burkholderia cenocepacia in cystic fibrosis patients in the Czech Republic. Author(s): Drevinek P, Vosahlikova S, Cinek O, Vavrova V, Bartosova J, Pohunek P, Mahenthiralingam E. Source: Journal of Medical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15947430&query_hl=25&itool=pubmed_docsum
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Worldwide distribution of Pseudomonas aeruginosa clone C strains in the aquatic environment and cystic fibrosis patients. Author(s): Romling U, Kader A, Sriramulu DD, Simm R, Kronvall G. Source: Environmental Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946300&query_hl=25&itool=pubmed_docsum
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X-ray microanalysis of apical fluid in cystic fibrosis airway epithelial cell lines. Author(s): Kozlova I, Nilsson H, Henriksnas J, Roomans GM. Source: Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16543717&query_hl=25&itool=pubmed_docsum
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Young adults with cystic fibrosis are shorter than healthy peers because their parents are also short. Author(s): Arrigo T, De Luca F, Sferlazzas C, Lucanto C, Messina MF, Valenzise M, Marseglia L, Wasniewska M. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16133236&query_hl=25&itool=pubmed_docsum
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Young people living with cystic fibrosis: an insight into their subjective experience. Author(s): Badlan K. Source: Health & Social Care in the Community. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16650123&query_hl=25&itool=pubmed_docsum
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CHAPTER 2. ALTERNATIVE MEDICINE AND CYSTIC FIBROSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cystic fibrosis. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to cystic 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 cystic 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 cystic 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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11160632&query_hl=1&itool=pubmed_docsum
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A disciplined approach to spiritual care giving for adults living with cystic fibrosis. Author(s): Palmer C. Source: Journal of Health Care Chaplaincy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11398539&query_hl=1&itool=pubmed_docsum
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A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr(-/-) mice. Author(s): Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10570187&query_hl=1&itool=pubmed_docsum
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A model for group intervention with the chronically ill: cystic fibrosis and the family. Author(s): Brown DG, Krieg K, Belluck F. Source: Social Work in Health Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8553194&query_hl=1&itool=pubmed_docsum
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Actions of genistein on cystic fibrosis transmembrane conductance regulator channel gating. Evidence for two binding sites with opposite effects. Author(s): Wang F, Zeltwanger S, Yang IC, Nairn AC, Hwang TC. Source: The Journal of General Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9482713&query_hl=1&itool=pubmed_docsum
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Activation of cystic fibrosis transmembrane conductance regulator in rat epididymal epithelium by genistein. Author(s): Leung GP, Wong PY. Source: Biology of Reproduction. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10611078&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10853862&query_hl=1&itool=pubmed_docsum
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Acupuncture pain management for patients with cystic fibrosis: a pilot study. Author(s): Lin YC, Ly H, Golianu B. Source: The American Journal of Chinese Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15844843&query_hl=1&itool=pubmed_docsum
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Acute lymphoblastic leukaemia in a child with cystic fibrosis. Author(s): Rizzari C, Conter V, Jankovic M, D'Angelo P, Masera G, Costantini D, Bettinelli ME, Giunta AM. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1483594&query_hl=1&itool=pubmed_docsum
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Acute respiratory distress due to vocal cord dysfunction in cystic fibrosis. Author(s): Rusakow LS, Blager FB, Barkin RC, White CW. Source: The Journal of Asthma : Official Journal of the Association for the Care of Asthma. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1744030&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11722291&query_hl=1&itool=pubmed_docsum
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Adult cystic fibrosis patients' experiences of primary care consultations: a qualitative study. Author(s): Lowton K, Ballard KD. Source: The British Journal of General Practice : the Journal of the Royal College of General Practitioners. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16834878&query_hl=1&itool=pubmed_docsum
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Airway clearance techniques in the treatment of cystic fibrosis. Author(s): McIlwaine MP, Davidson AG. Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9363183&query_hl=1&itool=pubmed_docsum
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Airway epithelium directed gene therapy for cystic fibrosis. Author(s): White AF, Ponnazhagan S. Source: Med Chem. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17017989&query_hl=1&itool=pubmed_docsum
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Alterations of pancreatic amylase secretion in the reserpinized rat model of cystic fibrosis. Effects of cerulein and EGF. Author(s): Morisset J, Berube FL, Vanier M, Benrezzak O. Source: International Journal of Pancreatology : Official Journal of the International Association of Pancreatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7528761&query_hl=1&itool=pubmed_docsum
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Alterations of pancreatic growth and of GP-2 content in the reserpinized rat model of cystic fibrosis. Author(s): Leblond FA, Morisset J, LeBel D. Source: Pediatric Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2717264&query_hl=1&itool=pubmed_docsum
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Altered calcium homeostasis in adults with cystic fibrosis. Author(s): Aris RM, Lester GE, Dingman S, Ontjes DA. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10501788&query_hl=1&itool=pubmed_docsum
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Altered channel properties of porins from Haemophilus influenzae: isolates from cystic fibrosis patients. Author(s): Arbing MA, Hanrahan JW, Coulton JW. Source: The Journal of Membrane Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12235488&query_hl=1&itool=pubmed_docsum
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An extract from the medicinal plant Phyllanthus acidus and its isolated compounds induce airway chloride secretion: A potential treatment for cystic fibrosis. Author(s): Sousa M, Ousingsawat J, Seitz R, Puntheeranurak S, Regalado A, Schmidt A, Grego T, Jansakul C, Amaral MD, Schreiber R, Kunzelmann K. Source: Molecular Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17065237&query_hl=1&itool=pubmed_docsum
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Antiinflammatory therapies for cystic fibrosis: past, present, and future. Author(s): Prescott WA Jr, Johnson CE. Source: Pharmacotherapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15977917&query_hl=1&itool=pubmed_docsum
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Assessment of CFTR chloride channel openers in intact normal and cystic fibrosis murine epithelia. Author(s): Cuthbert AW. Source: British Journal of Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11159718&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14762183&query_hl=1&itool=pubmed_docsum
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Autogenic drainage: a modern approach to physiotherapy in cystic fibrosis. Author(s): Schoni MH. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2657053&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12468376&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10790249&query_hl=1&itool=pubmed_docsum
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Beta-carotene supplementation in cystic fibrosis. Author(s): Winklhofer-Roob BM. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8757591&query_hl=1&itool=pubmed_docsum
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Binding site of activators of the cystic fibrosis transmembrane conductance regulator in the nucleotide binding domains. Author(s): Moran O, Galietta LJ, Zegarra-Moran O. Source: Cellular and Molecular Life Sciences : Cmls. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15719171&query_hl=1&itool=pubmed_docsum
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Bioavailability and safety of a high dose of docosahexaenoic acid triacylglycerol of algal origin in cystic fibrosis patients: a randomized, controlled study. Author(s): Lloyd-Still JD, Powers CA, Hoffman DR, Boyd-Trull K, Lester LA, Benisek DC, Arterburn LM. Source: Nutrition (Burbank, Los Angeles County, Calif.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16226012&query_hl=1&itool=pubmed_docsum
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Biological effects of a dietary omega-3 polyunsaturated fatty acids supplementation in cystic fibrosis patients: a randomized, crossover placebo-controlled trial. Author(s): Panchaud A, Sauty A, Kernen Y, Decosterd LA, Buclin T, Boulat O, Hug C, Pilet M, Roulet M. Source: Clinical Nutrition (Edinburgh, Lothian). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16325968&query_hl=1&itool=pubmed_docsum
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Bone mineral density in Australian children, adolescents and adults with cystic fibrosis: a controlled cross sectional study. Author(s): Buntain HM, Greer RM, Schluter PJ, Wong JC, Batch JA, Potter JM, Lewindon PJ, Powell E, Wainwright CE, Bell SC.
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Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14760157&query_hl=1&itool=pubmed_docsum •
Building life skills for children with cystic fibrosis: effectiveness of an intervention. Author(s): Christian BJ, D'Auria JP. Source: Nursing Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16980830&query_hl=1&itool=pubmed_docsum
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Can 5-methyltetrahydrofolate modify the phospholipid fatty acid pattern in cystic fibrosis pediatric patients? Author(s): Scambi C, Guarini P, De Franceschi L, Bambara LM. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16516563&query_hl=1&itool=pubmed_docsum
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Can curcumin cure cystic fibrosis? Author(s): Zeitlin P. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15295056&query_hl=1&itool=pubmed_docsum
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Capsaicin potentiates wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride-channel currents. Author(s): Ai T, Bompadre SG, Wang X, Hu S, Li M, Hwang TC. Source: Molecular Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15155835&query_hl=1&itool=pubmed_docsum
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Chest physiotherapy in cystic fibrosis: a comparative study of autogenic drainage and the active cycle of breathing techniques with postural drainage. Author(s): Miller S, Hall DO, Clayton CB, Nelson R. Source: Thorax. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7701456&query_hl=1&itool=pubmed_docsum
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Chest physiotherapy in cystic fibrosis: improved tolerance with nasal pressure support ventilation. Author(s): Fauroux B, Boule M, Lofaso F, Zerah F, Clement A, Harf A, Isabey D. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10049988&query_hl=1&itool=pubmed_docsum
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Children with cystic fibrosis benefit from massage therapy. Author(s): Hernandez-Reif M, Field T, Krasnegor J, Martinez E, Schwartzman M, Mavunda K.
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Source: Journal of Pediatric Psychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10361400&query_hl=1&itool=pubmed_docsum •
Cholesterol esterase activities in commercial pancreatic enzyme preparations and implications for use in pancreatic insufficient cystic fibrosis. Author(s): Walters MP, Conway SP. Source: Journal of Clinical Pharmacy and Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11722679&query_hl=1&itool=pubmed_docsum
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Comparison of a high lipase pancreatic enzyme extract with a regular pancreatin preparation in adult cystic fibrosis patients. Author(s): J Paediatr Child Health. 1995 Aug;31(4):364 Source: Alimentary Pharmacology & Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7576903&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14681839&query_hl=1&itool=pubmed_docsum
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Curcumin and cystic fibrosis. Author(s): Accurso F. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15319620&query_hl=1&itool=pubmed_docsum
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Curcumin does not stimulate cAMP-mediated chloride transport in cystic fibrosis airway epithelial cells. Author(s): Dragomir A, Bjorstad J, Hjelte L, Roomans GM. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15325250&query_hl=1&itool=pubmed_docsum
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Curcumin enhances cystic fibrosis transmembrane regulator expression by downregulating calreticulin. Author(s): Harada K, Okiyoneda T, Hashimoto Y, Oyokawa K, Nakamura K, Suico MA, Shuto T, Kai H. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17178109&query_hl=1&itool=pubmed_docsum
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Curcumin stimulates cystic fibrosis transmembrane conductance regulator Clchannel activity. Author(s): Berger AL, Randak CO, Ostedgaard LS, Karp PH, Vermeer DW, Welsh MJ. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15582996&query_hl=1&itool=pubmed_docsum
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Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Author(s): Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Glockner-Pagel J, Canny S, Du K, Lukacs GL, Caplan MJ. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15105504&query_hl=1&itool=pubmed_docsum
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Current knowledge on fatty acids in cystic fibrosis. Author(s): Biochemistry. 1997 Nov 11;36(45):13972 Source: Prostaglandins, Leukotrienes, and Essential Fatty Acids. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9546810&itool=pubmed_docsum
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Cystic fibrosis in Russia: background and a model for future collaboration with the West. Author(s): Kapranov N, Ginter E, Kashirskaja N, Hill CM, Ilangovan P, Rolles CJ. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8778450&query_hl=1&itool=pubmed_docsum
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Cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and Na-K-Cl cotransporter NKCC1 isoform mediate the vasorelaxant action of genistein in isolated rat aorta. Author(s): Valero MS, Garay RP, Gros P, Alda JO. Source: European Journal of Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16859673&query_hl=1&itool=pubmed_docsum
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Cystic fibrosis transmembrane conductance regulator activation by cAMPindependent mechanisms. Author(s): He Z, Raman S, Guo Y, Reenstra WW. Source: The American Journal of Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9755049&query_hl=1&itool=pubmed_docsum
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Cystic fibrosis: nutritional consequences and management. Author(s): Dodge JA, Turck D. Source: Best Practice & Research. Clinical Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16782527&query_hl=1&itool=pubmed_docsum
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Cystic fibrosis-related diabetes. Author(s): Mackie AD, Thornton SJ, Edenborough FP. Source: Diabetic Medicine : a Journal of the British Diabetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12786675&query_hl=1&itool=pubmed_docsum
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Dance/movement therapy for adults with cystic fibrosis: pilot data on mood and adherence. Author(s): Goodill SW. Source: Alternative Therapies in Health and Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15712769&query_hl=1&itool=pubmed_docsum
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Decreased peroxisome proliferator activated receptor alpha is associated with bile duct injury in cystic fibrosis transmembrane conductance regulator-/- mice. Author(s): Pall H, Zaman MM, Andersson C, Freedman SD. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16540796&query_hl=1&itool=pubmed_docsum
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Defective function of the cystic fibrosis-causing missense mutation G551D is recovered by genistein. Author(s): Illek B, Zhang L, Lewis NC, Moss RB, Dong JY, Fischer H. Source: The American Journal of Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10516113&query_hl=1&itool=pubmed_docsum
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Deficiency of vitamins E and A in cystic fibrosis is independent of pancreatic function and current enzyme and vitamin supplementation. Author(s): Lancellotti L, D'Orazio C, Mastella G, Mazzi G, Lippi U. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8777920&query_hl=1&itool=pubmed_docsum
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Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: drugs for cystic fibrosis and chronic bronchitis. Author(s): Hirsh AJ, Molino BF, Zhang J, Astakhova N, Geiss WB, Sargent BJ, Swenson BD, Usyatinsky A, Wyle MJ, Boucher RC, Smith RT, Zamurs A, Johnson MR. Source: Journal of Medicinal Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16821771&query_hl=1&itool=pubmed_docsum
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Detection of cystic fibrosis delta F508 mutation by anti-double-stranded DNA antibody. Author(s): Hopfer SM, Makowski GS, Davis EL, Aslanzadeh J.
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Source: Ann Clin Lab Sci. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8572556&query_hl=1&itool=pubmed_docsum •
Development and evaluation of a multi-family psychoeducational program for cystic fibrosis. Author(s): Goldbeck L, Babka C. Source: Patient Education and Counseling. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11479059&query_hl=1&itool=pubmed_docsum
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Development of the role-play inventory of situations and coping strategies for parents of children with cystic fibrosis. Author(s): Quittner AL, Tolbert VE, Regoli MJ, Orenstein DM, Hollingsworth JL, Eigen H. Source: Journal of Pediatric Psychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8920154&query_hl=1&itool=pubmed_docsum
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Dietary and circulating polyunsaturated fatty acids in cystic fibrosis: are they related to clinical outcomes? Author(s): Colombo C, Bennato V, Costantini D, Valmarana L, Dacco V, Zazzeron L, Ghisleni D, Bruzzese MG, Scaglioni S, Riva E, Agostoni C. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17130745&query_hl=1&itool=pubmed_docsum
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Dietary fat in cystic fibrosis. Author(s): Dodge JA. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7965447&query_hl=1&itool=pubmed_docsum
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Dietary intakes in adult patients with cystic fibrosis--do they achieve guidelines? Author(s): White H, Morton AM, Peckham DG, Conway SP. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15463880&query_hl=1&itool=pubmed_docsum
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Dietary supplementation with multiple micronutrients: No beneficial effects in pediatric cystic fibrosis patients. Author(s): Oudshoorn JH, Klijn PH, Hofman Z, Voorbij HA, van der Ent CK, Berger R, Houwen RH. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16784903&query_hl=1&itool=pubmed_docsum
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Differential stimulation of cytosolic phospholipase A2 by bradykinin in human cystic fibrosis cell lines. Author(s): Berguerand M, Klapisz E, Thomas G, Humbert L, Jouniaux AM, Olivier JL, Bereziat G, Masliah J. Source: American Journal of Respiratory Cell and Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9376123&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11224654&query_hl=1&itool=pubmed_docsum
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Docosahexaenoic acid trials in cystic fibrosis: a review of the rationale behind the clinical trials. Author(s): Van Biervliet S, Van Biervliet JP, Robberecht E, Christophe A. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15752678&query_hl=1&itool=pubmed_docsum
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Dual therapeutic utility of proteasome modulating agents for pharmaco-gene therapy of the cystic fibrosis airway. Author(s): Zhang LN, Karp P, Gerard CJ, Pastor E, Laux D, Munson K, Yan Z, Liu X, Godwin S, Thomas CP, Zabner J, Shi H, Caldwell CW, Peluso R, Carter B, Engelhardt JF. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15564131&query_hl=1&itool=pubmed_docsum
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Duodenal pH in cystic fibrosis and its relationship to fat malabsorption. Author(s): Robinson PJ, Smith AL, Sly PD. Source: Digestive Diseases and Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2120019&query_hl=1&itool=pubmed_docsum
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Effect of a medium dose of ursodeoxycholic acid with or without taurine supplementation on the nutritional status of patients with cystic fibrosis: a randomized, placebo-controlled, crossover trial. Author(s): Merli M, Bertasi S, Servi R, Diamanti S, Martino F, De Santis A, Goffredo F, Quattrucci S, Antonelli M, Angelico M. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7815243&query_hl=1&itool=pubmed_docsum
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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.
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Source: Jpen. Journal of Parenteral and Enteral Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12549599&query_hl=1&itool=pubmed_docsum •
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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12183711&query_hl=1&itool=pubmed_docsum
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Effect of double-blind crossover selenium supplementation on biological indices of selenium status in cystic fibrosis patients. Author(s): Portal B, Richard MJ, Ducros V, Aguilaniu B, Brunel F, Faure H, Gout JP, Bost M, Favier A. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8504531&query_hl=1&itool=pubmed_docsum
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Effect of double-blind cross-over selenium supplementation on lipid peroxidation markers in cystic fibrosis patients. Author(s): Portal B, Richard MJ, Coudray C, Arnaud J, Favier A. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7758213&query_hl=1&itool=pubmed_docsum
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Effect of misoprostol on fat malabsorption in cystic fibrosis. Author(s): Robinson PJ, Sly PD, Smith AL. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3140739&query_hl=1&itool=pubmed_docsum
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Effect of taurine supplementation on fat and energy absorption in cystic fibrosis. Author(s): De Curtis M, Santamaria F, Ercolini P, Vittoria L, De Ritis G, Garofalo V, Ciccimarra F. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1417050&query_hl=1&itool=pubmed_docsum
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Effect of taurine supplements on growth, fat absorption and bile acid on cystic fibrosis. Author(s): Carrasco S, Codoceo R, Prieto G, Lama R, Polanco I. Source: Acta Univ Carol [med] (Praha). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2130680&query_hl=1&itool=pubmed_docsum
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Effect of the addition of protease inhibitors to sputa from cystic fibrosis patients. Author(s): Costello CM, McQuaid K, O'Connor CM, Fitzgerald MX. Source: Biochemical Society Transactions. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8206281&query_hl=1&itool=pubmed_docsum
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Effect of vitamin K1 supplementation on vitamin K status in cystic fibrosis patients. Author(s): Beker LT, Ahrens RA, Fink RJ, O'Brien ME, Davidson KW, Sokoll LJ, Sadowski JA. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9161943&query_hl=1&itool=pubmed_docsum
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Effect on renal function of essential fatty acid supplementation in cystic fibrosis. Author(s): Strandvik B, Berg U, Kallner A, Kusoffsky E. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2754552&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11120904&query_hl=1&itool=pubmed_docsum
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Effects of creatine supplementation in cystic fibrosis: results of a pilot study. Author(s): Braegger CP, Schlattner U, Wallimann T, Utiger A, Frank F, Schaefer B, Heizmann CW, Sennhauser FH. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15463870&query_hl=1&itool=pubmed_docsum
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Effects of long-term oral beta-carotene supplementation on lipid peroxidation in patients with cystic fibrosis. Author(s): Rust P, Eichler I, Renner S, Elmadfa I. Source: Int J Vitam Nutr Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9565821&query_hl=1&itool=pubmed_docsum
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Eicosanoids in cystic fibrosis. Author(s): Steger B, Colvin HP. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15131835&query_hl=1&itool=pubmed_docsum
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Eicosanoids in cystic fibrosis. Author(s): Kida Y.
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Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15128902&query_hl=1&itool=pubmed_docsum •
Eicosapentaenoic acid in cystic fibrosis: evidence of a pathogenetic role for leukotriene B4. Author(s): Lawrence R, Sorrell T. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8102430&query_hl=1&itool=pubmed_docsum
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Eicosapentaenoic acid modulates neutrophil leukotriene B4 receptor expression in cystic fibrosis. Author(s): Lawrence RH, Sorrell TC. Source: Clinical and Experimental Immunology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7923869&query_hl=1&itool=pubmed_docsum
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Elevated vitamin A intake and serum retinol in preadolescent children with cystic fibrosis. Author(s): Graham-Maar RC, Schall JI, Stettler N, Zemel BS, Stallings VA. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16825693&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12674889&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11045840&query_hl=1&itool=pubmed_docsum
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Enhanced resistance to oxidation of low density lipoproteins and decreased lipid peroxide formation during beta-carotene supplementation in cystic fibrosis. Author(s): Winklhofer-Roob BM, Puhl H, Khoschsorur G, van't Hof MA, Esterbauer H, Shmerling DH. Source: Free Radical Biology & Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7797092&query_hl=1&itool=pubmed_docsum
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Enteral tube feeding for cystic fibrosis. Author(s): Conway SP, Morton A, Wolfe S. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10796753&query_hl=1&itool=pubmed_docsum
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Epithelial cell specific properties and genetic complementation in a delta F508 cystic fibrosis nasal polyp cell line. Author(s): Kunzelmann K, Lei DC, Eng K, Escobar LC, Koslowsky T, Gruenert DC. Source: In Vitro Cellular & Developmental Biology. Animal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8528517&query_hl=1&itool=pubmed_docsum
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Erythrocyte sodium-potassium transport in cystic fibrosis. Author(s): Sigstrom L, Strandvik B. Source: Pediatric Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1318537&query_hl=1&itool=pubmed_docsum
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Essential fatty acid deficiency and nutritional supplementation in cystic fibrosis. Author(s): Lloyd-Still JD. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12183705&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11713441&query_hl=1&itool=pubmed_docsum
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Essential fatty acid deficient rats in the study of cystic fibrosis: an X-ray microanalytical and ultrastructural study in chronically reserpinized rats. Author(s): Hjelte L, Strandvik B, Muller RM, Sagstrom S, Roomans GM. Source: J Submicrosc Cytol Pathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2390763&query_hl=1&itool=pubmed_docsum
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Essential fatty acid status and fluidity of plasma phospholipids in cystic fibrosis infants. Author(s): Lloyd-Still JD, Johnson SB, Holman RT. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1957818&query_hl=1&itool=pubmed_docsum
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Estrogen inhibition of cystic fibrosis transmembrane conductance regulator-mediated chloride secretion.
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Author(s): Singh AK, Schultz BD, Katzenellenbogen JA, Price EM, Bridges RJ, Bradbury NA. Source: The Journal of Pharmacology and Experimental Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10991979&query_hl=1&itool=pubmed_docsum •
Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease. Author(s): Hirsh AJ, Sabater JR, Zamurs A, Smith RT, Paradiso AM, Hopkins S, Abraham WM, Boucher RC. Source: The Journal of Pharmacology and Experimental Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15273255&query_hl=1&itool=pubmed_docsum
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Evidence that endoplasmic reticulum (ER)-associated degradation of cystic fibrosis transmembrane conductance regulator is linked to retrograde translocation from the ER membrane. Author(s): Xiong X, Chong E, Skach WR. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9915789&query_hl=1&itool=pubmed_docsum
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External ATP and its analogs activate the cystic fibrosis transmembrane conductance regulator by a cyclic AMP-independent mechanism. Author(s): Cantiello HF, Prat AG, Reisin IL, Ercole LB, Abraham EH, Amara JF, Gregory RJ, Ausiello DA. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7512560&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12242582&query_hl=1&itool=pubmed_docsum
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Failure of conventional strategies to improve nutritional status in malnourished adolescents and adults with cystic fibrosis. Author(s): Kalnins D, Corey M, Ellis L, Pencharz PB, Tullis E, Durie PR. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16182685&query_hl=1&itool=pubmed_docsum
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Failure of high-dose ergocalciferol to correct vitamin D deficiency in adults with cystic fibrosis. Author(s): Boyle MP, Noschese ML, Watts SL, Davis ME, Stenner SE, Lechtzin N.
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Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids. Author(s): Kalivianakis M, Minich DM, Bijleveld CM, van Aalderen WM, Stellaard F, Laseur M, Vonk RJ, Verkade HJ. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9925134&query_hl=1&itool=pubmed_docsum
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Fat malabsorption in cystic fibrosis patients. Author(s): Murphy J, Laiho K, Wootton S. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10539762&query_hl=1&itool=pubmed_docsum
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Fatty acid metabolism in cystic fibrosis. Author(s): Strandvik B. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14762189&query_hl=1&itool=pubmed_docsum
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Fatty acid pool size in plasma lipoprotein fractions of cystic fibrosis patients. Author(s): Clandinin MT, Zuberbuhler P, Brown NE, Kielo ES, Goh YK. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7491891&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12920976&query_hl=1&itool=pubmed_docsum
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Fatty acids in blood and intestine following docosahexaenoic acid supplementation in adults with cystic fibrosis. Author(s): Jumpsen JA, Brown NE, Thomson AB, Paul Man SF, Goh YK, Ma D, Clandinin MT. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16507353&query_hl=1&itool=pubmed_docsum
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Fatty acids in cystic fibrosis. Author(s): Freedman SD, Shea JC, Blanco PG, Alvarez JG.
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Source: Current Opinion in Pulmonary Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11100964&query_hl=1&itool=pubmed_docsum •
Fatty acids, alpha-fetoprotein, and cystic fibrosis. Author(s): Mizejewski GJ, Pass KA. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11731663&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12352527&query_hl=1&itool=pubmed_docsum
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Flow-dependency of exhaled nitric oxide in children with asthma and cystic fibrosis. Author(s): Kroesbergen A, Jobsis Q, Bel EH, Hop WC, de Jongste JC. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10573235&query_hl=1&itool=pubmed_docsum
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Framework for a proactive parent support group: the Syracuse cystic fibrosis model. Author(s): Matloff ET, Zimmerman SJ. Source: Journal of Pediatric Health Care : Official Publication of National Association of Pediatric Nurse Associates & Practitioners. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9052117&query_hl=1&itool=pubmed_docsum
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Future pharmacological treatment of cystic fibrosis. Author(s): Zeitlin PL. Source: Respiration; International Review of Thoracic Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10940786&query_hl=1&itool=pubmed_docsum
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Gender differences in health-related quality of life of adolescents with cystic fibrosis. Author(s): Arrington-Sanders R, Yi MS, Tsevat J, Wilmott RW, Mrus JM, Britto MT. Source: Health and Quality of Life Outcomes [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16433917&query_hl=1&itool=pubmed_docsum
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Gene and cell therapy for cystic fibrosis. Author(s): Davies JC.
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Gene therapy progress and prospects: cystic fibrosis. Author(s): Griesenbach U, Geddes DM, Alton EW. Source: Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16819538&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12386156&query_hl=1&itool=pubmed_docsum
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Genistein inhibits constitutive and inducible NFkappaB activation and decreases IL-8 production by human cystic fibrosis bronchial gland cells. Author(s): Tabary O, Escotte S, Couetil JP, Hubert D, Dusser D, Puchelle E, Jacquot J. Source: American Journal of Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10433940&query_hl=1&itool=pubmed_docsum
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Glycemic response to dietary supplements in cystic fibrosis is dependent on the carbohydrate content of the formula. Author(s): Milla C, Doherty L, Raatz S, Schwarzenberg SJ, Regelmann W, Moran A. Source: Jpen. Journal of Parenteral and Enteral Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8776690&query_hl=1&itool=pubmed_docsum
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Granulocyte elastase-mediated proteolysis of alpha 1-antitrypsin in cystic fibrosis bronchopulmonary secretions. Author(s): Cantin A, Bilodeau G, Begin R. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2788857&query_hl=1&itool=pubmed_docsum
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Growing up with chronic illness: the experience of growing up with cystic fibrosis. Author(s): Tracy JP. Source: Holistic Nursing Practice. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9384068&query_hl=1&itool=pubmed_docsum
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Growing up with cystic fibrosis. Author(s): Helms PJ.
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Gut inflammation in children with cystic fibrosis on high-dose enzyme supplementation. Author(s): Doull I, Langton-Hewer S. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8569382&query_hl=1&itool=pubmed_docsum
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Gut inflammation in children with cystic fibrosis on high-dose enzyme supplements. Author(s): Croft NM, Marshall TG, Ferguson A. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7475719&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12519749&query_hl=1&itool=pubmed_docsum
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High dose Nutrizym 22 in cystic fibrosis. Author(s): Shah A, Dinwiddie R, Madge S, Prescott P, Hudson G. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7693476&query_hl=1&itool=pubmed_docsum
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High-performance liquid chromatography/electrospray ionization ion-trap tandem mass spectrometric analysis and quantification of phosphatidylcholine molecular species in the serum of cystic fibrosis subjects supplemented with docosahexaenoic acid. Author(s): Pacetti D, Malavolta M, Bocci F, Boselli E, Frega NG. Source: Rapid Communications in Mass Spectrometry : Rcm. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15386630&query_hl=1&itool=pubmed_docsum
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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). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12762618&query_hl=1&itool=pubmed_docsum
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Hopkins Teen Central: Assessment of an internet-based support system for children with cystic fibrosis. Author(s): Johnson KB, Ravert RD, Everton A.
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10933092&query_hl=1&itool=pubmed_docsum
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Hypnosis, Theodore Roosevelt, and the patient with cystic fibrosis. Author(s): Anbar RD. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10920161&query_hl=1&itool=pubmed_docsum
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Impaired resistance to oxidation of low density lipoprotein in cystic fibrosis: improvement during vitamin E supplementation. Author(s): Winklhofer-Roob BM, Ziouzenkova O, Puhl H, Ellemunter H, Greiner P, Muller G, van't Hof MA, Esterbauer H, Shmerling DH. Source: Free Radical Biology & Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8582644&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12499335&query_hl=1&itool=pubmed_docsum
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Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein. Author(s): Grey V, Mohammed SR, Smountas AA, Bahlool R, Lands LC. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15463873&query_hl=1&itool=pubmed_docsum
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Improved pulmonary function and exercise tolerance with inspiratory muscle conditioning in children with cystic fibrosis. Author(s): Sawyer EH, Clanton TL. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8222813&query_hl=1&itool=pubmed_docsum
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Increase of long chain omega-3 fatty acids in the major serum lipid classes of patients with cystic fibrosis. Author(s): Christophe A, Robberecht E, De Baets F, Franckx H. Source: Annals of Nutrition & Metabolism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1492758&query_hl=1&itool=pubmed_docsum
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Inhibition of ATPase, GTPase and adenylate kinase activities of the second nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator by genistein. Author(s): Randak C, Auerswald EA, Assfalg-Machleidt I, Reenstra WW, Machleidt W. Source: The Biochemical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10229679&query_hl=1&itool=pubmed_docsum
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Inspiratory muscle training improves lung function and exercise capacity in adults with cystic fibrosis. Author(s): Enright S, Chatham K, Ionescu AA, Unnithan VB, Shale DJ. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15302725&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11207014&query_hl=1&itool=pubmed_docsum
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Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration. Author(s): Bruzzese E, Raia V, Gaudiello G, Polito G, Buccigrossi V, Formicola V, Guarino A. Source: Alimentary Pharmacology & Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15379842&query_hl=1&itool=pubmed_docsum
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Intestinal permeability to 51Cr-EDTA and orocecal transit time in cystic fibrosis. Author(s): Escobar H, Perdomo M, Vasconez F, Camarero C, del Olmo MT, Suarez L. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1593376&query_hl=1&itool=pubmed_docsum
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Is there a case for n-3 fatty acid supplementation in cystic fibrosis? Author(s): Cawood AL, Carroll MP, Wootton SA, Calder PC. Source: Current Opinion in Clinical Nutrition and Metabolic Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15716793&query_hl=1&itool=pubmed_docsum
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Knowledge, interests and educational needs of adults diagnosed with cystic fibrosis after age 18. Author(s): Widerman E. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15463857&query_hl=1&itool=pubmed_docsum
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Liver function in patients with cystic fibrosis ingesting fish oil. Author(s): Henderson WR Jr, Astley SJ, Ramsey BW. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8071770&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10838464&query_hl=1&itool=pubmed_docsum
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Long-term oral vitamin E supplementation in cystic fibrosis patients: RRR-alphatocopherol compared with all-rac-alpha-tocopheryl acetate preparations. Author(s): Winklhofer-Roob BM, van't Hof MA, Shmerling DH. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8615355&query_hl=1&itool=pubmed_docsum
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Long-term outcome of lung transplantation for cystic fibrosis--Danish results. Author(s): Bech B, Pressler T, Iversen M, Carlsen J, Milman N, Eliasen K, Perko M, Arendrup H. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15541981&query_hl=1&itool=pubmed_docsum
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Management of chronic sinusitis in cystic fibrosis. Author(s): Davidson TM, Murphy C, Mitchell M, Smith C, Light M. Source: The Laryngoscope. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7715376&query_hl=1&itool=pubmed_docsum
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Massive hepatomegaly, steatosis, and secondary plasma carnitine deficiency in an infant with cystic fibrosis. Author(s): Treem WR, Stanley CA. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2726354&query_hl=1&itool=pubmed_docsum
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Medical nutrition therapy for cystic fibrosis: beyond pancreatic enzyme replacement therapy. Author(s): Hayek KM. Source: Journal of the American Dietetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16863713&query_hl=1&itool=pubmed_docsum
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Mediterranean diet and cystic fibrosis. Author(s): Strandvik B. Source: The British Journal of Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16923213&query_hl=1&itool=pubmed_docsum
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Modulation of deltaF508 cystic fibrosis transmembrane regulator trafficking and function with 4-phenylbutyrate and flavonoids. Author(s): Lim M, McKenzie K, Floyd AD, Kwon E, Zeitlin PL. Source: American Journal of Respiratory Cell and Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15191910&query_hl=1&itool=pubmed_docsum
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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. Source: J Assoc Physicians India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12723646&query_hl=1&itool=pubmed_docsum
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Mucus clearance with three chest physiotherapy regimes in cystic fibrosis: a comparison between postural drainage, PEP and physical exercise. Author(s): Lannefors L, Wollmer P. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1628733&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12110684&query_hl=1&itool=pubmed_docsum
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Neutrophil elastase/alpha 1-proteinase inhibitor complex levels decrease in plasma of cystic fibrosis patients during long-term oral beta-carotene supplementation. Author(s): Winklhofer-Roob BM, Schlegel-Haueter SE, Khoschsorur G, van't Hof MA, Suter S, Shmerling DH.
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Source: Pediatric Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8798258&query_hl=1&itool=pubmed_docsum •
New and emerging therapies for pulmonary complications of cystic fibrosis. Author(s): Tonelli MR, Aitken ML. Source: Drugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11558827&query_hl=1&itool=pubmed_docsum
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Newer therapies for cystic fibrosis. Author(s): Schidlow DV. Source: Paediatric Respiratory Reviews. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12531102&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14514944&query_hl=1&itool=pubmed_docsum
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Nutrition and growth in cystic fibrosis. Author(s): Hankard R, Munck A, Navarro J. Source: Hormone Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12373008&query_hl=1&itool=pubmed_docsum
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Nutrition in patients with cystic fibrosis: a European Consensus. Author(s): Sinaasappel M, Stern M, Littlewood J, Wolfe S, Steinkamp G, Heijerman HG, Robberecht E, Doring G. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15463811&query_hl=1&itool=pubmed_docsum
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Nutrition intervention for weight gain in cystic fibrosis: a meta analysis. Author(s): Jelalian E, Stark LJ, Reynolds L, Seifer R. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9544906&query_hl=1&itool=pubmed_docsum
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Nutritional assessment and management in cystic fibrosis: a consensus report. The Consensus Committee. Author(s): Ramsey BW, Farrell PM, Pencharz P.
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Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1728810&query_hl=1&itool=pubmed_docsum •
Nutritional effects of long-term gastrostomy feedings in children with cystic fibrosis. Author(s): Rosenfeld M, Casey S, Pepe M, Ramsey BW. Source: Journal of the American Dietetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9972186&query_hl=1&itool=pubmed_docsum
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Nutritional follow-up of cystic fibrosis patients: the role of nutrition education. Author(s): Adde FV, Rodrigues JC, Cardoso AL. Source: Jornal De Pediatria. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15622424&query_hl=1&itool=pubmed_docsum
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Nutritional imperatives in cystic fibrosis therapy. Author(s): Erdman SH. Source: Pediatric Annals. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10036689&query_hl=1&itool=pubmed_docsum
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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. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10617704&query_hl=1&itool=pubmed_docsum
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Nutritional supplements in cystic fibrosis. Author(s): Kappler M, Griese M. Source: Bmj (Clinical Research Ed.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16543303&query_hl=1&itool=pubmed_docsum
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Ocular findings in cystic fibrosis patients receiving vitamin A supplementation. Author(s): Morkeberg JC, Edmund C, Prause JU, Lanng S, Koch C, Michaelsen KF. Source: Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8566828&query_hl=1&itool=pubmed_docsum
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Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis treated with daily vitamin A supplements. Author(s): Ansari EA, Sahni K, Etherington C, Morton A, Conway SP, Moya E, Littlewood JM.
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Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10340977&query_hl=1&itool=pubmed_docsum •
Omega-3 fatty acids (from fish oils) for cystic fibrosis. Author(s): Beckles Willson N, Elliott TM, Everard ML. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12137649&query_hl=1&itool=pubmed_docsum
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Omega-3 fatty acids suppress the enhanced production of 5-lipoxygenase products from polymorph neutrophil granulocytes in cystic fibrosis. Author(s): Keicher U, Koletzko B, Reinhardt D. Source: European Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8719931&query_hl=1&itool=pubmed_docsum
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Optimising nutrition in cystic fibrosis. Author(s): Bell SC, Shepherd RW. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15463810&query_hl=1&itool=pubmed_docsum
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Oral absorption of omega-3 fatty acids in patients with cystic fibrosis who have pancreatic insufficiency and in healthy control subjects. Author(s): Henderson WR Jr, Astley SJ, McCready MM, Kushmerick P, Casey S, Becker JW, Ramsey BW. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8120709&query_hl=1&itool=pubmed_docsum
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Oral calorie supplements for cystic fibrosis. Author(s): Smyth R, Walters S. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10796716&query_hl=1&itool=pubmed_docsum
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Oral L-arginine supplementation in cystic fibrosis patients: a placebo-controlled study. Author(s): Grasemann H, Grasemann C, Kurtz F, Tietze-Schillings G, Vester U, Ratjen F. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15640324&query_hl=1&itool=pubmed_docsum
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Oral protein energy supplements for children with cystic fibrosis: CALICO multicentre randomised controlled trial.
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Author(s): Poustie VJ, Russell JE, Watling RM, Ashby D, Smyth RL; CALICO Trial Collaborative Group. Source: Bmj (Clinical Research Ed.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16467348&query_hl=1&itool=pubmed_docsum •
Oral supplementation with a high-fat, high-energy product improves nutritional status and alters serum lipids in patients with cystic fibrosis. Author(s): Rettammel AL, Marcus MS, Farrell PM, Sondel SA, Koscik RE, Mischler EH. Source: Journal of the American Dietetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7699188&query_hl=1&itool=pubmed_docsum
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Overexpression of the cystic fibrosis transmembrane conductance regulator in NIH 3T3 cells lowers membrane potential and intracellular pH and confers a multidrug resistance phenotype. Author(s): Wei LY, Stutts MJ, Hoffman MM, Roepe PD. Source: Biophysical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8519988&query_hl=1&itool=pubmed_docsum
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Paradoxical effects of essential fatty acid supplementation on lipid profiles and sweat electrolytes in cystic fibrosis. Author(s): Dodge JA, Custance JM, Goodchild MC, Laing SC, Vaughan M. Source: The British Journal of Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2185826&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14719993&query_hl=1&itool=pubmed_docsum
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Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy. Author(s): Kerem E. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15880796&query_hl=1&itool=pubmed_docsum
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Pharmacological treatment of the ion transport defect in cystic fibrosis. Author(s): Roomans GM. Source: Expert Opinion on Investigational Drugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11116277&query_hl=1&itool=pubmed_docsum
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Pharmacotherapy of the ion transport defect in cystic fibrosis. Author(s): Kunzelmann K, Mall M. Source: Clinical and Experimental Pharmacology & Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11703384&query_hl=1&itool=pubmed_docsum
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Physiotherapy in cystic fibrosis. Author(s): Prasad SA, Tannenbaum EL, Mikelsons C. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10911816&query_hl=1&itool=pubmed_docsum
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Plant sources of acid stable lipases: potential therapy for cystic fibrosis. Author(s): Tursi JM, Phair PG, Barnes GL. Source: Journal of Paediatrics and Child Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7865271&query_hl=1&itool=pubmed_docsum
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Plasma immunoreactive cationic trypsin(ogen) pattern in reserpinized rat model of cystic fibrosis. Resemblance to humans. Author(s): Weizman Z. Source: Digestive Diseases and Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8625754&query_hl=1&itool=pubmed_docsum
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Plasma lipid concentrations in children with cystic fibrosis: the value of a high-fat diet and pancreatic supplementation. Author(s): Burdge GC, Goodale AJ, Hill CM, Halford PJ, Lambert EJ, Postle AD, Rolles CJ. Source: The British Journal of Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7518243&query_hl=1&itool=pubmed_docsum
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Posture and cystic fibrosis. Author(s): Tattersall R, Walshaw MJ. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12906321&query_hl=1&itool=pubmed_docsum
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Predicting response to rhDNase and hypertonic saline in children with cystic fibrosis. Author(s): Suri R, Metcalfe C, Wallis C, Bush A. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15022126&query_hl=1&itool=pubmed_docsum
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Providing services for families with a genetic condition: a contrast between cystic fibrosis and Down syndrome. Author(s): Collins V, Williamson R.
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Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14595065&query_hl=1&itool=pubmed_docsum •
Pseudomonas aeruginosa in public swimming pools and bathroom water of patients with cystic fibrosis. Author(s): Barben J, Hafen G, Schmid J; Swiss Paediatric Respiratory Research Group. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16081326&query_hl=1&itool=pubmed_docsum
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Psychological interventions for cystic fibrosis. Author(s): Glasscoe CA, Quittner AL. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12917948&query_hl=1&itool=pubmed_docsum
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Psychosocial risk associated with newborn screening for cystic fibrosis: parents' experience while awaiting the sweat-test appointment. Author(s): Tluczek A, Koscik RL, Farrell PM, Rock MJ. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15930234&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12513105&query_hl=1&itool=pubmed_docsum
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Quantitative lung perfusion scan as a predictor of aerosol distribution heterogeneity and disease severity in children with cystic fibrosis. Author(s): Itti E, Fauroux B, Pigeot J, Isabey D, Clement A, Evangelista E, Harf A, Meignan M. Source: Nuclear Medicine Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15167515&query_hl=1&itool=pubmed_docsum
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Randomised double blind placebo controlled trial investigating the effect of calcium and vitamin D supplementation on bone mineral density and bone metabolism in adult patients with cystic fibrosis. Author(s): Haworth CS, Jones AM, Adams JE, Selby PL, Webb AK. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15698940&query_hl=1&itool=pubmed_docsum
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Ranitidine in children with peptic ulcer and patients with pancreatic cystic fibrosis. Author(s): Scorza A, Conti-Nibali S, Sferlazzas C, Saitta G, Tedeschi A. Source: Int J Clin Pharmacol Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2228343&query_hl=1&itool=pubmed_docsum
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Relationships among nutritional status and skeletal and respiratory muscle function in cystic fibrosis: does early dietary supplementation make a difference? Author(s): Hanning RM, Blimkie CJ, Bar-Or O, Lands LC, Moss LA, Wilson WM. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8460615&query_hl=1&itool=pubmed_docsum
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Relationships between essential fatty acid levels, pulmonary function and fat absorption in pre-adolescent cystic fibrosis children with good clinical scores. Author(s): Thompson GN. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2707278&query_hl=1&itool=pubmed_docsum
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Religious/spiritual coping in childhood cystic fibrosis: a qualitative study. Author(s): Pendleton SM, Cavalli KS, Pargament KI, Nasr SZ. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11773576&query_hl=1&itool=pubmed_docsum
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Rescue of DeltaF508-CFTR (cystic fibrosis transmembrane conductance regulator) by curcumin: involvement of the keratin 18 network. Author(s): Lipecka J, Norez C, Bensalem N, Baudouin-Legros M, Planelles G, Becq F, Edelman A, Davezac N. Source: The Journal of Pharmacology and Experimental Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16424149&query_hl=1&itool=pubmed_docsum
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Response to oral beta-carotene supplementation in patients with cystic fibrosis: a 16month follow-up study. Author(s): Winklhofer-Roob BM, van't Hof MA, Shmerling DH. Source: Acta Paediatrica (Oslo, Norway : 1992). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8563224&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11906577&query_hl=1&itool=pubmed_docsum
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Self-administered chest physiotherapy in cystic fibrosis: a comparative study of highpressure PEP and autogenic drainage. Author(s): Pfleger A, Theissl B, Oberwaldner B, Zach MS. Source: Lung. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1434782&query_hl=1&itool=pubmed_docsum
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Self-hypnosis for patients with cystic fibrosis. Author(s): Anbar RD. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11109057&query_hl=1&itool=pubmed_docsum
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SERCA pump inhibitors do not correct biosynthetic arrest of deltaF508 CFTR in cystic fibrosis. Author(s): Grubb BR, Gabriel SE, Mengos A, Gentzsch M, Randell SH, Van Heeckeren AM, Knowles MR, Drumm ML, Riordan JR, Boucher RC. Source: American Journal of Respiratory Cell and Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16284361&query_hl=1&itool=pubmed_docsum
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Serum phospholipid fatty acid profile and dietary intake in an adult Mediterranean population with cystic fibrosis. Author(s): Olveira G, Dorado A, Olveira C, Padilla A, Rojo-Martinez G, Garcia-Escobar E, Gaspar I, Gonzalo M, Soriguer F. Source: The British Journal of Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16923229&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11330265&query_hl=1&itool=pubmed_docsum
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Single- and multiple-dose-response relationships of beta-carotene in cystic fibrosis. Author(s): Homnick DN, Spillers CR, Cox SR, Cox JH, Yelton LA, DeLoof MJ, Oliver LK, Ringer TV. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7658286&query_hl=1&itool=pubmed_docsum
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Spicy treatment for cystic fibrosis. Author(s): Schub T.
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Source: Lab Anim (Ny). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15179423&query_hl=1&itool=pubmed_docsum •
Sputum rheology changes in cystic fibrosis lung disease following two different types of physiotherapy: flutter vs autogenic drainage. Author(s): App EM, Kieselmann R, Reinhardt D, Lindemann H, Dasgupta B, King M, Brand P. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9674466&query_hl=1&itool=pubmed_docsum
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Stem cells and cystic fibrosis. Author(s): Conese M, Rejman J. Source: J Cyst Fibros. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16574502&query_hl=1&itool=pubmed_docsum
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Successful treatment of acute lymphoblastic leukemia in a child with cystic fibrosis. Author(s): Gururangan S, Horner M, Rodman JH, Marina NM. Source: Medical and Pediatric Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8152404&query_hl=1&itool=pubmed_docsum
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Supplemental calories improve essential fatty acid deficiency in cystic fibrosis patients. Author(s): Parsons HG, O'Loughlin EV, Forbes D, Cooper D, Gall DG. Source: Pediatric Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3211621&query_hl=1&itool=pubmed_docsum
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Supplementation with carotenoids corrects increased lipid peroxidation in children with cystic fibrosis. Author(s): Lepage G, Champagne J, Ronco N, Lamarre A, Osberg I, Sokol RJ, Roy CC. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8669420&query_hl=1&itool=pubmed_docsum
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Synergistic activation of guinea-pig cardiac cystic fibrosis transmembrane conductance regulator by the tyrosine kinase inhibitor genistein and cAMP. Author(s): Shuba LM, McDonald TF. Source: The Journal of Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9409469&query_hl=1&itool=pubmed_docsum
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Systematic reviews in cystic fibrosis. Author(s): Smyth RL, Cheng K, Motley J.
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Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9709384&query_hl=1&itool=pubmed_docsum •
The absorption and effect of dietary supplementation with omega-3 fatty acids on serum leukotriene B4 in patients with cystic fibrosis. Author(s): Kurlandsky LE, Bennink MR, Webb PM, Ulrich PJ, Baer LJ. Source: Pediatric Pulmonology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7838619&query_hl=1&itool=pubmed_docsum
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The cystic fibrosis mutation G1349D within the signature motif LSHGH of NBD2 abolishes the activation of CFTR chloride channels by genistein. Author(s): Melin P, Thoreau V, Norez C, Bilan F, Kitzis A, Becq F. Source: Biochemical Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15163550&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12124395&query_hl=1&itool=pubmed_docsum
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The effect of 12 months' treatment with eicosapentaenoic acid in five children with cystic fibrosis. Author(s): Thies NH. Source: Journal of Paediatrics and Child Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9323627&query_hl=1&itool=pubmed_docsum
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The effect of vitamin K supplementation on biochemical markers of bone formation in children and adolescents with cystic fibrosis. Author(s): Nicolaidou P, Stavrinadis I, Loukou I, Papadopoulou A, Georgouli H, Douros K, Priftis KN, Gourgiotis D, Matsinos YG, Doudounakis S. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16622660&query_hl=1&itool=pubmed_docsum
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The effects of biofeedback assisted breathing retraining on lung functions in patients with cystic fibrosis. Author(s): Delk KK, Gevirtz R, Hicks DA, Carden F, Rucker R. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8275737&query_hl=1&itool=pubmed_docsum
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The effects of massage therapy in improving outcomes for youth with cystic fibrosis: an evidence review. Author(s): Huth MM, Zink KA, Van Horn NR. Source: Pediatric Nursing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16229132&query_hl=1&itool=pubmed_docsum
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The effects of self-hypnosis for children with cystic fibrosis: a pilot study. Author(s): Belsky J, Khanna P. Source: Am J Clin Hypn. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8203356&query_hl=1&itool=pubmed_docsum
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The glycine residues G551 and G1349 within the ATP-binding cassette signature motifs play critical roles in the activation and inhibition of cystic fibrosis transmembrane conductance regulator channels by phloxine B. Author(s): Melin P, Norez C, Callebaut I, Becq F. Source: The Journal of Membrane Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16604470&query_hl=1&itool=pubmed_docsum
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The potential for stem cell therapy in cystic fibrosis. Author(s): Spencer H, Jaffe A. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15239295&query_hl=1&itool=pubmed_docsum
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The reserpine-treated rat as an experimental animal model for cystic fibrosis: abnormal Cl transport in pancreatic acinar cells. Author(s): Martinez JR, Martinez AM. Source: Pediatric Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3174287&query_hl=1&itool=pubmed_docsum
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The role of vitamins in cystic fibrosis. Author(s): Carr SB, McBratney J. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10911814&query_hl=1&itool=pubmed_docsum
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The spice of life for cystic fibrosis. Author(s): Croft NM. Source: Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15521034&query_hl=1&itool=pubmed_docsum
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The use of an intravenous fish oil emulsion enriched with omega-3 fatty acids in patients with cystic fibrosis. Author(s): Katz DP, Manner T, Furst P, Askanazi J. Source: Nutrition (Burbank, Los Angeles County, Calif.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8875517&query_hl=1&itool=pubmed_docsum
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Tracheal potential difference in the reserpine and isoproterenol rat models of cystic fibrosis. Author(s): Rogers DF, Alton EW, Dewar A, Geddes DM, Barnes PJ. Source: Experimental Lung Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2081507&query_hl=1&itool=pubmed_docsum
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Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Author(s): Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9023366&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10766914&query_hl=1&itool=pubmed_docsum
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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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11589624&query_hl=1&itool=pubmed_docsum
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Use of famotidine in severe exocrine pancreatic insufficiency with persistent maldigestion on enzymatic replacement therapy. A long-term study in cystic fibrosis. Author(s): Carroccio A, Pardo F, Montalto G, Iapichino L, Soresi M, Averna MR, Iacono G, Notarbartolo A. Source: Digestive Diseases and Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1505293&query_hl=1&itool=pubmed_docsum
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Use of nonmedical treatment by cystic fibrosis patients. Author(s): Stern RC, Canda ER, Doershuk CF.
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Vitamin C controls the cystic fibrosis transmembrane conductance regulator chloride channel. Author(s): Fischer H, Schwarzer C, Illek B. Source: Proceedings of the National Academy of Sciences of the United States of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14993613&query_hl=1&itool=pubmed_docsum
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Vitamin E status in children with cystic fibrosis and pancreatic insufficiency. Author(s): Huang SH, Schall JI, Zemel BS, Stallings VA. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16647424&query_hl=1&itool=pubmed_docsum
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Vitamin E supplementation in cystic fibrosis. Author(s): Winklhofer-Roob BM. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9226544&query_hl=1&itool=pubmed_docsum
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Vitamin E supplementation in cystic fibrosis. Author(s): Peters SA, Kelly FJ. Source: Journal of Pediatric Gastroenterology and Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8732895&query_hl=1&itool=pubmed_docsum
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Vitamin K supplementation in cystic fibrosis. Author(s): van Hoorn JH, Hendriks JJ, Vermeer C, Forget PP. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14612359&query_hl=1&itool=pubmed_docsum
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Volatile organic compounds in the exhaled breath of young patients with cystic fibrosis. Author(s): Barker M, Hengst M, Schmid J, Buers HJ, Mittermaier B, Klemp D, Koppmann R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16455833&query_hl=1&itool=pubmed_docsum
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://health.aol.com/healthyliving/althealth
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com®: http://www.drkoop.com/naturalmedicine.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Alternative/
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to cystic 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 Cystic Fibrosis Source: Healthnotes, Inc.; www.healthnotes.com Cystic Fibrosis Source: Integrative Medicine Communications; www.drkoop.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Malabsorption Source: Healthnotes, Inc.; www.healthnotes.com Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com
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Alternative Therapy Hypnotherapy Source: Integrative Medicine Communications; www.drkoop.com Massage Source: Integrative Medicine Communications; www.drkoop.com
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Herbs and Supplements Borago Alternative names: Borage; Borago officinalis Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Digestive Enzymes Source: Healthnotes, Inc.; www.healthnotes.com Lipase Source: Healthnotes, Inc.; www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng 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.
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CHAPTER 3. PATENTS ON CYSTIC 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.7 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 “cystic fibrosis“ (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cystic fibrosis, we have not necessarily excluded non-medical patents in this bibliography.
Patent Applications on Cystic Fibrosis As of December 2000, U.S. patent applications are open to public viewing.8 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 cystic fibrosis:
7Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm. 8 This has been a common practice outside the United States prior to December 2000.
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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 (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
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Animal model for chronic obstructive pulmonary disease and cystic fibrosis Inventor(s): Boucher, Richard C. JR.; (Chapel Hill, NC), Grubb, Barbara; (Hillsborough, NC), Mall, Marcus; (Chapel Hill, NC), O'Neal, Wanda; (Cary, NC) Correspondence: Myers Bigel Sibley & Sajovec; PO Box 37428; Raleigh; NC; 27627; US Patent Application Number: 20040244067 Date filed: May 30, 2003 Abstract: A nonhuman transgenic mammal is described whose genome comprises a promoter construct operably linked to a heterologous DNA encoding an epithelial sodium channel.beta. subunit, wherein said promoter construct directs expression of the epithelial sodium channel.beta. subunit in lung epithelial cells of said animal, and wherein said transgenic mammal has increased lung mucus retention as compared to the corresponding wild-type mammal. The animal is useful in screening compounds for activity in treating lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease.
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Excerpt(s): The present invention concerns non-human transgenic animals that are useful as models of lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Cystic fibrosis (CF) is among the most prevalent, lethal diseases of genetic origin. Approximately 30,000 children and adults are affected in the United States alone. In this disease, abnormal ion transport across the respiratory epithelia leads to dehydrated, viscous and poorly-cleared airway secretions that contribute to chronic infection of the airways and early death. Knowles, Clin. Chest. Med. 11, 75 (1986). Chronic obstructive pulmonary disease (COPD) affects 10 to 14 million individuals in the United States and is also characterized by mucus accumulation in airway lumens and metaplasia of mucus secreting goblet cells. See, e.g. Celli et al., Am J Respir Crit Care Med 152, S177-S210 (1995). Hence, there is a need to develop new ways to treat cystic fibrosis and chronic obstructive pulmonary disease. In cystic fibrosis several functions of airway epithelia are abnormal, and deficiencies in both Cl.sup.31 transport and Na.sup.30 absorption are well documented. See, e.g. Knowles et al., Science 221, 1067 (1983); Knowles et al., J. Clin. Invest. 71, 1410 (1983). It would be extremely useful to provide a mouse model of cystic fibrosis and chronic obstructive pulmonary disease so that treatment options to improve mucus clearance in vivo could be more vigorously pursued. Unfortunately, prior efforts to develop a mouse model of cystic fibrosis produced animals that did not develop spontaneous lung disease. See, e.g., B. Grubb and R. Boucher, Physiological Reviews 79, S193-S214 (1999). Accordingly, there is a need for new approaches to solving the problem of providing an animal model for cystic fibrosis or chronic obstructive pulmonary disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Combination enzyme for cystic fibrosis Inventor(s): Fallon; Joan M.; (Yonkers, NY) Correspondence: Maine & Asmus; 100 Main Street; P O Box 3445; Nashua; NH; 030613445; US Patent Application Number: 20060198838 Date filed: September 21, 2005 Abstract: A stable preparation of digestive/pancreatic enzymes which can be readily formed into a dosage formulation is provided as a treatment of pancreatic insufficiency in persons having cystic fibrosis. The dosage formulation can be administered either by an oral preparation including, but not limited to, a microcapsule, mini-capsule, time released capsule, sprinkle or other methodology. A further object of this invention is to provide a stabilized preparation of a combination medicant which resists degradation by light, heat, humidity or association with commonly used excipients. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/613,666, filed Sep. 28, 2004. The present invention is directed to therapeutic agents for the treatment of pancreatic insufficiency in those with cystic fibrosis and other pancreatic disorders. More specifically, the present invention relates to stable pharmaceutical preparations containing but not limited to digestive and/or pancreatic enzymes including but not limited to amylases, proteases, cellulase, papaya, bromelain, lipases, chymotrypsin, pancreatin and pancrelipase. This combination is made either by direct compression, wet granulation or other methods including but not limited to the use of Prosolv technology, and! or time-release technology. The invention further relates to novel combinations of these enzymes heretofore not previously utilized in the
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population with cystic fibrosis or other pancreatic insufficiencies. Cystic fibrosis (CF) is one of the most common fatal genetic disorders. If affects the lungs and digestive systems of children and adults with the disease preventing adequate enzymatic digestion of food, as well as difficult breathing associated with thick mucous secretions in the lungs. The lack of proper absorption of nutrients in this population due to improper release of digestive enzymes from the pancreas. Without proper digestion of foodstuffs by enzymatic breakdown will allow for a dearth of necessary nutrients for the child/adult with CF. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compositions and methods for the treatment of cystic fibrosis Inventor(s): Faller, Douglas V.; (Weston, MA), Perrine, Susan P.; (Weston, MA), Stamatoyannopoulos, George; (Seattle, WA) Correspondence: James Remenick; Intellectual Property Department; Brobeck, Phleger & Harrison Llp; 1333 H Street, N.W., Suite 800; Washington; DC; 20005; US Patent Application Number: 20010034367 Date filed: February 15, 2001 Abstract: The invention is directed to novel pharmaceutical compositions comprising chemicals agents that are useful in the treatment and prevention of cystic fibrosis and the prevention of signs and symptoms of this disease. These pharmaceutical compositions are surprisingly successful in the treatment disorders related to cystic fibrosis including disorders of blood production. Many of these compositions of the invention are even more effective when administered to a patient in pulses. Pulse therapy is not a form of discontinuous administration of the same amount of a composition over time, but comprises administration of the same dose of the composition at a reduced frequency or administration of reduced doses. Excerpt(s): The invention relates to pharmaceutically acceptable compositions for administration to humans to treat cystic fibrosis and also to methods for effectively utilizing these compositions. Cystic fibrosis (CF) is a systemic disorder that results when mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an apical membrane glycoprotein, lead to a reduction in apical membrane chloride transport. CFTR is a cAMP-dependent chloride channel that regulates fluid composition in the respiratory and gastrointestinal tracts. CF is a heritable disease that follows an autosomal recessive pattern of transmission. It is the most common invariably lethal genetic disease in the United States, with frequency among Caucasians being one in two thousand. One in twenty are carriers of the defective gene. CF is characterized by abnormal endocrine and exocrine gland function. In CF, unusually thick mucus leads chronic pulmonary disease and respiratory infections, insufficient pancreatic and digestive function, and abnormally concentrated sweat. Seventy percent of the mutant CFTR alleles in the Caucasian population result from deletion of phenylalanine at position 508 (.DELTA.F508-CFTR), the result of a three base pair deletion in the genetic code. Other mutations have also been described and many may exist. The.DELTA.F508CFTR mutation results in a CFTR protein capable of conducting chloride, but absent from the plasma membrane because of aberrant intracellular processing. Under usual conditions (37.degree. C.), the.DELTA.F508-CFTR protein is retained in the endoplasmic reticulum (ER), by prolonged association with the ER chaperones, including calnexin and hsp70. The retained CFTR protein is then targeted for degradation by the ubiquitin
Patents 155
proteasome pathway. Over expression of.DELTA.F508-CFTR can result in.DELTA.F508CFTR protein appearing at the cell surface, and this protein is functional once it reaches the cell surface. The.DELTA.F508 "trafficking" block is also reversible by incubation of cultured CF epithelial cells at reduced temperatures (25-27.degree. C.). Lowered temperature results in the appearance of CFTR protein and channel activity at the cell surface, suggesting an intrinsic thermodynamic instability in.DELTA.F508-CFTR at 37.degree. C. that leads to recognition of the mutant protein by the ER quality control mechanism, prevents further trafficking, and results in protein degradation. High concentrations of glycerol (1 M or 10%), a protein stabilizing agent or chemical chaperone, also appears to facilitate movement of.DELTA.F508-CFTR from the ER to the plasma membrane. Some of the palliative treatments involve the administration of biologically active proteins or chemical compounds to decrease the viscosity of secretions, or to suppress chronic infections of the airways. These treatments have a number of limitations, and do not address the illness directly, but rather attempt to treat the symptoms. Some require continuous use at fairly high doses while others have short effective half-lives. Tolerance to the active ingredient often develops rendering the composition functionally useless. In addition to problems associated with tolerance, the substances themselves or their metabolic by-products or carriers can quickly reach toxic levels in the patient's system which impair kidney or liver function. Further, the chemical compounds themselves can be rapidly destroyed by catabolic enzymes, found in the cells and serum such as aminases, oxidases and hydrolases. Many of these enzymes are also found in hepatic cells, the principal sites for cleansing of the blood. Those able to survive cellular and hepatic catabolic processes are quickly eliminated from the patient's system by the kidneys. Consequently, in vivo retention times for active compounds are extremely short and the ability to achieve any sort of sustained biological effect becomes nearly impossible or, at least, impractical. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Modulation of airway inflammation in patients with cystic fibrosis and related diseases Inventor(s): Karp, Christopher L.; (Cincinnati, OH), Petasis, Nicos A.; (Hacienda Heights, CA) Correspondence: Fish & Richardson, PC; 12390 EL Camino Real; San Diego; CA; 921302081; US Patent Application Number: 20050113443 Date filed: June 1, 2004 Abstract: This invention provides a method for treating pulmonary disease in patients with cystic fibrosis, variant cystic fibrosis, and non-cystic fibrosis bronchiectasis. The method involves administering a pharmaceutically effective amount of a lipoxin or lipoxin analogue to subjects with cystic fibrosis or related disease, in amounts sufficient to downregulate harmful neutrophilic airway inflammatory responses. Excerpt(s): Priority is claimed herein to U.S. provisional patent application Nos. 60/475,963, to Karp et al., filed Jun. 1, 2003, entitled "Methods And Compositions For The Modulation Of Airway Inflammation In Patients With Cystic Fibrosis" and Ser. No. 60/539,820, Karp et al., filed Jan. 27, 2004, entitled "Modulation Of Airway Inflammation In Patients With Cystic Fibrosis and Related Diseases." The disclosure of the abovereferenced applications is incorporated by reference herein in its entirety. The present
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invention relates generally to pharmaceutical compositions and methods of use thereof for the prevention, amelioration and treatment of pulmonary disease in cystic fibrosis and related diseases, including variant cystic fibrosis, and non-cystic fibrosis bronchiectasis. Cystic fibrosis (CF) is a common, lethal autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) [Fishman' Pulmonary Diseases and Disorders, Vol. 1, 803-824, McGraw-Hill, New York, 1998; Cystic Fibrosis, 2649 2680, McGraw-Hill, New York, 1989]. The major clinical manifestations of CF include exocrine pancreatic insufficiency, male infertility, and chronic pulmonary disease. Chronic pulmonary disease, remains the major cause of morbidity and mortality in CF. Despite the molecular insights afforded by identification of CFTR, a clear understanding of the pathogenesis of lung disease in CF has remained elusive. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Polyionenes for treating infections associated with cystic fibrosis Inventor(s): Fitzpatrick; Richard J.; (Marblehead, MA), Shackett; Keith K.; (Athol, MA) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20060002888 Date filed: May 18, 2005 Abstract: A method of using ionene polymers for the treatment or prevention of infections (e.g., pulmonary infections) in cystic fibrosis patients is provided. The method comprises administering to a mammal an effective amount of an ionene polymer to prophylactically or therapeutically treat infections associated with cystic fibrosis. Excerpt(s): This application is a continuation of International Application No. PCT/US03/36859, which designated the United States, was filed on Nov. 19, 2003, and was published in English, which claims the benefit of U.S. Provisional Application No. 60/427,512, filed on Nov. 19, 2002. The entire teachings of the International Application and U.S. Provisional Application are hereby incorporated herein by reference. Cystic fibrosis (CF) is a lethal autosomal recessive disorder, which affects about 30,000 people in the United States. As such, it is the most common fatal hereditary disorder for Caucasians in the United States. The average life expectancy for American CF patients is 31.3 years according to the U.S. Cystic Fibrosis Foundation Database for 1996. In South America, the median survival age remains at about 9 years. CF is caused by one of several mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR). CFTR is synthesized mainly in epithelial cells in the respiratory passages, small intestine, pancreas and sweat glands and serous glands of the lung. Normal CFTR is transported to the cell surface after synthesis, where it regulates the flow of chloride in and out of the cell and influences sodium transport. In CF patients, the mutant CFTR does not reach the cell surface, which leads to excess sodium in the cells and tissues. The exact symptoms and severity of the disease vary depending on the specific mutation in CFTR. Sometimes the disease is diagnosed soon after birth, but other cases of CF may not be detected for months or years. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Use of secretin-receptor ligands in treatment of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) Inventor(s): Davis, Richard J.; (Hertfordshire, GB), Page, Keith J.; (Hertfordshire, GB) Correspondence: Nixon & Vanderhye P.C.; 8th Floor; 1100 North Glebe Road; Arlington; VA; 22201; US Patent Application Number: 20020142956 Date filed: July 3, 2001 Abstract: The invention is based on the finding that the secretin receptor is expressed in tissues present in the distal lung of humans. In patient with CF, levels of the receptor are elevated compared to normal tissue. Treatment of tissue by secretin stimulates the movement of negative ions in the tissue. The invention provides methods of treatment of cystic fibrosis or COPD in a patient by administering to said patient an effective amount of an agent which triggers anion efflux in respiratory tissue via the activation of a secretin receptor. Excerpt(s): The present invention relates to the treatment of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) with or by activation of the hormone secretin or other secretin receptor ligands. Cystic Fibrosis. Cystic fibrosis (CF) is the most common, fatal, autosomal recessive inherited disease, with over 7000 people currently diagnosed in the UK alone and approximately 30,000 in the United States. The incidence of CF is strongly dependent on ethnic background. Caucasian individuals with Northern European ancestry are most at risk exhibiting a probability of approximately 1 in 2500, based on a heterozygous carrier rate of about 1 in 25. 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 cystic 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 cystic fibrosis (or a synonym) 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 cystic fibrosis. You can also use this procedure to view pending patent applications concerning cystic 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.
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CHAPTER 4. BOOKS ON CYSTIC FIBROSIS Overview This chapter provides bibliographic book references relating to cystic fibrosis. In addition to online booksellers such as www.amazon.com and www.bn.com, the National Library of Medicine is an excellent source for book titles on cystic fibrosis. Your local medical library also may have these titles available for loan.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for cystic fibrosis at online booksellers’ Web sites, you may discover non-medical books that use the generic term “cystic fibrosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for cystic fibrosis (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
21st Century Complete Medical Guide to Cystic Fibrosis (CF), Authoritative Government Documents, Clinical References, and Practical Information for Patients and Physicians (CD-ROM) PM Medical Health News (2004); ISBN: 1592487335; http://www.amazon.com/exec/obidos/ASIN/1592487335/icongroupinterna
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A guide to cystic fibrosis for parents and children James C Cunningham (1988); ISBN: B00071WQDG; http://www.amazon.com/exec/obidos/ASIN/B00071WQDG/icongroupinterna
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A more detailed map of the cystic fibrosis mutation DF508 frequencies in Europe.: An article from: Human Biology Gerard Lucotte and France Loirat (2005); ISBN: B00091ZH8U; http://www.amazon.com/exec/obidos/ASIN/B00091ZH8U/icongroupinterna
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A Parent's Guide to Cystic Fibrosis (University of Minnesota Guides to Birth and Childhood Disorders) Burton L. Shapiro and Ralph C. Heussner (1991); ISBN:
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0816614881; http://www.amazon.com/exec/obidos/ASIN/0816614881/icongroupinterna •
A study of the erythrocyte membrane proteins from normal and cystic fibrosis patients James B Kase (1976); ISBN: B0006YDSV8; http://www.amazon.com/exec/obidos/ASIN/B0006YDSV8/icongroupinterna
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A way of life: Cystic fibrosis nutrition handbook and cookbook Sherie Sondel (1989); ISBN: B000726V9A; http://www.amazon.com/exec/obidos/ASIN/B000726V9A/icongroupinterna
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Abnormal expression of the cystic fibrosis transmembrane regulator in chronic sinusitis in cystic fibrosis and non-cystic fibrosis patients: An article. Annals of Otology, Rhinology & Laryngology Marc D Coltrera, Tracy A Goodpaster, Susan M Mathison, and Allen M Gown (2005); ISBN: B000B5EIGG; http://www.amazon.com/exec/obidos/ASIN/B000B5EIGG/icongroupinterna
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ACOG, in Response to NIH, Is Preparing To Back Broader Cystic Fibrosis Screening.(Brief Article): An article from: Family Practice News Kate Johnson (2005); ISBN: B0009FDCDS; http://www.amazon.com/exec/obidos/ASIN/B0009FDCDS/icongroupinterna
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Adult Cystic Fibrosis care.(The Effective Physician): An article from: Internal Medicine News William E. Golden and Robert H. Hopkins (2005); ISBN: B00082RMQU; http://www.amazon.com/exec/obidos/ASIN/B00082RMQU/icongroupinterna
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Advances in the science and treatment of cystic fibrosis lung disease: A continuing medical education resource Thomas M Murphy (1998); ISBN: B0006R8MGQ; http://www.amazon.com/exec/obidos/ASIN/B0006R8MGQ/icongroupinterna
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Alive at 25: How I'm Beating Cystic Fibrosis (Understanding Health and Sickness Series) Andy Lipman (2002); ISBN: 1563526816; http://www.amazon.com/exec/obidos/ASIN/1563526816/icongroupinterna
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An introduction to cystic fibrosis for patients and families James C Cunningham (1994); ISBN: B0006QRP74; http://www.amazon.com/exec/obidos/ASIN/B0006QRP74/icongroupinterna
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Cftr and the Molecular Basis of Cystic Fibrosis (Medical Intelligence Unit Series) J. Wine (1998); ISBN: 0412134810; http://www.amazon.com/exec/obidos/ASIN/0412134810/icongroupinterna
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CFTR molecular analysis reveals infrequent allele frequencies in nine cystic fibrosis patients from Sao Paulo State, Brazil.(Brief Communications)(cystic. regulator): An article from: Human Biology Eny Maria Goloni-Bertollo, Andrea Regina B. Rossit, Joao Batista, Junior Salomao, and Agnes Cristina Fett-Conte (2005); ISBN: B0008E5986; http://www.amazon.com/exec/obidos/ASIN/B0008E5986/icongroupinterna
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Clinical Ecology of Cystic Fibrosis: Proceedings of the 18th European Cystic Fibrosis Conference, Madrid, 21-26 May 1993 (International Congress Series) H. Escobar, F. Baquero, and L. Suarez (1993); ISBN: 0444816704; http://www.amazon.com/exec/obidos/ASIN/0444816704/icongroupinterna
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Complete map of cystic fibrosis mutation DF508 frequencies in Western Europe and correlation between mutation frequencies and incidence of disease.: An article from: Human Biology Gerard Lucotte, Serge Hazout, and Marc de Braekeller (2005); ISBN: B00093R3AS; http://www.amazon.com/exec/obidos/ASIN/B00093R3AS/icongroupinterna
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Consensus Conference on the Management of Cystic Fibrosis with Enzymes a.G. Knoll (1994); ISBN: 3540587667; http://www.amazon.com/exec/obidos/ASIN/3540587667/icongroupinterna
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Cooking For Friends: A Commemorative Cookbook Celebrating The 10th Anniversary Of A Culinary Evening With The California Winemasters (benefiting The Cystic Fibrosis Foundation) The Cystic Fibrosis Foundation) (1998); ISBN: B000GA7TPS; http://www.amazon.com/exec/obidos/ASIN/B000GA7TPS/icongroupinterna
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Costs and benefits of prenatal screening for cystic fibrosis (NBER working paper series; working paper) Joseph P Fenerty (1988); ISBN: B00071IBVM; http://www.amazon.com/exec/obidos/ASIN/B00071IBVM/icongroupinterna
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Cystic Fibrosis Mutations and Associated Haplotypes in Turkish Cystic Fibrosis Patients.(Statistical Data Included): An article from: Human Biology Tuncer Onay, Julian Zielenski, Ozlem Topaloglu, and Nalan Gokgoz (2005); ISBN: B0008I6JGI; http://www.amazon.com/exec/obidos/ASIN/B0008I6JGI/icongroupinterna
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Defects of Secretion in Cystic Fibrosis (Advances in Experimental Medicine and Biology) Carsten Schultz (2005); ISBN: 0387230769; http://www.amazon.com/exec/obidos/ASIN/0387230769/icongroupinterna
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Development of a rapid clinical screening test for the cystic fibrosis gene J. N Mathis (1990); ISBN: B0006D7VX0; http://www.amazon.com/exec/obidos/ASIN/B0006D7VX0/icongroupinterna
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Diseases and Disorders - Cystic Fibrosis (Diseases and Disorders) Melissa Abramovitz (2003); ISBN: 1590182995; http://www.amazon.com/exec/obidos/ASIN/1590182995/icongroupinterna
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Everything You Need to Know About Cystic Fibrosis (Need to Know Library) Justin Lee (2001); ISBN: 0823933210; http://www.amazon.com/exec/obidos/ASIN/0823933210/icongroupinterna
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Facilitating positive psychosocial adaptation in children with cystic fibrosis by increasing family communication and problem-solving skills Brian Stabler (1981); ISBN: B000727NVA; http://www.amazon.com/exec/obidos/ASIN/B000727NVA/icongroupinterna
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Facts about cystic fibrosis (SuDoc HE 20.3202:C 99) U.S. Dept of Health and Human Services (1995); ISBN: B00010Q1QQ; http://www.amazon.com/exec/obidos/ASIN/B00010Q1QQ/icongroupinterna
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Fibrosing colonopathy in an adult cystic fibrosis patient after discontinuing pancreatic enzyme therapy.(Case Report): An article from: Southern Medical Journal Elizabeth H. Mack, Allan S. Brett, and Daniel Brown (2005); ISBN: B000848LBI; http://www.amazon.com/exec/obidos/ASIN/B000848LBI/icongroupinterna
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FPs lag in offering genetic cystic fibrosis test. (Screening Recommended in 2001 by ACOG).(family physicians): An article from: Family Practice News Mitchel L. Zoler (2005); ISBN: B0008DGM74; http://www.amazon.com/exec/obidos/ASIN/B0008DGM74/icongroupinterna
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Fundamental problems of cystic fibrosis and related diseases;: Selected papers (1973); ISBN: 0883720191; http://www.amazon.com/exec/obidos/ASIN/0883720191/icongroupinterna
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G542X as a probable Phoenician cystic fibrosis mutation.: An article from: Human Biology France Loirat, Serge Hazout, and Gerard Lucotte (2005); ISBN: B00097MGCE; http://www.amazon.com/exec/obidos/ASIN/B00097MGCE/icongroupinterna
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Genetic Counseling and Cystic Fibrosis Carrier Screening: Results of a Survey (Background Paper) United States (1992); ISBN: 0160380936; http://www.amazon.com/exec/obidos/ASIN/0160380936/icongroupinterna
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Genetic Modulators of Pulmonary Function in Cystic Fibrosis & Genetic Susceptibility Factors of Emphysema (ACTA Biomedica Lovaniensia) Jennifer S. Yarden (2005); ISBN: 9058674800; http://www.amazon.com/exec/obidos/ASIN/9058674800/icongroupinterna
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Genetic screening as a technique of government: The case of neonatal screening for cystic fibrosis in France J. Vailly (2006); ISBN: B000LKAH0M; http://www.amazon.com/exec/obidos/ASIN/B000LKAH0M/icongroupinterna
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Genetic Studies of the Cystic Fibrosis Transmembrane Conductance Regulator Gene in Belgian Cf Patients (Acta Biomedica Lovaniensia , No 110) Harry Cuppens (1995); ISBN: 9061866820; http://www.amazon.com/exec/obidos/ASIN/9061866820/icongroupinterna
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Genetic studies on cystic fibrosis in Hawaii Stanley W Wright (1968); ISBN: B0006S7Y28; http://www.amazon.com/exec/obidos/ASIN/B0006S7Y28/icongroupinterna
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Genetic testing for cystic fibrosis : January 1989 through February 1997 : 1224 citations (SuDoc HE 20.3615/2:97-2) Cynthia B. Love (1997); ISBN: B00010T7D0; http://www.amazon.com/exec/obidos/ASIN/B00010T7D0/icongroupinterna
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Geographic and ethnic distributions of the more frequent cystic fibrosis mutations in Europe show that a founder effect is apparent for several mutant alleles.: An article from: Human Biology Gerard Lucotte and Serge Hazout (2005); ISBN: B00093MH1I; http://www.amazon.com/exec/obidos/ASIN/B00093MH1I/icongroupinterna
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Geographic Heterogeneity of 4 Common Worldwide Cystic Fibrosis Non-DF508 Mutations in Brazil.: An article from: Human Biology Salmo Raskin, John A. Phillips, Gail Kaplan, and Melodie Mcclure (2005); ISBN: B00099NSFQ; http://www.amazon.com/exec/obidos/ASIN/B00099NSFQ/icongroupinterna
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Hemolytic-uremic syndrome: Cystic fibrosis / David M. Orenstein (Current problems in peditrics) Wm. Lane M Robson (1993); ISBN: B0006PH8XQ; http://www.amazon.com/exec/obidos/ASIN/B0006PH8XQ/icongroupinterna
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I Have Cystic Fibrosis (One World S.) Brenda Pettenuzzo and Victoria Haines (1988); ISBN: 0863137466; http://www.amazon.com/exec/obidos/ASIN/0863137466/icongroupinterna
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Immunological Aspects of Cystic Fibrosis (Crc Series in Immunology and Lymphoid Cell Biology) Emmanuel Shapira and Gregory B. Wilson (1985); ISBN: 084936373X; http://www.amazon.com/exec/obidos/ASIN/084936373X/icongroupinterna
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Individualize counseling for cystic fibrosis coping.(Clinical Rounds)(Disease/Disorder overview): An article from: Pediatric News Damian McNamara (2006); ISBN: B000LMPQ7O; http://www.amazon.com/exec/obidos/ASIN/B000LMPQ7O/icongroupinterna
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Inhalation Therapy: Roche and Genentech Symposium European Cystic Fibrosis Conference, Paris, June 1994 (Respiration, Vol 62, Suppl 1) Ch Koch and E. Puchelle
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(1995); ISBN: 3805561644; http://www.amazon.com/exec/obidos/ASIN/3805561644/icongroupinterna •
Involvement of immune response genes in the progression of lung disease in cystic fibrosis patients Shannon M Schmura (1995); ISBN: B0006PFHQQ; http://www.amazon.com/exec/obidos/ASIN/B0006PFHQQ/icongroupinterna
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Keppra, Tag-It Cystic Fibrosis Kit.(New & Approved): An article from: Family Practice News Damian McNamara (2005); ISBN: B000BQGGOC; http://www.amazon.com/exec/obidos/ASIN/B000BQGGOC/icongroupinterna
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Learn from cystic fibrosis for other feeding problems: nutritional strategies overlap.(Behavioral Pediatrics): An article from: Pediatric News Sherry Boschert (2005); ISBN: B00082DII6; http://www.amazon.com/exec/obidos/ASIN/B00082DII6/icongroupinterna
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Living With Cystic Fibrosis (Living Well Chronic Conditions) Susan Heinrichs Gray (2002); ISBN: 156766105X; http://www.amazon.com/exec/obidos/ASIN/156766105X/icongroupinterna
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Local firm unveils new cystic fibrosis testing; analyst notes complex test speaks for firm's platform technology. (Biotech).(Nanogen Inc. )(Brief Article): An article from: San Diego Business Journal Marion Webb (2006); ISBN: B00096SMZU; http://www.amazon.com/exec/obidos/ASIN/B00096SMZU/icongroupinterna
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Medical Discoveries files patent application on cystic fibrosis treatment.: An article from: BIOTECH Patent News (2005); ISBN: B00082NELC; http://www.amazon.com/exec/obidos/ASIN/B00082NELC/icongroupinterna
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Michigan hospital expands cystic fibrosis screening: few opt for testing.(Women's Health): An article from: Family Practice News Damian McNamara (2005); ISBN: B00082BKWW; http://www.amazon.com/exec/obidos/ASIN/B00082BKWW/icongroupinterna
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Molecular analysis of 23 exons of the CFTR gene in Brazilian patients leads to the finding of rare cystic fibrosis mutations.(cystic fibrosis transmembrane. regulator): An article from: Human Biology Giselda M.K. Cabello, Pedro H. Cabello, Koko Otsuki, and Maria Emilia Gombarovits (2005); ISBN: B000AMCPUG; http://www.amazon.com/exec/obidos/ASIN/B000AMCPUG/icongroupinterna
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Molecular Analysis of Cftr Mutations in Cystic Fibrosis Patients With Atypical Cf and in Patients With Congenital Bilateral Absence of the Vas (Acta Biomedica Lovaniensia , No 146) Molecular Teng (1997); ISBN: 906186805X; http://www.amazon.com/exec/obidos/ASIN/906186805X/icongroupinterna
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Molecular temporal bone pathology: III. genotyping of the F‚…‚€‚ˆ deletion in the DNA of patients with cystic fibrosis (Supplement) Phillip A Wackym (1998); ISBN: B0006QZ7MY; http://www.amazon.com/exec/obidos/ASIN/B0006QZ7MY/icongroupinterna
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Mpex wants to start trials on cystic fibrosis drug: drug would reverse resistance to antibiotics.(Biotech): An article from: San Diego Business Journal Marion Webb (2005); ISBN: B0009GJWZO; http://www.amazon.com/exec/obidos/ASIN/B0009GJWZO/icongroupinterna
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New CF screening test offers greater accuracy.(Clinical Rounds)(Tag-It Cystic Fibrosis Kit): An article from: Internal Medicine News Christine Kilgore (2006); ISBN: B000EGCY3G; http://www.amazon.com/exec/obidos/ASIN/B000EGCY3G/icongroupinterna
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Pediatric cystic fibrosis pain is understudied, undertreated.: An article from: Family Practice News Betsy Bates (2006); ISBN: B000LPQ73I; http://www.amazon.com/exec/obidos/ASIN/B000LPQ73I/icongroupinterna
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Practical Guidelines for Cystic Fibrosis Care Catherine M. Hill (1998); ISBN: 044306234X; http://www.amazon.com/exec/obidos/ASIN/044306234X/icongroupinterna
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Prenatal screening halves cystic fibrosis births: carrier rate of 1 in 28.(Women's Health): An article from: Family Practice News Betsy Bates (2005); ISBN: B0008IRNXQ; http://www.amazon.com/exec/obidos/ASIN/B0008IRNXQ/icongroupinterna
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Progress In Cystic Fibrosis Research Margaret A. Harrison (2005); ISBN: 1594542325; http://www.amazon.com/exec/obidos/ASIN/1594542325/icongroupinterna
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Research on Pathogenesis of Cystic Fibrosis of the Pancreas (Mucoviscidosis) Ed. Paul A. DiSant'Agnese (1966); ISBN: B000IULR5O; http://www.amazon.com/exec/obidos/ASIN/B000IULR5O/icongroupinterna
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Saline inhalation eases cystic fibrosis symptoms: the rehydration appears to produce a sustained acceleration of mucus clearance in the airways.(Pulmonary. An article from: Internal Medicine News Mary Ann Moon (2006); ISBN: B000F7CHRW; http://www.amazon.com/exec/obidos/ASIN/B000F7CHRW/icongroupinterna
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Should preconceptual and prenatal cystic fibrosis carrier screening be routinely offered? (Pro & Con).: An article from: Internal Medicine News (2005); ISBN: B0008F05A2; http://www.amazon.com/exec/obidos/ASIN/B0008F05A2/icongroupinterna
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Study of the Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Protein in Human and Mouse Vas Deferens (Acta Biomedica Lovaniensia, 189) Ingrid Reynaert (1998); ISBN: 9061869404; http://www.amazon.com/exec/obidos/ASIN/9061869404/icongroupinterna
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Surveillance of cystic fibrosis patients with multi-drug resistant Gram-negative rods R.-P. Vonberg, A. Wolter, S. Ziesing, and P. Gastmeier (2006); ISBN: B000HD1S2O; http://www.amazon.com/exec/obidos/ASIN/B000HD1S2O/icongroupinterna
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Survival rose in children with cystic fibrosis from 1985 to 1999. (Probably Due to Better Care).: An article from: Pediatric News Mitchell L. Zoler (2005); ISBN: B0009FWLV2; http://www.amazon.com/exec/obidos/ASIN/B0009FWLV2/icongroupinterna
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Tailored insulin tames cystic fibrosis diabetes.(Metabolic Disorders)(drug usages): An article from: Family Practice News Bruce Jancin (2006); ISBN: B000IYW4DY; http://www.amazon.com/exec/obidos/ASIN/B000IYW4DY/icongroupinterna
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The (Delta)F508 mutation in the cystic fibrosis transmembrane conductance regulator alters control of essential fatty acid utilization in epithelial cells: An article from: The Journal of Nutrition Farah N Bhura-Bandali, Miyoung Suh, S F Paul Man, and M Thomas Clandinin (2005); ISBN: B000B9CEKY; http://www.amazon.com/exec/obidos/ASIN/B000B9CEKY/icongroupinterna
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The 3120 +1G[right arrow]A Splicing Mutation in CFTR Is Common in Brazilian Cystic Fibrosis Patients.(Statistical Data Included): An article from: Human Biology Giselda M. K. Cabello, Pedro H. Cabello, Juan Llerena Jr., and Octavio Fernandes (2005); ISBN: B0008I6JL8; http://www.amazon.com/exec/obidos/ASIN/B0008I6JL8/icongroupinterna
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The comparative effectiveness of digestive aid, cotazym, and viokase in children with cystic fibrosis (Massachusetts Institute of Technology. Dept. of Nutrition and Food Science. Thesis. 1977. M.S) John Dewey Palombo (1977); ISBN: B0006WT4E0; http://www.amazon.com/exec/obidos/ASIN/B0006WT4E0/icongroupinterna
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The Cystic Fibrosis Transmembrane Conductance Regulator (Molecular Biology Intelligence Unit) Kevin L. Kirk and David C. Dawson (2003); ISBN: 0306478374; http://www.amazon.com/exec/obidos/ASIN/0306478374/icongroupinterna
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The incidence of cystic fibrosis in Hawaii Stanley W Wright (1968); ISBN: B0006S7YEG; http://www.amazon.com/exec/obidos/ASIN/B0006S7YEG/icongroupinterna
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This is Paul: An introduction to cystic fibrosis for children age five and older Kirsten Webster Griebel (1987); ISBN: B0006QK6UW; http://www.amazon.com/exec/obidos/ASIN/B0006QK6UW/icongroupinterna
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Treatment of the Hospitalized Cystic Fibrosis Patient (Lung Biology in Health and Disease) Orenstein (1998); ISBN: 0824795008; http://www.amazon.com/exec/obidos/ASIN/0824795008/icongroupinterna
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Treatment of the Hospitalized Cystic Fibrosis Patient (Lung Biology in Health and Disease) Orenstein (1998); ISBN: 0824795008; http://www.amazon.com/exec/obidos/ASIN/0824795008/icongroupinterna
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Understanding Cystic Fibrosis (Understanding Health and Sickness Series) Karen Hopkin (1998); ISBN: 0878059679; http://www.amazon.com/exec/obidos/ASIN/0878059679/icongroupinterna
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VEB-1 in Achromobacter xylosoxidans from cystic fibrosis patient, France.(DISPATCHES): An article from: Emerging Infectious Diseases Catherine Neuwirth, Carine Freby, Agathe Ogier-Desserrey, and Stephanie Perez-Martin (2006); ISBN: B000KQGRK6; http://www.amazon.com/exec/obidos/ASIN/B000KQGRK6/icongroupinterna
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What is the incidence of cystic fibrosis in Italy? Data from the National Registry (1988-2001).: An article from: Human Biology Anna Bossi, Giovanni Casazza, Rita Padoan, and Silvano Milani (2005); ISBN: B00084AF3U; http://www.amazon.com/exec/obidos/ASIN/B00084AF3U/icongroupinterna
The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select LocatorPlus. Once you are in the search area, simply type cystic fibrosis (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Books. From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine9: 9 In addition to LocatorPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a Books button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the
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A Perspective of sodium and chloride ion-sensitive electrode sweat tests for screening in cystic fibrosis Author: Bray, P. T.; Year: 1975; Cardiff, Wales: Chemistry Dept., Univ. of Wales Institute of Science and Technology, 1975
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Chest physical therapy in cystic fibrosis and chronic obstructive pulmonary diseases Author: Baran, D.; Year: 1977; Ghent: European Press, 1977; ISBN: 9789062951 http://www.amazon.com/exec/obidos/ASIN/9789062951/icongroupinterna
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Chronic bronchitis and cystic fibrosis: two chronic obstructive lung diseases of adults: February 1-2, 1977, San Diego, California. Author: George and Elizabeth Frankel GAP Conference, San Diego, Calif., Feb. 1-2, 1977.; Year: 1977; Foundation, [1977]
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Communications, VIIe Congrès international de la mucoviscidose = Proceedings, VIIth International Cystic Fibrosis Congress, Paris, 31 mai, 1, 2, 3 juin 1976.; Year: 1978; Paris: [s.n.], 1978
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Current problems and new trends in cystic fibrosis Author: Kraemer, R.; Year: 1981; Basel; New York: Karger, 1981; ISBN: 9783805534 http://www.amazon.com/exec/obidos/ASIN/9783805534/icongroupinterna
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Directory of cystic fibrosis care, teaching and research centers and clinical centers. Author: National Cystic Fibrosis Research Foundation (U.S.); Year: 1972; Atlanta [1972?]
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Fundamental problems of cystic fibrosis and related diseases; selected papers. edited by John A. Mangos [and] Richard C. Talamo.; Year: 1973; New York, Intercontinental Medical Book Corp. [c1973]; ISBN: 9780883720 http://www.amazon.com/exec/obidos/ASIN/9780883720/icongroupinterna
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Guide to diagnosis and management of cystic fibrosis: a syllabus for physicians. Author: Cystic Fibrosis Foundation. Professional Education Committee.; Year: 1971; Atlanta: The Foundation, 1971
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Mucous secretions and cystic fibrosis Author: Forstner, Gordon G.; Year: 1977; Basel; New York: Karger, 1977; ISBN: 9783805526 http://www.amazon.com/exec/obidos/ASIN/9783805526/icongroupinterna
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Procedure for the quantitative iontophoretic sweat test for cystic fibrosis Author: Gibson, Lewis E.,; Year: 1975; Foundation, [1975]
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Proceedings of the fifth International Cystic Fibrosis Conference, Churchill College, Cambridge, England, September 22nd-26th, 1969. Editor: David Lawson. Author: Lawson, David.; Year: 1969; Research Trust [c1969]
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Pseudomonas aeruginosa infection in cystic fibrosis: diagnostic and prognostic significance of Pseudomonas aeruginosa precipitins determined by means of crossed immunoelectrophoresis: a survey Author: Høiby, Niels.; Year: 1977; Copenhagen: Munksgaard, 1977; ISBN: 9788716021 http://www.amazon.com/exec/obidos/ASIN/9788716021/icongroupinterna
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Psychosocial aspects of heterozygote detection in cystic fibrosis; [proceedings] May 14-15, 1975, New Orleans, Louisiana.; Year: 1975; Foundation, 1975
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Recent advances in cystic fibrosis research: 8th annual meeting of the European Working Group for Cystic Fibrosis, Bad Gastein, June 2-3, 1978 Author: European
majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
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Working Group for Cystic Fibrosis.; Year: 1979; Basel; New York: Karger, 1979; ISBN: 9783805529 http://www.amazon.com/exec/obidos/ASIN/9783805529/icongroupinterna •
Studies of the function of the sweat gland, parotid gland, and the pancreas in chronic bronchitis and heterozygous mucoviscidosis or cystic fibrosis. Author: Toivonen, Seppo.; Year: 1967; Helsinki, 1967
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The diagnosis of cystic fibrosis of the pancreas. Author: O’Neal, Ruth.; Year: 1948; Minneapolis] 1948
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CHAPTER 5. MULTIMEDIA ON CYSTIC FIBROSIS Overview In this chapter, we show you how to find bibliographic information related to multimedia sources of information on cystic fibrosis.
Bibliography: Multimedia on Cystic Fibrosis The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select LocatorPlus. Once you are in the search area, simply type cystic fibrosis (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Audiovisuals and Computer Files. From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on cystic fibrosis: •
Diagnosing & treating cystic fibrosis [videorecording] Source: a presentation of Films for the Humanities & Sciences; a Leeds University Television production for Shotlist; Year: 1999; Format: Videorecording; Princeton, N.J.: Films for the Humanities & Sciences, c1999
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Diagnosis and management of cystic fibrosis [motion picture] Source: National Institute of Arthritis and Metabolic Diseases and National Cystic Fibrosis Research Foundation; [made by] Sturgis-Grant Productions, inc; Year: 1967; Format: Motion picture; New York: The Foundation; [Atlanta: for loan by National Medical Audiovisual Center], 1967
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Diagnosis of cystic fibrosis in adults [slide] Source: presented by the American Thoracic Society, American Lung Association, ALA/ATS Component Committee on Learning Resources; Year: 1981; Format: Slide; New York, N.Y.]: The Committee, 1981
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Diary of a disease [videorecording]: cystic fibrosis Source: WLTV 39 Lehigh Valley Public Television; HealthEast Communications; Year: 1985; Format: Videorecording; St. Paul, Minn.]: HealthEast Communications, 1985
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DNA & cystic fibrosis [videorecording] Source: CBC News; a production of the Canadian Broadcasting Corporation; Year: 2002; Format: Videorecording; Boston, MA: Fanlight Productions, c2002
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Highlights [electronic resource]: selected proceedings from the Thirteenth Annual North American Cystic Fibrosis Conference, Seattle, Washington, October 7-10, 1999 Source: Cystic Fibrosis Foundation; produced by Med Doc Medical Communications; Year: 1999; Format: Electronic resource; Bloomsbury, NJ: Med Doc Medical Communications, [1999?]
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Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society. Source: 2002-9999; Amsterdam; New York: Elsevier, c2002-
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Living with cystic fibrosis [motion picture] Source: [produced by] Amram Nowak Associates for the National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Public Health Service, the Department of Health and Human Servi; Year: 1980; Format: Motion picture; Rockville, Md.: The Foundation, c1980
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New concepts in managing malabsorption in cystic fibrosis [videorecording] Source: developed and produced for Temple University School of Medicine by GardinerCaldwell SynerMed; Year: 1991; Format: Videorecording; Califon, N.J.]: GardinerCaldwell SynerMed, c1991
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PKU and cystic fibrosis [slide]: sterilization and artificial insemination Source: coauthored by Garrett E. Bergman, John H. Sorenson; produced by the Medical College of Pennsylvania, Office of Medical Education, Audiovisual Section; Year: 1978; Format: Slide; Philadelphia]: The Section, c1978
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Sweat testing for cystic fibrosis of the pancreas [videorecording] Source: author, George K. Summer; Year: 1981; Format: Videorecording; Chapel Hill, NC: Health Sciences Consortium, 1981
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The Early diagnosis of cystic fibrosis [slide] Source: American Lung Association, American Thoracic Society; produced by Emerson-Braxton & Co; Year: 1985; Format: Slide; New York, N.Y.]: American Lung Association, c1985
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APPENDIX A. HELP ME UNDERSTAND GENETICS Overview This appendix presents basic information about genetics in clear language and provides links to online resources.10
The Basics: Genes and How They Work This section gives you information on the basics of cells, DNA, genes, chromosomes, and proteins. What Is a Cell? Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the body, take in nutrients from food, convert those nutrients into energy, and carry out specialized functions. Cells also contain the body’s hereditary material and can make copies of themselves. Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell. Human cells contain the following major parts, listed in alphabetical order: •
Cytoplasm: The cytoplasm is fluid inside the cell that surrounds the organelles.
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Endoplasmic reticulum (ER): This organelle helps process molecules created by the cell and transport them to their specific destinations either inside or outside the cell.
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Golgi apparatus: The golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.
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Lysosomes and peroxisomes: These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.
10 This appendix is an excerpt from the National Library of Medicine’s handbook, Help Me Understand Genetics. For the full text of the Help Me Understand Genetics handbook, see http://ghr.nlm.nih.gov/handbook.
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Mitochondria: Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.
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Nucleus: The nucleus serves as the cell’s command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.
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Plasma membrane: The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.
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Ribosomes: Ribosomes are organelles that process the cell’s genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum. What Is DNA?
DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.
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DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone. What Is Mitochondrial DNA? Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of
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DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins. What Is a Gene? A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.
Genes are made up of DNA. Each chromosome contains many genes. What Is a Chromosome? In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are not visible in the cell’s nucleus—not even under a microscope—when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know about chromosomes was learned by observing chromosomes during cell division. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.
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DNA and histone proteins are packaged into structures called chromosomes. How Many Chromosomes Do People Have? In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twentytwo of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.
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The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype. How Do Geneticists Indicate the Location of a Gene? Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene’s position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome. Cytogenetic Location Geneticists use a standardized way of describing a gene’s cytogenetic location. In most cases, the location describes the position of a particular band on a stained chromosome: 17q12 It can also be written as a range of bands, if less is known about the exact location: 17q12-q21 The combination of numbers and letters provide a gene’s “address” on a chromosome. This address is made up of several parts: •
The chromosome on which the gene can be found. The first number or letter used to describe a gene’s location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.
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The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene’s address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.
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The position of the gene on the p or q arm. The position of a gene is based on a distinctive pattern of light and dark bands that appear when the chromosome is stained in a certain way. The position is usually designated by two digits (representing a region and a band), which are sometimes followed by a decimal point and one or more additional digits (representing sub-bands within a light or dark area). The number indicating the gene position increases with distance from the centromere. For example: 14q21 represents position 21 on the long arm of chromosome 14. 14q21 is closer to the centromere than 14q22.
Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene’s cytogenetic location. “Cen” indicates that the gene is very close to the centromere. For example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter” stands for terminus, which indicates that the gene is very close to the end of the p or q arm. For example, 14qter refers to the tip of the long arm of chromosome 14. (“Tel” is also sometimes used to describe a gene’s location. “Tel” stands for telomeres, which are at the ends of each chromosome. The abbreviations “tel” and “ter” refer to the same location.)
The CFTR gene is located on the long arm of chromosome 7 at position 7q31.2.
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Molecular Location The Human Genome Project, an international research effort completed in 2003, determined the sequence of base pairs for each human chromosome. This sequence information allows researchers to provide a more specific address than the cytogenetic location for many genes. A gene’s molecular address pinpoints the location of that gene in terms of base pairs. For example, the molecular location of the APOE gene on chromosome 19 begins with base pair 50,100,901 and ends with base pair 50,104,488. This range describes the gene’s precise position on chromosome 19 and indicates the size of the gene (3,588 base pairs). Knowing a gene’s molecular location also allows researchers to determine exactly how far the gene is from other genes on the same chromosome. Different groups of researchers often present slightly different values for a gene’s molecular location. Researchers interpret the sequence of the human genome using a variety of methods, which can result in small differences in a gene’s molecular address. For example, the National Center for Biotechnology Information (NCBI) identifies the molecular location of the APOE gene as base pair 50,100,901 to base pair 50,104,488 on chromosome 19. The Ensembl database identifies the location of this gene as base pair 50,100,879 to base pair 50,104,489 on chromosome 19. Neither of these addresses is incorrect; they represent different interpretations of the same data. For consistency, Genetics Home Reference presents data from NCBI for the molecular location of genes. What Are Proteins and What Do They Do? Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique 3-dimensional structure and its specific function.
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Examples of Protein Functions Proteins can be described according to their large range of functions in the body, listed in alphabetical order: Function Antibody
Description Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.
Example Immunoglobulin G (IgG)
Enzyme
Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.
Phenylalanine hydroxylase
Messenger
Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.
Growth hormone
Structural component
These proteins provide structure and support for cells. On a larger scale, they also allow the body to move. These proteins bind and carry atoms and small molecules within cells and throughout the body.
Actin
Transport/storage
Ferritin
How Does a Gene Make a Protein? Most genes contain the information needed to make functional molecules called proteins. (A few genes produce other molecules that help the cell assemble proteins.) The journey from gene to protein is complex and tightly controlled within each cell. It consists of two major steps: transcription and translation. Together, transcription and translation are known as gene expression. During the process of transcription, the information stored in a gene’s DNA is transferred to a similar molecule called RNA (ribonucleic acid) in the cell nucleus. Both RNA and DNA are made up of a chain of nucleotide bases, but they have slightly different chemical properties. The type of RNA that contains the information for making a protein is called messenger RNA (mRNA) because it carries the information, or message, from the DNA out of the nucleus into the cytoplasm. Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which “reads” the sequence of mRNA bases. Each sequence of three bases, called a codon, usually codes for
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one particular amino acid. (Amino acids are the building blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three bases that does not code for an amino acid). The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the “central dogma.”
Through the processes of transcription and translation, information from genes is used to make proteins.
Can Genes Be Turned On and Off in Cells? Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood. Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is transferred to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.
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How Do Cells Divide? There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells. Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by a number of genes. When mitosis is not regulated correctly, health problems such as cancer can result. The other type of cell division, meiosis, ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of DNA shuffling while the cells are dividing.
Mitosis and meiosis, the two types of cell division. How Do Genes Control the Growth and Division of Cells? A variety of genes are involved in the control of cell growth and division. The cell cycle is the cell’s way of replicating itself in an organized, step-by-step fashion. Tight regulation of this process ensures that a dividing cell’s DNA is copied properly, any errors in the DNA are repaired, and each daughter cell receives a full set of chromosomes. The cycle has checkpoints (also called restriction points), which allow certain genes to check for mistakes and halt the cycle for repairs if something goes wrong.
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If a cell has an error in its DNA that cannot be repaired, it may undergo programmed cell death (apoptosis). Apoptosis is a common process throughout life that helps the body get rid of cells it doesn’t need. Cells that undergo apoptosis break apart and are recycled by a type of white blood cell called a macrophage. Apoptosis protects the body by removing genetically damaged cells that could lead to cancer, and it plays an important role in the development of the embryo and the maintenance of adult tissues. Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor.
Genetic Mutations and Health This section presents basic information about gene mutations, chromosomal changes, and conditions that run in families.11 What Is a Gene Mutation and How Do Mutations Occur? A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome. Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body. Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder. Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation. Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism. Some genetic changes are very rare; others are common in the population. Genetic changes that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are 11
This section has been adapted from the National Library of Medicine’s handbook, Help Me Understand Genetics, which presents basic information about genetics in clear language and provides links to online resources: http://ghr.nlm.nih.gov/handbook.
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responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders. How Can Gene Mutations Affect Health and Development? To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder. In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life. It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene. Do All Gene Mutations Affect Health and Development? No, only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene’s DNA base sequence but do not change the function of the protein made by the gene. Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein). Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease. A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria. For More Information about DNA Repair and the Health Effects of Gene Mutations •
The University of Utah Genetic Science Learning Center provides information about genetic disorders that explains why some mutations cause disorders but others do not. (Refer to the questions in the far right column.) See http://learn.genetics.utah.edu/units/disorders/whataregd/.
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Additional information about DNA repair is available from the NCBI Science Primer. In the chapter called “What Is A Cell?”, scroll down to the heading “DNA Repair Mechanisms.” See http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html. What Kinds of Gene Mutations Are Possible?
The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The types of mutations include: •
Missense mutation: This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.
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Nonsense mutation: A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.
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Insertion: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.
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Deletion: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).
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Duplication: A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.
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Frameshift mutation: This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.
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Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly. Can Changes in Chromosomes Affect Health and Development?
Changes that affect entire chromosomes or segments of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and alter the proteins made by those genes. Conditions caused by a change in the number or structure of chromosomes are known as chromosomal disorders. Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes leads to a chromosomal disorder. These
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changes can occur during the formation of reproductive cells (eggs and sperm) or in early fetal development. A gain or loss of chromosomes from the normal 46 is called aneuploidy. The most common form of aneuploidy is trisomy, or the presence of an extra chromosome in each cell. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in each cell instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy—people with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell. Monosomy, or the loss of one chromosome from each cell, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in each cell instead of the normal two copies. Turner syndrome is a condition caused by monosomy. Women with Turner syndrome are often missing one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell. Chromosomal disorders can also be caused by changes in chromosome structure. These changes are caused by the breakage and reunion of chromosome segments when an egg or sperm cell is formed or in early fetal development. Pieces of DNA can be rearranged within one chromosome, or transferred between two or more chromosomes. The effects of structural changes depend on their size and location. Many different structural changes are possible; some cause medical problems, while others may have no effect on a person’s health. Many cancer cells also have changes in their chromosome number or structure. These changes most often occur in somatic cells (cells other than eggs and sperm) during a person’s lifetime. Can Changes in Mitochondrial DNA Affect Health and Development? Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision. Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.
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What Are Complex or Multifactorial Disorders? Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. By 2010, however, researchers predict they will have found the major contributing genes for many common complex disorders. What Information about a Genetic Condition Can Statistics Provide? Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person’s family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient. Common Statistical Terms Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include: Statistical Term Incidence
Description The incidence of a gene mutation or a genetic disorder is the number of people who are born with the mutation or disorder in a specified group per year. Incidence is often written in the form “1 in [a number]” or as a total number of live births.
Examples About 1 in 200,000 people in the United States are born with syndrome A each year. An estimated 15,000 infants with syndrome B were born last year worldwide.
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Prevalence
The prevalence of a gene mutation or a genetic disorder is the total number of people in a specified group at a given time who have the mutation or disorder. This term includes both newly diagnosed and preexisting cases in people of any age. Prevalence is often written in the form “1 in [a number]” or as a total number of people who have a condition.
Approximately 1 in 100,000 people in the United States have syndrome A at the present time. About 100,000 children worldwide currently have syndrome B.
Mortality
Mortality is the number of deaths from a particular disorder occurring in a specified group per year. Mortality is usually expressed as a total number of deaths.
An estimated 12,000 people worldwide died from syndrome C in 2002.
Lifetime risk
Lifetime risk is the average risk of developing a particular disorder at some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a number].” It is important to remember that the risk per year or per decade is much lower than the lifetime risk. In addition, other factors may increase or decrease a person’s risk as compared with the average.
Approximately 1 percent of people in the United States develop disorder D during their lifetimes. The lifetime risk of developing disorder D is 1 in 100.
Naming Genetic Conditions Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment. Disorder names are often derived from one or a combination of sources: •
The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency)
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One or more major signs or symptoms of the disorder (for example, sickle cell anemia)
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The parts of the body affected by the condition (for example, retinoblastoma)
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The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan)
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A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea)
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The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after a famous baseball player who had the condition).
Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer’s disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine. Genetics Home Reference uses the nonpossessive form of eponyms. Genetics Home Reference consults with experts in the field of medical genetics to provide the current, most accurate name for each disorder. Alternate names are included as synonyms. Naming genes The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome. During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature. Genetics Home Reference describes genes using the HGNC’s official gene names and gene symbols. Genetics Home Reference frequently presents the symbol and name separated with a colon (for example, FGFR4: Fibroblast growth factor receptor 4).
Inheriting Genetic Conditions This section gives you information on inheritance patterns and understanding risk. What Does It Mean If a Disorder Seems to Run in My Family? A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not inherited. Instead, environmental factors such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders.
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It is not always easy to determine whether a condition in a family is inherited. A genetics professional can use a person’s family history (a record of health information about a person’s immediate and extended family) to help determine whether a disorder has a genetic component.
Some disorders are seen in more than one generation of a family. Why Is It Important to Know My Family Medical History? A family medical history is a record of health information about a person and his or her close relatives. A complete record includes information from three generations of relatives, including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins.
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Families have many factors in common, including their genes, environment, and lifestyle. Together, these factors can give clues to medical conditions that may run in a family. By noticing patterns of disorders among relatives, healthcare professionals can determine whether an individual, other family members, or future generations may be at an increased risk of developing a particular condition. A family medical history can identify people with a higher-than-usual chance of having common disorders, such as heart disease, high blood pressure, stroke, certain cancers, and diabetes. These complex disorders are influenced by a combination of genetic factors, environmental conditions, and lifestyle choices. A family history also can provide information about the risk of rarer conditions caused by mutations in a single gene, such as cystic fibrosis and sickle cell anemia. While a family medical history provides information about the risk of specific health concerns, having relatives with a medical condition does not mean that an individual will definitely develop that condition. On the other hand, a person with no family history of a disorder may still be at risk of developing that disorder. Knowing one’s family medical history allows a person to take steps to reduce his or her risk. For people at an increased risk of certain cancers, healthcare professionals may recommend more frequent screening (such as mammography or colonoscopy) starting at an earlier age. Healthcare providers may also encourage regular checkups or testing for people with a medical condition that runs in their family. Additionally, lifestyle changes such as adopting a healthier diet, getting regular exercise, and quitting smoking help many people lower their chances of developing heart disease and other common illnesses. The easiest way to get information about family medical history is to talk to relatives about their health. Have they had any medical problems, and when did they occur? A family gathering could be a good time to discuss these issues. Additionally, obtaining medical records and other documents (such as obituaries and death certificates) can help complete a family medical history. It is important to keep this information up-to-date and to share it with a healthcare professional regularly. What Are the Different Ways in which a Genetic Condition Can Be Inherited? Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several straightforward patterns, depending on the gene involved: Inheritance Pattern Autosomal dominant
Description One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Autosomal dominant disorders tend to occur in every generation of an affected family.
Examples Huntington disease, neurofibromatosis type 1
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Autosomal recessive
Two mutated copies of the gene are present in each cell when a person has an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Autosomal recessive disorders are typically not seen in every generation of an affected family.
cystic fibrosis, sickle cell anemia
X-linked dominant
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women. Families with an X-linked dominant disorder often have both affected males and affected females in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
fragile X syndrome
X-linked recessive
X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
hemophilia, Fabry disease
Codominant
In codominant inheritance, two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition.
ABO blood group, alpha-1 antitrypsin deficiency
Mitochondrial
This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.
Leber hereditary optic neuropathy (LHON)
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Many other disorders are caused by a combination of the effects of multiple genes or by interactions between genes and the environment. Such disorders are more difficult to analyze because their genetic causes are often unclear, and they do not follow the patterns of inheritance described above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, diabetes, schizophrenia, and certain types of cancer. Disorders caused by changes in the number or structure of chromosomes do not follow the straightforward patterns of inheritance listed above. Other genetic factors can also influence how a disorder is inherited. If a Genetic Disorder Runs in My Family, What Are the Chances That My Children Will Have the Condition? When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person’s chances of developing a genetic condition. One important factor is how the condition is inherited. For example: •
Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent.
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Autosomal recessive inheritance: Two unaffected people who each carry one copy of the mutated gene for an autosomal recessive disorder (carriers) have a 25 percent chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50 percent, and the chance that a child will not have the disorder and will not be a carrier is 25 percent.
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X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy.
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X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50 percent chance of having sons who are affected and a 50 percent chance of having daughters who carry one copy of the mutated gene.
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Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child.
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Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial
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disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected. Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health. Factors that Influence the Effects of Particular Genetic Changes Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern. Reduced Penetrance Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations. Variable Expressivity Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and
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symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience lifethreatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose. What Do Geneticists Mean by Anticipation? The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation. Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation. What Is Genomic Imprinting? Genomic imprinting is a factor that influences how some genetic conditions are inherited. People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited
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from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13). What Is Uniparental Disomy? Uniparental disomy is a factor that influences how some genetic conditions are inherited. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems. Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11. Are Chromosomal Disorders Inherited? Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next. Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.
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Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional. Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next. Why Are Some Genetic Conditions More Common in Particular Ethnic Groups? Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.
Genetic Consultation This section presents information on finding and visiting a genetic counselor or other genetics professional. What Is a Genetic Consultation? A genetic consultation is a health service that provides information and support to people who have, or may be at risk for, genetic disorders. During a consultation, a genetics professional meets with an individual or family to discuss genetic risks or to diagnose, confirm, or rule out a genetic condition. Genetics professionals include medical geneticists (doctors who specialize in genetics) and genetic counselors (certified healthcare workers with experience in medical genetics and counseling). Other healthcare professionals such as nurses, psychologists, and social workers trained in genetics can also provide genetic consultations. Consultations usually take place in a doctor’s office, hospital, genetics center, or other type of medical center. These meetings are most often in-person visits with individuals or families, but they are occasionally conducted in a group or over the telephone.
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Why Might Someone Have a Genetic Consultation? Individuals or families who are concerned about an inherited condition may benefit from a genetic consultation. The reasons that a person might be referred to a genetic counselor, medical geneticist, or other genetics professional include: •
A personal or family history of a genetic condition, birth defect, chromosomal disorder, or hereditary cancer.
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Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.
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A child with a known inherited disorder, a birth defect, mental retardation, or developmental delay.
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A woman who is pregnant or plans to become pregnant at or after age 35. (Some chromosomal disorders occur more frequently in children born to older women.)
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Abnormal test results that suggest a genetic or chromosomal condition.
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An increased risk of developing or passing on a particular genetic disorder on the basis of a person’s ethnic background.
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People related by blood (for example, cousins) who plan to have children together. (A child whose parents are related may be at an increased risk of inheriting certain genetic disorders.)
A genetic consultation is also an important part of the decision-making process for genetic testing. A visit with a genetics professional may be helpful even if testing is not available for a specific condition, however. What Happens during a Genetic Consultation? A genetic consultation provides information, offers support, and addresses a patient’s specific questions and concerns. To help determine whether a condition has a genetic component, a genetics professional asks about a person’s medical history and takes a detailed family history (a record of health information about a person’s immediate and extended family). The genetics professional may also perform a physical examination and recommend appropriate tests. If a person is diagnosed with a genetic condition, the genetics professional provides information about the diagnosis, how the condition is inherited, the chance of passing the condition to future generations, and the options for testing and treatment. During a consultation, a genetics professional will: •
Interpret and communicate complex medical information.
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Help each person make informed, independent decisions about their health care and reproductive options.
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Respect each person’s individual beliefs, traditions, and feelings.
A genetics professional will NOT: •
Tell a person which decision to make.
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Advise a couple not to have children.
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Recommend that a woman continue or end a pregnancy.
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Tell someone whether to undergo testing for a genetic disorder.
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How Can I Find a Genetics Professional in My Area? To find a genetics professional in your community, you may wish to ask your doctor for a referral. If you have health insurance, you can also contact your insurance company to find a medical geneticist or genetic counselor in your area who participates in your plan. Several resources for locating a genetics professional in your community are available online: •
GeneTests from the University of Washington provides a list of genetics clinics around the United States and international genetics clinics. You can also access the list by clicking on “Clinic Directory” at the top of the GeneTests home page. Clinics can be chosen by state or country, by service, and/or by specialty. State maps can help you locate a clinic in your area. See http://www.genetests.org/.
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The National Society of Genetic Counselors offers a searchable directory of genetic counselors in the United States. You can search by location, name, area of practice/specialization, and/or ZIP Code. See http://www.nsgc.org/resourcelink.cfm.
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The National Cancer Institute provides a Cancer Genetics Services Directory, which lists professionals who provide services related to cancer genetics. You can search by type of cancer or syndrome, location, and/or provider name at the following Web site: http://cancer.gov/search/genetics_services/.
Genetic Testing This section presents information on the benefits, costs, risks, and limitations of genetic testing. What Is Genetic Testing? Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. Genetic testing is voluntary. Because testing has both benefits and limitations, the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing.
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What Are the Types of Genetic Tests? Genetic testing can provide information about a person’s genes and chromosomes. Available types of testing include: •
Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental retardation if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). Most states also test for other genetic disorders.
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Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person’s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person’s choices about health care and the management of the disorder.
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Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition.
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Prenatal testing is used to detect changes in a fetus’s genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however.
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Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques such as in-vitro fertilization. In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing them with sperm cells outside the body. To perform preimplantation testing, a small number of cells are taken from these embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.
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Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person’s risk of developing disorders with a genetic basis, such as certain types of cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder and help with making decisions about medical care.
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Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).
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How Is Genetic Testing Done? Once a person decides to proceed with genetic testing, a medical geneticist, primary care doctor, specialist, or nurse practitioner can order the test. Genetic testing is often done as part of a genetic consultation. Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person’s doctor or genetic counselor. Newborn screening tests are done on a small blood sample, which is taken by pricking the baby’s heel. Unlike other types of genetic testing, a parent will usually only receive the result if it is positive. If the test result is positive, additional testing is needed to determine whether the baby has a genetic disorder. Before a person has a genetic test, it is important that he or she understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission is called informed consent. What Is Direct-to-Consumer Genetic Testing? Traditionally, genetic tests have been available only through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers order the appropriate test from a laboratory, collect and send the samples, and interpret the test results. Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. If a consumer chooses to purchase a genetic test directly, the test kit is mailed to the consumer instead of being ordered through a doctor’s office. The test typically involves collecting a DNA sample at home, often by swabbing the inside of the cheek, and mailing the sample back to the laboratory. In some cases, the person must visit a health clinic to have blood drawn. Consumers are notified of their results by mail or over the telephone, or the results are posted online. In some cases, a genetic counselor or other healthcare provider is available to explain the results and answer questions. The price for this type of at-home genetic testing ranges from several hundred dollars to more than a thousand dollars. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins. At-home genetic tests, however, have significant risks and limitations. Consumers are vulnerable to being misled by the results of unproven or invalid tests. Without guidance from a healthcare provider, they may make important decisions about treatment or prevention based on inaccurate, incomplete, or misunderstood information about their health. Consumers may also experience an invasion of genetic privacy if testing companies use their genetic information in an unauthorized way.
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Genetic testing provides only one piece of information about a person’s health—other genetic and environmental factors, lifestyle choices, and family medical history also affect a person’s risk of developing many disorders. These factors are discussed during a consultation with a doctor or genetic counselor, but in many cases are not addressed by athome genetic tests. More research is needed to fully understand the benefits and limitations of direct-to-consumer genetic testing. What Do the Results of Genetic Tests Mean? The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, healthcare professionals consider a person’s medical history, family history, and the type of genetic test that was done. A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify an increased risk of developing a disease (such as cancer) in the future, or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health professionals typically cannot use a positive test result to predict the course or severity of a condition. A negative test result means that the laboratory did not find a change in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic mutation, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing may be required to confirm a negative result. In some cases, a negative result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been associated with a disorder in other people, it can be difficult to tell whether it is a natural polymorphism or a disease-causing mutation. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result. What Is the Cost of Genetic Testing, and How Long Does It Take to Get the Results? The cost of genetic testing can range from under $100 to more than $2,000, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members must be tested to obtain a meaningful result. For newborn
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screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant. From the date that a sample is taken, it may take a few weeks to several months to receive the test results. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. The doctor or genetic counselor who orders a particular test can provide specific information about the cost and time frame associated with that test. Will Health Insurance Cover the Costs of Genetic Testing? In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person’s doctor. Health insurance providers have different policies about which tests are covered, however. A person interested in submitting the costs of testing may wish to contact his or her insurance company beforehand to ask about coverage. Some people may choose not to use their insurance to pay for testing because the results of a genetic test can affect a person’s health insurance coverage. Instead, they may opt to pay out-of-pocket for the test. People considering genetic testing may want to find out more about their state’s privacy protection laws before they ask their insurance company to cover the costs. What Are the Benefits of Genetic Testing? Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible. What Are the Risks and Limitations of Genetic Testing? The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus. Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern.
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Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision. What Is Genetic Discrimination? Genetic discrimination occurs when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder. People who undergo genetic testing may be at risk for genetic discrimination. The results of a genetic test are normally included in a person’s medical records. When a person applies for life, disability, or health insurance, the insurance company may ask to look at these records before making a decision about coverage. An employer may also have the right to look at an employee’s medical records. As a result, genetic test results could affect a person’s insurance coverage or employment. People making decisions about genetic testing should be aware that when test results are placed in their medical records, the results might not be kept private. Fear of discrimination is a common concern among people considering genetic testing. Several laws at the federal and state levels help protect people against genetic discrimination; however, genetic testing is a fast-growing field and these laws don’t cover every situation. How Does Genetic Testing in a Research Setting Differ from Clinical Genetic Testing? The main differences between clinical genetic testing and research testing are the purpose of the test and who receives the results. The goals of research testing include finding unknown genes, learning how genes work, and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers. Clinical testing, on the other hand, is done to find out about an inherited disorder in an individual patient or family. People receive the results of a clinical test and can use them to help them make decisions about medical care or reproductive issues. It is important for people considering genetic testing to know whether the test is available on a clinical or research basis. Clinical and research testing both involve a process of informed consent in which patients learn about the testing procedure, the risks and benefits of the test, and the potential consequences of testing.
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Gene Therapy This section presents information on experimental techniques, safety, ethics, and availability of gene therapy. What Is Gene Therapy? Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including: •
Replacing a mutated gene that causes disease with a healthy copy of the gene.
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Inactivating, or “knocking out,” a mutated gene that is functioning improperly.
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Introducing a new gene into the body to help fight a disease.
Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures. How Does Gene Therapy Work? Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can’t cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patient’s cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein. Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.
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A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.
Is Gene Therapy Safe? Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible. Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants. The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RAC’s public meetings.
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An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution’s potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research. What Are the Ethical Issues surrounding Gene Therapy? Because gene therapy involves making changes to the body’s set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding gene therapy include: •
How can “good” and “bad” uses of gene therapy be distinguished?
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Who decides which traits are normal and which constitute a disability or disorder?
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Will the high costs of gene therapy make it available only to the wealthy?
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Could the widespread use of gene therapy make society less accepting of people who are different?
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Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?
Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a person’s children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy. The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they can’t choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people. Is Gene Therapy Available to Treat My Disorder? Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States. Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate. You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for
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specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) patients.
The Human Genome Project and Genomic Research This section presents information on the goals, accomplishments, and next steps in understanding the human genome. What Is a Genome? A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. What Was the Human Genome Project and Why Has It Been Important? The Human Genome Project was an international research effort to determine the sequence of the human genome and identify the genes that it contains. The Project was coordinated by the National Institutes of Health and the U.S. Department of Energy. Additional contributors included universities across the United States and international partners in the United Kingdom, France, Germany, Japan, and China. The Human Genome Project formally began in 1990 and was completed in 2003, 2 years ahead of its original schedule. The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge will have a major impact in the fields of medicine, biotechnology, and the life sciences. What Were the Goals of the Human Genome Project? The main goals of the Human Genome Project were to provide a complete and accurate sequence of the 3 billion DNA base pairs that make up the human genome and to find all of the estimated 20,000 to 25,000 human genes. The Project also aimed to sequence the genomes of several other organisms that are important to medical research, such as the mouse and the fruit fly. In addition to sequencing DNA, the Human Genome Project sought to develop new tools to obtain and analyze the data and to make this information widely available. Also, because advances in genetics have consequences for individuals and society, the Human Genome Project committed to exploring the consequences of genomic research through its Ethical, Legal, and Social Implications (ELSI) program. What Did the Human Genome Project Accomplish? In April 2003, researchers announced that the Human Genome Project had completed a high-quality sequence of essentially the entire human genome. This sequence closed the
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gaps from a working draft of the genome, which was published in 2001. It also identified the locations of many human genes and provided information about their structure and organization. The Project made the sequence of the human genome and tools to analyze the data freely available via the Internet. In addition to the human genome, the Human Genome Project sequenced the genomes of several other organisms, including brewers’ yeast, the roundworm, and the fruit fly. In 2002, researchers announced that they had also completed a working draft of the mouse genome. By studying the similarities and differences between human genes and those of other organisms, researchers can discover the functions of particular genes and identify which genes are critical for life. The Project’s Ethical, Legal, and Social Implications (ELSI) program became the world’s largest bioethics program and a model for other ELSI programs worldwide. What Were Some of the Ethical, Legal, and Social Implications Addressed by the Human Genome Project? The Ethical, Legal, and Social Implications (ELSI) program was founded in 1990 as an integral part of the Human Genome Project. The mission of the ELSI program was to identify and address issues raised by genomic research that would affect individuals, families, and society. A percentage of the Human Genome Project budget at the National Institutes of Health and the U.S. Department of Energy was devoted to ELSI research. The ELSI program focused on the possible consequences of genomic research in four main areas: •
Privacy and fairness in the use of genetic information, including the potential for genetic discrimination in employment and insurance.
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The integration of new genetic technologies, such as genetic testing, into the practice of clinical medicine.
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Ethical issues surrounding the design and conduct of genetic research with people, including the process of informed consent.
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The education of healthcare professionals, policy makers, students, and the public about genetics and the complex issues that result from genomic research. What Are the Next Steps in Genomic Research?
Discovering the sequence of the human genome was only the first step in understanding how the instructions coded in DNA lead to a functioning human being. The next stage of genomic research will begin to derive meaningful knowledge from the DNA sequence. Research studies that build on the work of the Human Genome Project are under way worldwide. The objectives of continued genomic research include the following: •
Determine the function of genes and the elements that regulate genes throughout the genome.
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Find variations in the DNA sequence among people and determine their significance. These variations may one day provide information about a person’s disease risk and response to certain medications.
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Discover the 3-dimensional structures of proteins and identify their functions.
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Explore how DNA and proteins interact with one another and with the environment to create complex living systems.
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Develop and apply genome-based strategies for the early detection, diagnosis, and treatment of disease.
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Sequence the genomes of other organisms, such as the rat, cow, and chimpanzee, in order to compare similar genes between species.
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Develop new technologies to study genes and DNA on a large scale and store genomic data efficiently.
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Continue to explore the ethical, legal, and social issues raised by genomic research. What Is Pharmacogenomics?
Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Many drugs that are currently available are “one size fits all,” but they don’t work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.
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APPENDIX B. 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: •
National Institutes of Health (NIH); guidelines consolidated across agencies available at http://health.nih.gov/
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/Publications/FactSheets.htm
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancertopics/pdq
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/health/
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/HealthInformation/Publications/
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/Publications/
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These publications are typically written by one or more of the various NIH Institutes.
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidcr.nih.gov/HealthInformation/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/healthinformation/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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
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).
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citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine14: •
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
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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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/index.html
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Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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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
14
See http://www.nlm.nih.gov/databases/index.html.
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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 cystic 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. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 27092 426 72 106 4 27700
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 cystic 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 15
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
16
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). 17 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 18 19
The HSTAT URL is http://hstat.nlm.nih.gov/.
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.
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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/.
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: •
MD Consult: Access to electronic clinical resources, see http://www.mdconsult.com/.
•
Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Cystic Fibrosis In the following section, we will discuss databases and references which relate to the Genome Project and cystic 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 cystic fibrosis (or synonyms) into the search box, and click Go. 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. The following is an example of the results you can obtain from the OMIM for cystic fibrosis:
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. 23 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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•
CYSTIC FIBROSIS with HELICOBACTER PYLORI GASTRITIS, MEGALOBLASTIC ANEMIA, and SUBNORMAL MENTALITY Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=219721
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CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602421
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CYSTIC FIBROSIS MODIFIER 1; CFM1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603855 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
•
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
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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: •
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
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GEO DataSets: Curated gene expression and molecular abundance data sets assembled from the Gene Expression Omnibus (GEO) repository, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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GEO Profiles: Individual gene expression and molecular abundance profiles assembled from the Gene Expression Omnibus (GEO) repository, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
•
Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi, and then select the database that you
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would like to search. Or, to search across databases, you can enter cystic 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 GDB Human 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 Name/GDB ID. Type cystic fibrosis (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word and or or (using or might be useful when using synonyms).
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://www.gdb.org/gdb/aboutGDB.html#mission.
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APPENDIX C. 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 cystic 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 This section directs you to sources which either publish fact sheets or can help you find additional guidelines on topics related to cystic 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 cystic 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 cystic fibrosis:
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Acne http://www.nlm.nih.gov/medlineplus/acne.html Cystic Fibrosis http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html Lung Diseases http://www.nlm.nih.gov/medlineplus/lungdiseases.html Lung Transplantation http://www.nlm.nih.gov/medlineplus/lungtransplantation.html Newborn Screening http://www.nlm.nih.gov/medlineplus/newbornscreening.html Organ Transplantation http://www.nlm.nih.gov/medlineplus/organtransplantation.html Pancreatic Diseases http://www.nlm.nih.gov/medlineplus/pancreaticdiseases.html Pulmonary Fibrosis http://www.nlm.nih.gov/medlineplus/pulmonaryfibrosis.html 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 National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword cystic fibrosis (or synonyms). The following was recently posted: •
Guidelines for the performance of the sweat test for the investigation of cystic fibrosis in the UK Source: Association of Clinical Biochemists; 2003; 97 pages http://www.guideline.gov/summary/summary.aspx?doc_id=5059&nbr=003543& amp;string=Cystic+AND+fibrosis Healthfinder™
Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database:
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AANMA - Medical Center Summary: Cystic fibrosis is an inherited (genetic) disease that affects the respiratory system(airways and lungs) as well as the digestive system… Source: www.aanma.org http://www.aanma.org/medicalcenter/mc_anc_basics.htm
•
Diseases - About Cystic Fibrosis - National Jewish Medical and. Summary: Since cystic fibrosis affects the pancreas, symptoms in babies include problems with feeding, diarrhea and growth lag. Source: www.nationaljewish.org http://www.nationaljewish.org/disease-info/diseases/cystic-fibrosis/about.aspx
•
Diseases - Management of Cystic Fibrosis (CF) - National Jewish. Summary: How is cystic fibrosis best managed? Source: www.nationaljewish.org http://www.nationaljewish.org/disease-info/diseases/cystic-fibrosis/mgmt.aspx
•
MedlinePlus: Pancreatic Diseases Source: www.nlm.nih.gov http://www.nlm.nih.gov/medlineplus/pancreaticdiseases.html
•
What Is Cystic Fibrosis? Summary: Cystic fibrosis (CF) is the most common, fatal hereditary disease in the US. Source: www.cfri.org http://www.cfri.org/framesfaq.htm 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 cystic 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://health.nih.gov/index.asp. Under Search Health Topics, type cystic fibrosis (or synonyms) into the search box, and click Search.
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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: •
Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
•
Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
•
WebMD®Health: http://www.webmd.com/diseases_and_conditions/default.htm
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to cystic fibrosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with cystic 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 cystic 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://sis.nlm.nih.gov/dirline.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. Simply type in cystic 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://healthhotlines.nlm.nih.gov/. 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.
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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 cystic fibrosis (or a synonym) into the search box, and click Submit Query.
Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families26: •
Genetic Alliance: http://geneticalliance.org
•
Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html
•
Madisons Foundation: http://www.madisonsfoundation.org/
•
March of Dimes: http://www.marchofdimes.com
•
National Organization for Rare Disorders (NORD): http://www.rarediseases.org/ For More Information on Genetics
The following publications offer detailed information for patients about the science of genetics: •
What Is a Genome?: http://www.ncbi.nlm.nih.gov/About/primer/genetics_genome.html
•
A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html
•
Genetic Mapping: http://www.genome.gov/10000715
26
Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.
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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
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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/archive//20040831/nichsr/ta101/ta10108.html
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on cystic fibrosis: •
Basic Guidelines for Cystic Fibrosis Cystic fibrosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000107.htm Cystic fibrosis - nutritional considerations Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002437.htm Cystic fibrosis - resources Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002176.htm
•
Signs & Symptoms for Cystic Fibrosis Abdominal distention Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003122.htm Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm
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Breathing difficulty Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Clubbing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003282.htm Cough Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Coughing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Delayed growth Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003021.htm Diarrhea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003126.htm Discouraged Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Dyspnea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Easy fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Foul smelling stools Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003132.htm Hemoptysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003073.htm Lung disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000066.htm Osteoarthropathy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003282.htm Stools, pale or clay colored Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003129.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Tachypnea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003071.htm
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Weight loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003107.htm Wheezing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003070.htm •
Diagnostics and Tests for Cystic Fibrosis Albumin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003480.htm ALT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm ANA Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003535.htm CAT scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Chest CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003788.htm Chest X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Diffusing capacity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003854.htm Echocardiogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm Fecal fat Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003588.htm Pulmonary function Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003443.htm Pulmonary function tests Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003853.htm Secretin stimulation test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003892.htm Sweat chloride Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003630.htm Sweat test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003630.htm
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Trypsin and chymotrypsin in stool Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003594.htm Upper GI and small bowel series Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003816.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm •
Nutrition for Cystic Fibrosis Fat Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002468.htm Fats Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002468.htm Normal growth and development Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002456.htm Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm Vitamins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002399.htm Yogurt Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002463.htm
•
Surgery and Procedures for Cystic Fibrosis Lung transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003010.htm
•
Background Topics for Cystic Fibrosis Bile Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002237.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Cystic fibrosis - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002176.htm Distal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002346.htm Meconium Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002262.htm
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Pain reliever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002123.htm Percussion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002281.htm Respiratory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002290.htm Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.htm
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
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
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CYSTIC FIBROSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acne Vulgaris: A chronic disorder of the pilosebaceous apparatus associated with an increase in sebum secretion. It is characterized by open comedones (blackheads), closed comedones (whiteheads), and pustular nodules. The cause is unknown, but heredity and age are predisposing factors. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acuity: Clarity or clearness, especially of the vision. [EU] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing
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of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate 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 Kinase: An enzyme that catalyzes the phosphorylation of AMP to ADP in the presence of ATP or inorganic triphosphate. EC 2.7.4.3. [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] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agarose: A polysaccharide complex, free of nitrogen and prepared from agar-agar which is produced by certain seaweeds (red algae). It dissolves in warm water to form a viscid
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solution. [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 Pollutants: Substances which pollute the air. [NIH] 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] Airway Obstruction: Any hindrance to the passage of air into and out of the lungs. [NIH] AK: Enzyme of the biosynthetic pathway. [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] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [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-Defensins: Defensins found in azurophilic granules of neutrophils and in the secretory granules of intestinal paneth cells. [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] Alpha-helix: One of the secondary element of protein. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Ambulatory Care: Health care services provided to patients on an ambulatory basis, rather
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than by admission to a hospital or other health care facility. The services may be a part of a hospital, augmenting its inpatient services, or may be provided at a free-standing facility. [NIH]
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 Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] 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] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]
Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amylase: An enzyme that helps the body digest starches. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] 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] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] 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] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers
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or other tissues are called xenograft models. [NIH] Anionic: Pertaining to or containing an anion. [EU] 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]
Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]
Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [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] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including
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phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [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] Aorta: The main trunk of the systemic arteries. [NIH] Apnea: A transient absence of spontaneous respiration. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aquaporins: Membrane proteins which facilitate the passage of water. They are members of the family of membrane channel proteins which includes the lens major intrinsic protein and bacterial glycerol transporters. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH]
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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] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] 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] Asparaginase: A hydrolase enzyme that converts L-asparagine and water to L-aspartate and NH3. EC 3.5.1.1. [NIH] Aspartate: A synthetic amino acid. [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] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Audiometry: The testing of the acuity of the sense of hearing to determine the thresholds of the lowest intensity levels at which an individual can hear a set of tones. The frequencies between 125 and 8000 Hz are used to test air conduction thresholds, and the frequencies between 250 and 4000 Hz are used to test bone conduction thresholds. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autogenic: A type of succession when the developing vegetation itself is the cause for the succession. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Azithromycin: A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. [NIH] 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]
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Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial toxin: A toxic substance, made by bacteria, that can be modified to kill specific tumor cells without harming normal cells. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Belladonna: A species of very poisonous Solanaceous plants yielding atropine (hyoscyamine), scopolamine, and other belladonna alkaloids, used to block the muscarinic autonomic nervous system. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Beta-Defensins: Defensins found mainly in epithelial cells. [NIH] Beta-glucans: Polysaccharides made by several types of mushrooms. Beta-glucans have been used to treat patients with gastric cancer and colorectal cancer. They may be able to stimulate the immune system. [NIH] Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bewilderment: Impairment or loss of will power. [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
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digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] 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] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [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] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] 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
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clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [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] 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 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 Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [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] 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] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU]
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Bromelain: An enzyme found in pineapples that breaks down other proteins, such as collagen and muscle fiber, and has anti-inflammatory properties. It is used as a meat tenderizer in the food industry. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiectasis: Persistent abnormal dilatation of the bronchi. [NIH] Bronchiole: The smaller airways of the lungs. [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] Bronchoalveolar Lavage Fluid: Fluid obtained by washout of the alveolar compartment of the lung. It is used to assess biochemical and inflammatory changes in and effects of therapy on the interstitial lung tissue. [NIH] Bronchodilator: A drug that relaxes the smooth muscles in the constricted airway. [NIH] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Budesonide: A glucocorticoid used in the management of asthma, the treatment of various skin disorders, and allergic rhinitis. [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] 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] 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] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
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Cardiac: Having to do with the heart. [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] 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] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [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] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [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] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] CD-ROM: An optical disk storage system for computers on which data can be read or from which data can be retrieved but not entered or modified. A CD-ROM unit is almost identical to the compact disk playback device for home use. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH]
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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 Fusion: Fusion of somatic cells in vitro or in vivo, which results in somatic cell hybridization. [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 Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell Polarity: Orientation of intracellular structures especially with respect to the apical and basolateral domains of the plasma membrane. Polarized cells must direct proteins from the Golgi apparatus to the appropriate domain since tight junctions prevent proteins from diffusing between the two domains. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell 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] Cellular metabolism: The sum of all chemical changes that take place in a cell through which energy and basic components are provided for essential processes, including the synthesis of new molecules and the breakdown and removal of others. [NIH] Cellulase: An enzyme isolated from fungi and bacteria. It catalyzes the endohydrolysis of 1,4-beta-glucosidic linkages in cellulose, lichenin, and cereal beta-glucans. EC 3.2.1.4. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] 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] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Chaperonins: A class of sequence-related molecular chaperones found in bacteria, mitochondria, and plastids. Chaperonins are abundant constitutive proteins that increase in amount after stresses such as heat shock, bacterial infection of macrophages, and an increase in the cellular content of unfolded proteins. Bacterial chaperonins are major immunogens in human bacterial infections because of their accumulation during the stress of infection. Two members of this class of chaperones are chaperonin 10 and chaperonin 60. [NIH] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning,
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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] 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] Chest wall: The ribs and muscles, bones, and joints that make up the area of the body between the neck and the abdomen. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chimeric Proteins: Proteins in individuals that are derived from genetically different zygotes. [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] Chlorhexidine: Disinfectant and topical anti-infective agent used also as mouthwash to prevent oral plaque. [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] Cholangitis: Inflammation of a bile duct. [NIH] Choleretic: A choleretic agent. [EU] 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] Cholic Acid: A major primary bile acid produced in the liver and usually conjugated with glycine or taurine. It facilitates fat absorption and cholesterol excretion. [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] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all
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human cells contain 46 chromosomes. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [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 myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Chymotrypsin: A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. [NIH] 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] 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] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] 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,
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prevention, diagnosis, or treatment of a disease. [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] Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colistin: Cyclic polypeptide antibiotic from Bacillus colistinus. It is composed of Polymyxins E1 and E2 (or Colistins A, B, and C) which act as detergents on cell membranes. Colistin is less toxic than Polymyxin B, but otherwise similar; the methanesulfonate is used orally. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] 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] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with
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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] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concentric: Having a common center of curvature or symmetry. [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] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH]
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Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] 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] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Corpuscle: A small mass or body; a sensory nerve end bulb; a cell, especially that of the blood or the lymph. [NIH] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]
Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Crowding: Behavior with respect to an excessive number of individuals, human or animal, in relation to available space. [NIH] Cryptosporidiosis: Parasitic intestinal infection with severe diarrhea caused by a protozoan, Cryptosporidium. It occurs in both animals and humans. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH]
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Cutaneous: Having to do with the skin. [NIH] Cyanide: An extremely toxic class of compounds that can be lethal on inhaling of ingesting in minute quantities. [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] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
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] Cytochrome b: Cytochromes (electron-transporting proteins) with protoheme or a related heme as the prosthetic group. The prosthetic group is not covalently bound to the protein moiety. [NIH] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] 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] 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] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]
Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH]
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De novo: In cancer, the first occurrence of cancer in the body. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Defensins: Family of antimicrobial peptides that have been identified in humans, animals, and plants. They are thought to play a role in host defenses against infections, inflammation, wound repair, and acquired immunity. Based on the disulfide pairing of their characteristic six cysteine residues, they are divided into alpha-defensins and beta-defensins. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] 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] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] 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] 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
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that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [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]
Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [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, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of Corynebacterium diphtheriae. It is characterized by the presence of a pseudomembrane at the site of infection. Diphtheria toxin, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. [NIH] 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] Directed Molecular Evolution: Techniques used to produce molecules exhibiting properties that conform to the demands of the experimenter. [NIH] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH]
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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] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] 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] Distention: The state of being distended or enlarged; the act of distending. [EU] 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] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Monitoring: The process of observing, recording, or detecting the effects of a chemical substance administered to an individual therapeutically or diagnostically. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH]
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Duodenum: The first part of the small intestine. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] 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] Effusion: The escape of fluid into a part or tissue, as an exudation or a transudation. [EU] Ejaculation: The release of semen through the penis during orgasm. [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] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [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
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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] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endosomes: Cytoplasmic vesicles formed when coated vesicles shed their clathrin coat. Endosomes internalize macromolecules bound by receptors on the cell surface. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energetic: Exhibiting energy : strenuous; operating with force, vigour, or effect. [EU] 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] Energy Intake: Total number of calories taken in daily whether ingested or by parenteral routes. [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] Enterohepatic: Of or involving the intestine and liver. [EU] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]
Environmental Health: The science of controlling or modifying those conditions, influences,
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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] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] 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] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermal growth factor receptor: EGFR. The protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. Also known as ErbB1 or HER1. [NIH] 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] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [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] Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach.
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[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] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH] 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] Exercise Tolerance: The exercise capacity of an individual as measured by endurance (maximal exercise duration and/or maximal attained work load) during an exercise test. [NIH]
Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exons: Coding regions of messenger RNA included in the genetic transcript which survive the processing of RNA in cell nuclei to become part of a spliced messenger of structural RNA in the cytoplasm. They include joining and diversity exons of immunoglobulin genes. [NIH]
Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH]
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Eye Color: Color of the iris. [NIH] 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] 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] Famotidine: A competitive histamine H2-receptor antagonist. Its main pharmacodynamic effect is the inhibition of gastric secretion. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [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] 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] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [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 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] Feverfew: Aromatic perennial Tanacetum parthenium used to treat migraines, arthritis, and as a febrifuge. It contains tannins, volatile oils (oils, essential), and sesquiterpene lactones, especially parthenolide. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] 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] Flagellin: A protein with a molecular weight of 40,000 isolated from bacterial flagella. At appropriate pH and salt concentration, three flagellin monomers can spontaneously
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reaggregate to form structures which appear identical to intact flagella. [NIH] Flagellum: A whiplike appendage of a cell. It can function either as an organ of locomotion or as a device for moving the fluid surrounding the cell. [NIH] Flatus: Gas passed through the rectum. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Flutter: A rapid vibration or pulsation. [EU] Foetoplacental: Pertaining to the fetus and placenta. [EU] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Founder Effect: The principle that when a small subgroup of a larger population establishes itself as a separate and isolated entity, its gene pool carries only a fraction of the genetic diversity of the parental population. This may result in an increased frequency of certain diseases in the subgroup, especially those diseases known to be autosomal recessive. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [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 Acid: Hydrochloric acid present in gastric juice. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH]
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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]
Gastrointestinal: Refers to the stomach and intestines. [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] 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 Pool: The total genetic information possessed by the reproductive members of a population of sexually reproducing organisms. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] 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] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [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,
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transplanting whole nuclei, transplanting cell hybrids, etc. [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] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] 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]
Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] 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]
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Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] 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]
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] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] 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] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [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] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granulomatous Disease, Chronic: A recessive X-linked defect of leukocyte function in which phagocytic cells ingest but fail to digest bacteria, resulting in recurring bacterial infections with granuloma formation. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and
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pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [NIH] Hair Color: Color of hair or fur. [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] 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] 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] Heat-Shock Proteins: Proteins which are synthesized in eukaryotic organisms and bacteria in response to hyperthermia and other environmental stresses. They increase thermal tolerance and perform functions essential to cell survival under these conditions. [NIH] Heat-Shock Proteins 90: A class of molecular chaperones whose members act in the mechanism of signal transduction by steroid receptors. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hematopoietic tissue: Tissue in which new blood cells are formed. [NIH] 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] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [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] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH]
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Hepatic: Refers to the liver. [NIH] Hepatobiliary: Pertaining to the liver and the bile or the biliary ducts. [EU] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimers: 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]
Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Heterozygote Detection: Identification of genetic carriers for a given trait. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [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] 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] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H,
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atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] 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] Hyperglycemia: Abnormally high blood sugar. [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] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertension, Renal: Hypertension due to renal diseases, especially chronic parenchymal disease. Hypertension as a result of compression or obstruction of the renal artery or its branches is hypertension, renovascular. [NIH] Hypertension, Renovascular: Hypertension due to compression or obstruction of the renal artery or its branches. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [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] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Idiopathic: Describes a disease of unknown cause. [NIH] Ileal: Related to the ileum, the lowest end of the small intestine. [NIH] Ileum: The lower end of the small intestine. [NIH] Ileus: Obstruction of the intestines. [EU] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
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Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
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] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] 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] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized,
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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]
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] 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]
Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [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] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [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] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, T-
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lymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [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] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
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 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] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] 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] Isodesmosine: 2-(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] Isoproterenol: Isopropyl analog of epinephrine; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant. [NIH] Isotretinoin: A topical dermatologic agent that is used in the treatment of acne vulgaris and
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several other skin diseases. The drug has teratogenic and other adverse effects. [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] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] 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] Kinetic: Pertaining to or producing motion. [EU] Lactation: The period of the secretion of milk. [EU] Lactoperoxidase: An enzyme derived from cow's milk. It catalyzes the radioiodination of tyrosine and its derivatives and of peptides containing tyrosine. [NIH] Lag: The time elapsing between application of a stimulus and the resulting reaction. [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] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH]
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Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and 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] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] 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] Lesion: An area of abnormal tissue change. [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] Leukemia: Cancer of blood-forming tissue. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] 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] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [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
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electron acceptor. [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] 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 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] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [NIH]
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Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [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] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [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] Macrolides: A group of organic compounds that contain a macrocyclic lactone ring linked glycosidically to one or more sugar moieties. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] 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] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammography: Radiographic examination of the breast. [NIH] Mannans: Polysaccharides consisting of mannose units. [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] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [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]
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
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the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] 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] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane 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 Microdomains: Detergent-insoluble cell membrane components. They are enriched in sphingolipids and cholesterol and clustered with glycosyl-phosphatidylinositol (GPI)-anchored proteins. [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] 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] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]
Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies
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(usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] 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] Metoclopramide: A dopamine D2 antagonist that is used as an antiemetic. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiological: Pertaining to microbiology : the science that deals with microorganisms, including algae, bacteria, fungi, protozoa and viruses. [EU] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] 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] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [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] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Millimeter: A measure of length. A millimeter is approximately 26-times smaller than an inch. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Misoprostol: A synthetic analog of natural prostaglandin E1. It produces a dose-related inhibition of gastric acid and pepsin secretion, and enhances mucosal resistance to injury. It is an effective anti-ulcer agent and also has oxytocic properties. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which
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the learner is to imitate and make part of his repertoire. [NIH] Models, Animal: Non-human animals, selected because of specific characteristics, for use in experimental research, teaching, or testing. [NIH] 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 Chaperones: A family of cellular proteins that mediate the correct assembly or disassembly of other polypeptides, and in some cases their assembly into oligomeric structures, but which are not components of those final structures. It is believed that chaperone proteins assist polypeptides to self-assemble by inhibiting alternative assembly pathways that produce nonfunctional structures. Some classes of molecular chaperones are the nucleoplasmins, the chaperonins, the heat-shock proteins 70, and the heat-shock proteins 90. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocyte: A type of white blood cell. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [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] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] 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] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells,
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water, inorganic salts, and exfoliated cells. [NIH] Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Music Therapy: The use of music as an adjunctive therapy in the treatment of neurological, mental, or behavioral disorders. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mycobacterial disease: Any disease caused by Mycobacterium other than M. tuberculosis, M. bovis, and M. avium. [NIH] Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Nasal Polyps: Focal accumulations of edema fluid in the nasal mucosa accompanied by hyperplasia of the associated submucosal connective tissue. Polyps may be neoplasms, foci of inflammation, degenerative lesions, or malformations. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nebramycin: A complex of antibiotic substances produced by Streptomyces tenebrarius. [NIH]
Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] 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] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] 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] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and
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ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] 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] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [NIH] 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] 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 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
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mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [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] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Nursing Care: Care given to patients by nursing service personnel. [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] Oculogyric: Pertaining to, characterized by, or causing oculogyration (circular movements of the eyeballs, as in an oculogyric crisis). [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] 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.
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[EU]
Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [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] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Orderly: A male hospital attendant. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Oropharynx: Oral part of the pharynx. [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] 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] 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]
Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [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] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Oxytocic: 1. Pertaining to, characterized by, or promoting oxytocia (= rapid labor). 2. An
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agent that hastens evacuation of the uterus by stimulating contractions of the myometrium. [EU]
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 enzymes: A group of proteins secreted by the pancreas which aid in the digestion of food. [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] Pancreatin: A mammalian pancreatic extract composed of enzymes with protease, amylase and lipase activities. It is used as a digestant in pancreatic malfunction. [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 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]
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]
Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Partnership Practice: A voluntary contract between two or more doctors who may or may not share responsibility for the care of patients, with proportional sharing of profits and losses. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH]
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PDQ: Physician Data Query. PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information is available on the CancerNet Web site, and more specific information about PDQ can be found at http://cancernet.nci.nih.gov/pdq.html. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] 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] Perennial: Lasting through the year of for several years. [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] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Peripheral blood: Blood circulating throughout the body. [NIH] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Perspiration: Sweating; the functional secretion of sweat. [EU] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] 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] 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]
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Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] 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] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [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] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylbutyrate: An anticancer drug that belongs to the family of drugs called differentiating agents. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: 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] Photoreceptors: Cells specialized to detect and transduce light. [NIH] Phylogeny: The relationships of groups of organisms as reflected by their evolutionary
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history. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physical Therapy: The restoration of function and the prevention of disability following disease or injury with the use of light, heat, cold, water, electricity, ultrasound, and exercise. [NIH]
Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] 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] 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] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [NIH]
Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form.
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Also called thrombocytes. [NIH] Pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] 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] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyneuritis: Inflammation of several peripheral nerves at the same time. [NIH] Polyp: A growth that protrudes from a mucous membrane. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyphosphates: Linear polymers in which orthophosphate residues are linked with energy-rich 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] Polyvalent: Having more than one valence. [EU] 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] 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
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cirrhosis. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Portosystemic Shunt: An operation to create an opening between the portal vein and other veins around the liver. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] 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] Postural: Pertaining to posture or position. [EU] 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] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitation: The act or process of precipitating. [EU] Precipitins: Antibodies which elicit precipitation when combined with antigen. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Care: Care provided the pregnant woman in order to prevent complications, and decrease the incidence of maternal and prenatal mortality. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Private Practice: Practice of a health profession by an individual, offering services on a person-to-person basis, as opposed to group or partnership practice. [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]
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Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [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] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [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] 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 lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU]
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Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Folding: A rapid biochemical reaction involved in the formation of proteins. It begins even before a protein has been completely synthesized and proceeds through discrete intermediates (primary, secondary, and tertiary structures) before the final structure (quaternary structure) is developed. [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] 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] 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] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pseudomonas: A genus of gram-negative, aerobic, rod-shaped bacteria widely distributed in nature. Some species are pathogenic for humans, animals, and plants. [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] Public Health: Branch of medicine concerned with the prevention and control of disease
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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] Pulsation: A throb or rhythmical beat, as of the heart. [EU] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] 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] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [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]
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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] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] 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] 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] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [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] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands
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and ureters. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [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] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Reserpine: An alkaloid found in the roots of Rauwolfia serpentina and R. vomitoria. Reserpine inhibits the uptake of norepinephrine into storage vesicles resulting in depletion of catecholamines and serotonin from central and peripheral axon terminals. It has been used as an antihypertensive and an antipsychotic as well as a research tool, but its adverse effects limit its clinical use. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory Burst: A large increase in oxygen uptake by neutrophils and most types of tissue macrophages through activation of an NADPH-cytochrome b-dependent oxidase that reduces oxygen to a superoxide. Individuals with an inherited defect in which the oxidase that reduces oxygen to superoxide is decreased or absent (granulomatous disease, chronic) often die as a result of recurrent bacterial infections. [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] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [NIH] 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] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU]
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Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [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] Ribonuclease: RNA-digesting enzyme. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Role-play: In this method, a conflict is artificially constructed, and the trainee is given a strategic position in it. [NIH] Saline: A solution of salt and water. [NIH] 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] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] 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] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Scleroproteins: Simple proteins characterized by their insolubility and fibrous structure. Within the body, they perform a supportive or protective function. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Scrotum: In males, the external sac that contains the testicles. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter.
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They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [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] Sediment: A precipitate, especially one that is formed spontaneously. [EU] 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] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Seminal vesicles: Glands that help produce semen. [NIH] Sepsis: The presence of bacteria in the bloodstream. [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] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [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] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Sigma Factor: A protein which is a subunit of RNA polymerase. It effects initiation of specific RNA chains from DNA. [NIH]
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Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Silver Compounds: Inorganic compounds that contain silver as an integral part of the molecule. [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] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [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] Social Work: The use of community resources, individual case work, or group work to
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promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [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] Sperm: The fecundating fluid of the male. [NIH] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] 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]
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Splenectomy: An operation to remove the spleen. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] 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] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [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]
Steatorrhea: A condition in which the body cannot absorb fat. Causes a buildup of fat in the stool and loose, greasy, and foul bowel movements. [NIH] 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] 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] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open. [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] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on
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muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] 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] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Sulfides: Chemical groups containing the covalent sulfur bonds -S-. The sulfur atom can be bound to inorganic or organic moieties. [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] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH]
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Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] 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]
Surrogate Mothers: Women who allow themselves to be impregnated with the understanding that the offspring are to be given over to the parents who have commissioned the surrogate. [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 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] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] 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] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [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] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end
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of transcription. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [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] Thermoregulation: Heat regulation. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [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] 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] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] 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] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tobramycin: An aminoglycoside, broad-spectrum antibiotic produced by Streptomyces tenebrarius. It is effective against gram-negative bacteria, especially the Pseudomonas species. It is a 10% component of the antibiotic complex, nebramycin, produced by the same species. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] 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]
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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] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] 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] Toxoplasmosis: The acquired form of infection by Toxoplasma gondii in animals and man. [NIH]
Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH]
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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] Transport Vesicles: Vesicles that are involved in shuttling cargo from the interior of the cell to the cell surface, from the cell surface to the interior, across the cell or around the cell to various locations. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Triage: The sorting out and classification of patients or casualties to determine priority of need and proper place of treatment. [NIH] Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]
Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] 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] 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] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [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 condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin
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specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Unsaturated Fats: A type of fat. [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] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinalysis: Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. [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] 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 gallstones. It is used as a cholagogue and choleretic. [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] 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] Vacuole: A fluid-filled cavity within the cytoplasm of a cell. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vas Deferens: The excretory duct of the testes that carries spermatozoa. It rises from the scrotum and joins the seminal vesicles to form the ejaculatory duct. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [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]
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Venous: Of or pertaining to the veins. [EU] 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] 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] 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] Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [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] Vocal cord: The vocal folds of the larynx. [NIH] Weight Perception: Recognition and discrimination of the heaviness of a lifted object. [NIH] Wheezing: Breathing with a rasp or whistling sound; a sign of airway constriction or obstruction. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection
298
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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] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
299
INDEX 3 3-dimensional, 177, 208, 227, 282 A Abdomen, 227, 236, 240, 251, 263, 266, 276, 289, 291, 297 Abdominal, 70, 104, 222, 227, 228, 275, 284, 295 Abdominal Pain, 227, 295 Aberrant, 27, 30, 46, 154, 227 Acceptor, 227, 266, 274, 294 Acetylcholine, 40, 227, 240, 272 Acetylcysteine, 89, 227 Acne, 218, 227, 263, 285 Acne Vulgaris, 227, 263 Actin, 17, 24, 106, 178, 227, 255 Acuity, 227, 233 Acute lymphoblastic leukemia, 51, 144, 227 Acute lymphocytic leukemia, 227 Adaptability, 227, 239 Adaptation, 40, 50, 67, 83, 87, 160, 227, 271 Adenine, 35, 171, 228, 283 Adenosine, 35, 172, 228, 233, 277 Adenosine Triphosphate, 35, 172, 228, 233, 277 Adenovirus, 38, 204, 228 Adenylate Kinase, 133, 228 Adipocytes, 228, 265 Adjunctive Therapy, 228, 271 Adjustment, 227, 228 Adrenal Cortex, 228, 273 Adrenergic, 33, 228, 232, 248, 251, 292 Adverse Effect, 228, 264, 285, 287 Aerobic, 228, 252, 269, 282 Aerosol, 73, 141, 228 Afferent, 228, 253, 265 Affinity, 17, 228, 229, 289 Agarose, 228, 261 Agonist, 47, 229, 248 Air Pollutants, 39, 229 Air Sacs, 229 Airway Obstruction, 14, 99, 229 AK, 75, 92, 99, 101, 116, 127, 132, 141, 229 Algorithms, 229, 235 Alimentary, 118, 133, 229, 234, 263, 275 Alkaline, 47, 229, 230, 237, 277 Alkaloid, 229, 233, 285 Alleles, 13, 154, 161, 173, 190, 229, 259, 265 Allergic Rhinitis, 229, 237
Alpha 1-Antitrypsin, 130, 229 Alpha Particles, 229, 283 Alpha-1, 186, 190, 229, 277 Alpha-Defensins, 229, 246 Alpha-fetoprotein, 129, 229, 253 Alpha-helix, 229, 264 Alternative medicine, 229 Alveoli, 49, 229, 297 Ambulatory Care, 229 Amino Acid Sequence, 21, 230, 231, 255 Ammonia, 230, 257, 292, 296 Amnion, 230 Amniotic Fluid, 199, 201, 230, 267 Amplification, 48, 230 Amylase, 114, 230, 275 Anaerobic, 60, 230 Anaesthesia, 230, 261 Anal, 230, 266 Analgesic, 27, 230 Analog, 12, 40, 230, 263, 269 Analogous, 230, 294 Anatomical, 230, 240, 247, 250, 261, 286 Anemia, 185, 186, 189, 190, 195, 230 Anesthesia, 229, 230 Aneuploidy, 184, 230 Aneurysm, 230, 296 Animal model, 12, 15, 28, 31, 32, 34, 49, 52, 146, 152, 153, 230 Anionic, 24, 231 Anions, 21, 24, 44, 231, 263 Annealing, 231, 279 Anode, 231 Antagonism, 15, 231 Antibacterial, 24, 231, 289 Antibiotic, 14, 32, 54, 57, 61, 74, 76, 89, 103, 132, 231, 233, 236, 242, 251, 271, 276, 289, 293 Antibodies, 33, 90, 178, 231, 233, 258, 261, 278, 280 Antibody, 18, 33, 76, 120, 178, 228, 231, 242, 258, 259, 261, 268, 270, 283, 289 Anticoagulant, 231, 282 Antiemetic, 231, 232, 269 Antigen, 35, 228, 231, 243, 246, 259, 261, 268, 280 Antigen-presenting cell, 231, 246 Antihypertensive, 231, 285 Anti-infective, 28, 231, 240, 260, 288
300
Cystic Fibrosis
Anti-inflammatory, 15, 19, 27, 30, 39, 71, 82, 231, 237, 256 Antimicrobial, 24, 37, 49, 53, 60, 61, 70, 83, 99, 231, 246 Antineoplastic, 231, 236, 256 Antioxidant, 49, 132, 231, 274 Antipsychotic, 231, 285 Antiviral, 227, 232, 262 Anuria, 232, 264 Anus, 230, 232, 236, 242, 263 Aorta, 119, 232, 284, 297 Apnea, 232 Apolipoproteins, 232, 266 Apoptosis, 18, 34, 35, 37, 39, 40, 172, 181, 232 Aquaporins, 91, 232 Aqueous, 232, 234, 245, 249, 260, 265 Arachidonic Acid, 232, 281 Archaea, 232, 269 Arginine, 12, 138, 232, 259, 272, 295 Arterial, 83, 232, 240, 260, 282, 292 Arteries, 232, 233, 236, 244, 266, 283 Arteriolar, 233, 236 Arterioles, 233, 236, 237, 269 Artery, 74, 230, 232, 233, 249, 275, 283, 286 Asbestos, 34, 233 Asbestosis, 233 Asparaginase, 50, 233 Aspartate, 233 Aspergillosis, 35, 71, 81, 233 Assay, 13, 26, 34, 42, 233 Asymptomatic, 233, 275 Atropine, 40, 233, 234 Atypical, 162, 194, 233 Audiometry, 70, 233 Autoantibodies, 73, 233 Autoantigens, 233 Autodigestion, 233, 275 Autogenic, 115, 117, 143, 144, 233 Autosuggestion, 233, 260 Azithromycin, 71, 95, 233 B Bacterial Infections, 3, 23, 61, 233, 239, 257, 285 Bacterial Physiology, 228, 233 Bacterial toxin, 18, 234 Bactericidal, 83, 234 Bacterium, 50, 57, 234 Bacteriuria, 234, 296 Basal cells, 11, 234
Base, 9, 20, 41, 154, 171, 172, 175, 177, 181, 182, 183, 206, 228, 234, 245, 246, 252, 253, 254, 255, 264, 276, 277, 279, 292, 296 Base Sequence, 182, 234, 254, 255 Basophils, 234, 257 Belladonna, 233, 234 Benign, 58, 234, 271 Beta-Defensins, 234, 246 Beta-glucans, 234, 239 Beta-Thromboglobulin, 234, 263 Bewilderment, 234, 243 Bezoars, 89, 234 Bilateral, 8, 100, 105, 162, 234 Bile, 20, 47, 120, 123, 225, 234, 235, 240, 254, 259, 266, 267, 287, 290, 292, 296 Bile Acids, 234, 290, 292 Bile Acids and Salts, 234 Bile duct, 120, 235, 240 Bile Pigments, 235, 267 Biliary, 46, 73, 235, 259, 275 Biliary Tract, 235, 275 Bilirubin, 47, 235 Binding Sites, 113, 235 Bioavailability, 53, 116, 235 Bioavailable, 41, 52, 235 Biofilms, 14, 29, 57, 62, 69, 88, 89, 235 Biogenesis, 15, 26, 27, 32, 34, 65, 235 Biological response modifier, 235, 262 Biomarkers, 43, 48, 73, 235 Biophysics, 11, 59, 66, 235 Biosynthesis, 34, 57, 106, 232, 235, 282, 287 Biotechnology, 5, 68, 164, 177, 204, 206, 211, 235 Biotransformation, 235 Bladder, 236, 281, 296 Blast phase, 236, 241 Blastocyst, 236, 243 Bleomycin, 36, 236 Blood Coagulation, 236, 237, 293 Blood Glucose, 236, 258, 262 Blood pressure, 189, 231, 236, 238, 260, 270, 279, 283, 289 Blood vessel, 193, 236, 238, 239, 240, 250, 266, 268, 276, 288, 289, 290, 291, 293, 296 Blot, 31, 236 Body Composition, 74, 236 Body Fluids, 235, 236, 248, 273, 289, 295 Bone Marrow, 34, 205, 227, 236, 241, 255, 267, 289, 291 Bone scan, 236, 286 Boron, 236, 244
Index 301
Bowel, 94, 225, 230, 236, 247, 262, 263, 290, 291, 295 Bowel Movement, 236, 247, 290, 291 Bradykinin, 122, 236, 264, 272 Broad-spectrum, 236, 293 Bromelain, 153, 236 Bronchi, 237, 251, 263, 294 Bronchial, 40, 47, 66, 74, 80, 92, 130, 237, 259 Bronchiectasis, 36, 43, 96, 98, 155, 156, 237 Bronchiole, 26, 237 Bronchitis, 18, 47, 120, 165, 166, 237, 241 Bronchoalveolar Lavage, 14, 237 Bronchoalveolar Lavage Fluid, 14, 237 Bronchodilator, 90, 237, 263 Bronchopulmonary, 35, 71, 81, 130, 237 Buccal, 199, 201, 237 Budesonide, 47, 237 C Calcium, 40, 115, 141, 233, 237, 242, 255, 267, 282, 288 Capillary, 236, 237, 297 Capillary Permeability, 236, 237 Capsules, 237, 250 Carbohydrate, 16, 31, 130, 237, 256, 257, 279 Carcinogenic, 237, 262, 274, 281, 290 Carcinoma, 18, 105, 237 Cardiac, 42, 83, 144, 237, 249, 251, 290 Cardiovascular, 40, 48, 56, 64, 208, 238, 252, 287 Cardiovascular disease, 64, 208, 238 Cardiovascular System, 40, 238 Carnitine, 134, 238 Carotene, 116, 124, 125, 134, 135, 142, 143, 238 Carotenoids, 144, 238 Case report, 79, 83, 131, 142, 238, 241 Case series, 80, 238, 241 Catecholamine, 238, 248, 277 Cathode, 231, 238, 249 Cations, 21, 238, 263 Cause of Death, 47, 57, 61, 238, 246 Caveolae, 16, 238 Caveolins, 238, 242 CD-ROM, 73, 158, 238 Cell Cycle, 18, 180, 181, 238 Cell Death, 24, 35, 38, 40, 181, 232, 238, 271 Cell Differentiation, 33, 239, 288 Cell Division, 173, 180, 181, 193, 194, 233, 238, 239, 245, 268, 269, 278, 281 Cell Fusion, 34, 239
Cell membrane, 8, 9, 33, 238, 239, 240, 242, 246, 252, 263, 268, 277 Cell Membrane Structures, 238, 239 Cell Polarity, 33, 59, 239 Cell proliferation, 48, 239, 288 Cell Respiration, 239, 269, 285 Cell Survival, 40, 239, 258 Cellular metabolism, 53, 239 Cellulase, 153, 239 Centromere, 173, 176, 239 Cerebral, 239, 251, 252 Cerebral Cortex, 239, 252 Cerebrovascular, 238, 239 Cervix, 239, 285 Chaperonins, 239, 270 Chemical Warfare, 239, 240, 246 Chemical Warfare Agents, 240, 246 Chemokines, 11, 16, 64, 240 Chemotherapy, 30, 56, 70, 99, 240 Chenodeoxycholic Acid, 240, 296 Chest wall, 81, 97, 240 Chimeras, 18, 240 Chimeric Proteins, 18, 240 Chin, 240, 268 Chlorhexidine, 109, 240 Chloride Channels, 21, 44, 145, 152, 240 Chlorophyll, 240, 254 Cholangitis, 47, 240 Choleretic, 240, 296 Cholesterol, 118, 172, 234, 238, 240, 241, 244, 266, 268, 290 Cholesterol Esters, 240, 266 Cholic Acid, 47, 240 Choline, 83, 240 Cholinergic, 41, 232, 240 Chromatin, 232, 240, 251, 267, 289 Chromosomal, 181, 183, 184, 194, 195, 196, 198, 230, 240, 259, 270, 278, 286 Chromosome Fragility, 241, 295 Chronic Disease, 65, 241, 265 Chronic myelogenous leukemia, 236, 241 Chronic Obstructive Pulmonary Disease, 11, 47, 152, 153, 157, 165, 241 Chronic phase, 12, 241 Chronic renal, 241, 279, 296 Chylomicrons, 241, 266 Chymotrypsin, 153, 225, 241 Ciliary, 33, 241, 270 Ciliated cells, 11, 241 Cirrhosis, 46, 95, 241, 258, 280 CIS, 241, 255 Clamp, 56, 59, 60, 241
302
Cystic Fibrosis
Clathrin, 241, 242, 250 Clinical Medicine, 35, 207, 241, 280 Clinical study, 241, 244 Clinical trial, 10, 26, 28, 30, 44, 122, 141, 204, 205, 208, 211, 241, 244, 248, 276, 282, 284 Cloning, 31, 235, 242, 265 Coated Vesicles, 241, 242, 250 Codon, 178, 242, 255 Coenzyme, 78, 242 Cofactor, 242, 282, 293 Colistin, 80, 242 Colitis, 59, 242 Collagen, 11, 237, 242, 252, 253, 267, 278, 281 Collapse, 242, 288 Colloidal, 242, 249, 276 Colon, 64, 187, 242, 262, 264, 295 Colonopathy, 84, 85, 129, 160, 242 Colonoscopy, 189, 242 Complement, 242, 243, 255, 264 Complementary and alternative medicine, 112, 150, 243 Complementary medicine, 112, 243 Complementation, 126, 243 Computational Biology, 211, 243 Computed tomography, 43, 75, 89, 94, 107, 110, 243, 286 Computerized axial tomography, 243, 286 Computerized tomography, 55, 243 Concentric, 243, 273 Conception, 180, 243, 253, 289, 290 Concomitant, 64, 243 Conduction, 233, 243 Confusion, 187, 243, 248, 296 Congestive heart failure, 58, 244 Conjugated, 234, 240, 244, 245 Connective Tissue, 236, 242, 244, 246, 253, 254, 268, 271, 291 Consciousness, 230, 244, 246, 248 Constriction, 173, 176, 244, 286, 297 Consultation, 195, 196, 199, 200, 244 Contraindications, ii, 244 Controlled clinical trial, 25, 244 Controlled study, 116, 138, 244 Coordination, 66, 244 Coronary, 238, 244 Coronary heart disease, 238, 244 Corpuscle, 244, 251 Creatine, 124, 244 Creatinine, 244, 264, 296 Crowding, 51, 244
Cryptosporidiosis, 233, 244 Cues, 58, 244 Curative, 244, 293 Curcumin, 117, 118, 119, 142, 244 Cutaneous, 40, 245 Cyanide, 100, 245 Cyclic, 14, 127, 242, 245, 257, 272, 281, 287 Cysteine, 109, 227, 240, 245, 246, 291 Cystine, 245 Cytochrome, 245, 274, 285 Cytochrome b, 245, 285 Cytogenetics, 245, 286 Cytokine, 16, 36, 38, 40, 92, 93, 245, 262 Cytomegalovirus, 94, 245 Cytoplasm, 27, 170, 171, 172, 178, 232, 234, 239, 245, 251, 252, 257, 267, 273, 286, 296 Cytosine, 171, 245, 283 Cytoskeletal Proteins, 23, 33, 241, 245 Cytoskeleton, 17, 20, 58, 245 Cytotoxic, 245, 288 Cytotoxicity, 39, 245 D Data Collection, 56, 245 De novo, 78, 181, 246 Death Certificates, 189, 246 Decontamination, 109, 246 Defense Mechanisms, 40, 246 Defensins, 24, 229, 234, 246 Degenerative, 246, 271 Dehydration, 69, 91, 246 Deletion, 9, 27, 31, 45, 69, 154, 162, 183, 232, 246 Dementia, 184, 232, 246 Denaturation, 246, 279 Dendrites, 246, 272 Dendritic, 36, 246 Dendritic cell, 36, 246 Deoxyribonucleic, 171, 246, 286 Deoxyribonucleic acid, 171, 246, 286 Deoxyribonucleotides, 246 Depolarization, 246, 288 Dermis, 246, 292 Desmosine, 43, 246 Detergents, 242, 246, 253 Detoxification, 48, 61, 247 Deuterium, 52, 247, 260 Developing Countries, 35, 247 Diabetes Mellitus, 73, 92, 247, 256, 258 Diagnostic procedure, 151, 247 Diarrhea, 4, 35, 45, 56, 59, 219, 223, 244, 247 Diastolic, 247, 260
Index 303
Dietary Fats, 247, 265 Diffusion, 237, 247, 261, 263 Digestion, 4, 154, 229, 234, 236, 247, 263, 265, 266, 275, 276, 291 Digestive system, 3, 8, 154, 219, 247 Digestive tract, 247, 288, 290 Dilatation, Pathologic, 247, 296 Dilation, 236, 247, 296 Dimerization, 43, 247 Diphtheria, 67, 247 Diploid, 230, 243, 247, 270, 278, 295 Direct, iii, 11, 19, 26, 27, 36, 44, 50, 54, 60, 153, 199, 200, 201, 239, 241, 247, 248, 284, 292 Directed Molecular Evolution, 24, 247 Discrete, 247, 282 Discrimination, 201, 202, 207, 247, 297 Disease Progression, 43, 248 Disorientation, 243, 248 Dissociation, 228, 248, 263 Distal, 47, 64, 157, 225, 248, 249, 282 Distention, 222, 248 DNA Topoisomerase, 248, 256 Dopamine, 232, 248, 269, 272, 277 Double-blind, 25, 103, 123, 248 Drive, 11, 13, 14, 27, 39, 248, 263 Drug Monitoring, 96, 248 Drug Resistance, 20, 62, 248 Drug Tolerance, 248, 293 Duct, 25, 46, 64, 105, 116, 248, 252, 286, 292, 296 Duodenum, 234, 241, 249, 254, 275, 276, 287, 291 Dyspnea, 223, 249, 283 Dystrophy, 80, 249 E Edema, 249, 271, 296 Effector, 12, 64, 227, 242, 249 Efficacy, 18, 28, 47, 51, 61, 249 Effusion, 42, 249 Ejaculation, 249, 287 Elastic, 81, 249, 292 Elasticity, 24, 249 Elastin, 43, 242, 246, 249, 252, 263 Electrode, 41, 165, 231, 238, 249 Electrolysis, 231, 238, 249 Electrolyte, 35, 45, 46, 249, 264, 273, 280, 289, 296 Electrons, 231, 234, 238, 249, 263, 274, 283 Electrophoresis, 91, 249, 261 Emboli, 74, 249 Embolization, 74, 249
Embryo, 180, 181, 182, 190, 230, 236, 239, 249, 261, 273 Emollient, 249, 257 Emphysema, 34, 161, 229, 241, 249 Empirical, 55, 249 Emulsion, 147, 249 Enamel, 250, 264 Endocytosis, 64, 238, 250 Endogenous, 11, 24, 40, 53, 60, 233, 248, 250, 294 Endosomes, 17, 250 Endothelial cell, 250, 263, 293 Endothelium, 131, 250, 272 Endothelium, Lymphatic, 250 Endothelium, Vascular, 250 Endothelium-derived, 250, 272 Endotoxic, 250, 265 Endotoxin, 11, 250 End-stage renal, 241, 250, 279 Energetic, 43, 56, 250 Energy balance, 82, 250, 265 Energy Intake, 72, 82, 102, 250 Enteric-coated, 71, 82, 250 Enterohepatic, 47, 250 Enteropeptidase, 250, 295 Environmental Health, 210, 211, 250 Enzymatic, 40, 147, 154, 237, 238, 243, 251, 259, 268, 279 Eosinophils, 64, 251, 257 Epidemic, 61, 67, 79, 108, 251, 290 Epidermal, 33, 47, 251, 264 Epidermal Growth Factor, 33, 47, 251 Epidermal growth factor receptor, 33, 47, 251 Epidermis, 234, 246, 251, 264 Epidermoid carcinoma, 251, 290 Epigastric, 251, 275 Epinephrine, 228, 248, 251, 263, 272, 295 Epithelial, 14, 15, 16, 17, 18, 19, 20, 24, 25, 33, 34, 38, 39, 40, 42, 44, 45, 46, 47, 48, 53, 58, 59, 60, 61, 64, 66, 71, 78, 80, 92, 93, 105, 108, 111, 113, 118, 120, 126, 130, 152, 155, 156, 163, 234, 241, 251, 257, 259 Epithelium, 11, 16, 19, 24, 25, 40, 47, 58, 59, 61, 94, 113, 114, 250, 251, 263 Erythrocyte Membrane, 159, 251 Erythrocytes, 230, 236, 251, 258 Erythromycin, 233, 251 Esophagus, 247, 251, 276, 277, 284, 291 Ethnic Groups, 4, 195, 198, 252 Eukaryotic Cells, 245, 252, 261, 274, 295 Evacuation, 252, 254, 275
304
Cystic Fibrosis
Evoke, 60, 252, 291 Excipients, 153, 252 Excrete, 232, 252, 264 Exercise Test, 252 Exercise Tolerance, 81, 132, 252 Exhaustion, 231, 252 Exocrine, 84, 147, 154, 156, 252, 275 Exocytosis, 40, 61, 252 Exogenous, 235, 250, 252, 255 Exons, 162, 252 Extracellular, 40, 53, 60, 64, 103, 235, 244, 250, 252, 253, 267, 269, 289 Extracellular Matrix, 244, 252, 253, 267 Extracellular Matrix Proteins, 252, 267 Extracellular Space, 252, 269 Eye Color, 182, 253 Eye Infections, 228, 253 F Facial, 253, 275 Facial Nerve, 253, 275 Faecal, 84, 127, 253 Fallopian tube, 253, 285 Family Planning, 211, 253 Famotidine, 147, 253 Fathers, 190, 253 Fatigue, 223, 253, 258 Fatty acids, 119, 128, 129, 253, 257, 267, 281, 288 Feces, 253, 291 Ferritin, 38, 178, 253 Fetoprotein, 253 Fetus, 94, 198, 199, 201, 205, 229, 253, 254, 261, 267, 280, 290, 296 Feverfew, 27, 253 Fibroblasts, 31, 253, 263 Fish Oils, 138, 253 Flagellin, 14, 16, 253 Flagellum, 106, 254 Flatus, 254 Fluorescence, 24, 31, 44, 51, 85, 254 Flutter, 144, 254 Foetoplacental, 254, 273 Fold, 16, 23, 33, 60, 133, 254 Forearm, 41, 236, 254 Founder Effect, 161, 254 Frameshift, 183, 254 Frameshift Mutation, 183, 254 Free Radicals, 40, 231, 248, 254 Fungus, 35, 63, 254 G Gallbladder, 227, 235, 247, 254 Ganglia, 227, 232, 254, 272
Gas, 101, 230, 247, 254, 260, 272, 283, 285, 297 Gas exchange, 254, 285, 297 Gastric, 78, 89, 233, 234, 238, 251, 253, 254, 255, 259, 269, 276 Gastric Acid, 254, 269 Gastric Emptying, 78, 254 Gastric Juices, 255, 276 Gastrin, 255, 259 Gastrointestinal, 59, 154, 233, 236, 251, 255, 287, 290, 291, 295 Gastrointestinal Neoplasms, 233, 255 Gastrointestinal tract, 154, 255, 287, 290, 295 Gastrostomy, 95, 137, 255 Gelsolin, 24, 255 Gene Expression, 11, 25, 36, 48, 65, 178, 179, 255 Gene Pool, 12, 254, 255 Gene Products, rev, 255 Gene Targeting, 31, 255 Gene Therapy, 11, 24, 30, 49, 70, 77, 86, 87, 94, 114, 122, 130, 203, 204, 205, 206, 228, 255 Genes, env, 189, 255 Genetic Code, 154, 255, 273 Genetic Engineering, 235, 242, 255 Genetic testing, 19, 161, 192, 196, 197, 198, 199, 200, 201, 202, 207, 256, 279 Genetics, 3, 5, 6, 7, 8, 9, 12, 27, 30, 44, 54, 60, 67, 68, 70, 88, 170, 177, 181, 182, 183, 185, 187, 188, 192, 195, 196, 197, 202, 205, 206, 207, 221, 245, 256, 276 Genistein, 112, 113, 119, 120, 130, 133, 144, 145, 147, 256 Genital, 8, 9, 256 Genomics, 35, 39, 208, 256 Genotype, 10, 37, 75, 80, 87, 98, 126, 256, 277 Germ Cells, 181, 205, 256, 268, 274, 289, 293 Germline mutation, 51, 181, 256, 259 Gestation, 256, 276 Ginseng, 32, 150, 256 Gland, 26, 46, 92, 130, 154, 166, 228, 256, 275, 281, 287, 291, 292, 293 Glomerular, 256, 264, 285 Glucocorticoid, 237, 256 Glucose, 23, 62, 236, 247, 256, 257, 258, 262, 277, 284 Glucose Intolerance, 247, 256 Glucose tolerance, 23, 256
Index 305
Glucose Tolerance Test, 256 Glutamate, 44, 109, 257 Glutamic Acid, 257, 272, 281 Glutamine, 98, 257 Glutathione Peroxidase, 257, 287 Glycerol, 155, 232, 257, 277 Glycerophospholipids, 257, 277 Glycine, 146, 234, 240, 257, 272, 287 Glycogen, 257, 277 Glycoprotein, 14, 56, 154, 229, 257, 270, 293 Glycoside, 257, 260 Glycosidic, 257, 277 Glycosylation, 16, 30, 257 Goblet Cells, 153, 257 Governing Board, 257, 280 Gram-negative, 37, 50, 62, 163, 250, 257, 279, 282, 293 Granule, 257, 286 Granulocytes, 138, 257, 265, 288, 298 Granulomatous Disease, Chronic, 257, 285 Guanine, 171, 257, 283 Guanylate Cyclase, 257, 272 H Habitat, 258, 272 Haematological, 77, 258 Haematology, 77, 258 Hair Color, 182, 258 Half-Life, 17, 258 Haptens, 228, 258 Heart attack, 238, 258 Heart failure, 258, 283 Heat-Shock Proteins, 258, 270 Heat-Shock Proteins 90, 258, 270 Hematopoietic Stem Cells, 42, 258 Hematopoietic tissue, 42, 236, 258 Hemochromatosis, 198, 258 Hemodialysis, 258, 264 Hemoglobin, 172, 230, 251, 258 Hemoglobinopathies, 255, 258 Hemolysis, 251, 258 Hemophilia, 190, 258 Hemorrhage, 109, 258, 291 Hepatic, 47, 155, 256, 259, 266 Hepatobiliary, 47, 259 Hepatocytes, 20, 259 Hereditary, 64, 156, 170, 171, 181, 190, 196, 219, 229, 256, 258, 259, 276, 285 Hereditary mutation, 181, 256, 259 Heredity, 173, 227, 255, 256, 259 Herpes, 18, 29, 79, 259 Herpes virus, 29, 259
Herpes Zoster, 259 Heterodimers, 43, 259 Heterogeneity, 89, 141, 161, 228, 259 Heterozygote, 165, 259 Heterozygote Detection, 165, 259 Histamine, 232, 253, 259 Histology, 47, 259 Histones, 173, 240, 259 Homeostasis, 33, 46, 48, 49, 64, 115, 259 Homologous, 31, 229, 255, 259, 292 Hormone, 4, 71, 88, 136, 157, 178, 251, 255, 259, 262, 265, 268, 286, 287, 288, 293 Hybrid, 13, 18, 259 Hybridization, 12, 31, 48, 50, 108, 239, 259 Hydration, 22, 259 Hydrogen, 49, 52, 60, 132, 227, 234, 237, 246, 247, 252, 257, 259, 260, 265, 270, 272, 273, 274, 282 Hydrogen Peroxide, 49, 60, 257, 260, 265 Hydrolases, 155, 260, 277 Hydrolysis, 42, 44, 45, 62, 152, 235, 260, 263, 276, 277, 279, 282, 295 Hydrophobic, 247, 257, 260, 266 Hydroxylysine, 242, 260 Hydroxyproline, 242, 260 Hyperglycemia, 23, 260 Hyperplasia, 64, 260, 271 Hypertension, 30, 48, 61, 64, 238, 260, 279, 296 Hypertension, Renal, 64, 260 Hypertension, Renovascular, 260 Hyperthermia, 40, 258, 260 Hypertrophy, 11, 260 I Iatrogenic, 55, 260 Idiopathic, 9, 36, 51, 63, 260 Ileal, 47, 260 Ileum, 260 Ileus, 4, 137, 260 Immune response, 16, 32, 36, 57, 64, 65, 162, 231, 233, 258, 260, 261, 291, 297 Immune system, 36, 53, 231, 234, 260, 261, 267, 276, 296, 297 Immune Tolerance, 36, 261 Immunity, 15, 29, 33, 36, 37, 53, 83, 246, 261, 274 Immunodiffusion, 261 Immunoelectrophoresis, 165, 261 Immunogenic, 261, 265 Immunologic, 30, 261 Immunology, 33, 71, 72, 106, 125, 161, 228, 261
306
Cystic Fibrosis
Impairment, 43, 114, 234, 253, 261, 263, 268 Implantation, 243, 261, 273 In situ, 85, 261 In Situ Hybridization, 85, 261 Incision, 261, 263 Incubation, 155, 261, 265 Incubation period, 261, 265 Induction, 36, 139, 232, 261 Infancy, 55, 208, 261 Infertility, 4, 10, 152, 156, 262 Inflammatory bowel disease, 59, 262 Informed Consent, 199, 202, 207, 262 Ingestion, 19, 256, 262 Inhalation, 161, 163, 228, 233, 262 Initiation, 55, 262, 287, 294 Inorganic, 228, 262, 271, 288, 291 Inositol, 52, 262, 287 Inpatients, 39, 262 Insight, 21, 25, 53, 59, 111, 262 Insulin, 4, 23, 163, 256, 262 Insulin-dependent diabetes mellitus, 262 Interferon, 103, 262, 267 Interferon-alpha, 262 Interleukin-8, 40, 80, 92, 93, 262 Interstitial, 49, 76, 237, 252, 263, 285 Intestinal, 35, 47, 59, 103, 128, 133, 229, 238, 240, 244, 250, 256, 263, 267 Intestinal Obstruction, 103, 263 Intestine, 4, 128, 234, 236, 250, 263, 264 Intracellular Membranes, 263, 268 Intravenous, 70, 74, 89, 93, 99, 147, 263, 275 Intrinsic, 155, 228, 232, 263 Invasive, 49, 136, 261, 263, 267 Involuntary, 263, 284, 293 Ion Channels, 16, 33, 52, 59, 263 Ion Transport, 17, 63, 139, 140, 153, 263 Ionization, 11, 58, 131, 263 Ions, 4, 8, 9, 93, 152, 157, 234, 240, 248, 249, 255, 260, 263, 279 Iris, 253, 263 Isodesmosine, 43, 263 Isoproterenol, 147, 263 Isotretinoin, 92, 263 K Kallidin, 236, 264 Karyotype, 175, 264 Keratin, 142, 264 Keratinocytes, 263, 264 Kidney Disease, 72, 210, 264 Kidney Failure, 42, 184, 250, 264
Kidney Failure, Acute, 264 Kidney Failure, Chronic, 264 Kinetic, 21, 22, 52, 264 L Lactation, 264, 273 Lactoperoxidase, 57, 264 Lag, 160, 219, 264 Large Intestine, 247, 263, 264, 284, 288 Larynx, 264, 294, 297 Latent, 265, 280 Lectin, 72, 106, 265, 268 Lens, 232, 265 Lentivirus, 52, 94, 265 Leptin, 104, 265 Lesion, 265, 266, 295 Lethal, 17, 26, 41, 52, 55, 56, 153, 154, 156, 234, 245, 265 Leucocyte, 229, 265, 267 Leukaemia, 113, 265 Leukemia, 67, 241, 255, 265 Life Expectancy, 43, 56, 156, 265 Ligands, 16, 24, 36, 157, 265 Ligase, 109, 265 Linkage, 69, 89, 265 Linkage Disequilibrium, 89, 265 Lipase, 84, 118, 150, 265, 275 Lipid A, 123, 265 Lipid Peroxidation, 123, 124, 144, 265, 274 Lipopolysaccharide, 16, 37, 53, 147, 257, 266 Lipoprotein, 128, 132, 257, 266 Liver cancer, 229, 266 Liver Cirrhosis, 73, 149, 266 Liver scan, 266, 286 Liver Transplantation, 73, 109, 266 Localization, 13, 18, 33, 59, 266 Localized, 22, 33, 58, 247, 261, 266, 278, 295 Locomotion, 254, 266, 278 Longitudinal Studies, 50, 266 Longitudinal study, 82, 266 Loop, 60, 266 Low-density lipoprotein, 266 Luciferase, 39, 266 Lung Transplantation, 47, 55, 77, 78, 80, 86, 89, 92, 97, 100, 105, 134, 218, 266 Lymph, 244, 250, 267, 291 Lymphatic, 250, 262, 267, 268, 289 Lymphoblastic, 113, 267 Lymphoblasts, 227, 267 Lymphocytes, 33, 101, 231, 246, 262, 265, 267, 289, 298
Index 307
Lymphocytic, 241, 267 Lymphoid, 161, 231, 265, 267 Lymphoma, 267 Lysine, 41, 246, 259, 260, 263, 267, 295 M Macrolides, 71, 267 Macrophage, 34, 38, 181, 267 Magnetic Resonance Imaging, 102, 267, 286 Malabsorption, 47, 82, 122, 123, 128, 149, 168, 267 Malignant, 58, 231, 266, 267, 271 Malnutrition, 4, 55, 267 Mammography, 189, 267 Mannans, 254, 267 Matrix metalloproteinase, 43, 267 Meat, 237, 247, 267 Meconium, 4, 137, 225, 267 Mediate, 34, 40, 44, 59, 94, 119, 248, 267, 270 Mediator, 19, 20, 267, 278, 287 Medical Records, 189, 202, 268 MEDLINE, 211, 268 Meiosis, 180, 268, 292 Melanin, 263, 268, 277, 295 Melanoma, 268, 295 Membrane Glycoproteins, 268 Membrane Lipids, 268, 277 Membrane Microdomains, 20, 268 Membrane Proteins, 20, 22, 27, 31, 56, 238, 268 Memory, 246, 268 Menopause, 268, 273 Menstrual Cycle, 268, 273 Mental Health, iv, 10, 210, 212, 268, 283 Mental Retardation, 194, 196, 198, 268 Mentors, 44, 268 Mesenchymal, 34, 251, 268 Meta-Analysis, 88, 268 Metabolite, 235, 269, 281 Metaplasia, 153, 269 Metastasis, 267, 269, 271 Metoclopramide, 69, 269 Microbe, 269, 294 Microbiological, 37, 66, 269 Microcirculation, 266, 269 Microdialysis, 41, 269 Micronutrients, 121, 269 Microorganism, 242, 269, 275, 297 Microscopy, 24, 29, 47, 269 Millimeter, 66, 269 Miscarriage, 201, 269
Misoprostol, 123, 269 Mitochondria, 171, 172, 184, 190, 191, 239, 269, 274 Mitochondrial Swelling, 269, 271 Mitosis, 180, 232, 269 Modeling, 56, 269 Models, Animal, 49, 270 Modification, 13, 38, 93, 122, 255, 270, 283 Molecular Chaperones, 26, 239, 258, 270 Monitor, 41, 49, 59, 244, 270, 273 Monoclonal, 18, 270, 283 Monocyte, 36, 64, 270 Monosomy, 184, 230, 270 Morphological, 249, 254, 270 Morphology, 33, 232, 258, 270 Mosaicism, 181, 270 Motility, 255, 270, 287 Mucilaginous, 267, 270 Mucins, 257, 270, 286 Mucociliary, 33, 270, 288 Mucociliary Clearance, 33, 270 Mucolytic, 227, 237, 270 Mucosa, 270, 291 Mucus, 3, 4, 8, 9, 14, 23, 26, 60, 66, 135, 152, 153, 154, 163, 270, 295 Multidrug resistance, 42, 56, 139, 271 Music Therapy, 116, 271 Mutagenesis, 32, 62, 271 Mutagens, 254, 271 Mycobacterial disease, 76, 271 Myocarditis, 247, 271 Myotonic Dystrophy, 193, 271, 295 N Nasal Mucosa, 271 Nasal Polyps, 108, 271 Natural selection, 235, 271 NCI, 1, 209, 241, 271, 276 Nebramycin, 271, 293 Necrosis, 35, 40, 232, 271 Neonatal, 29, 30, 55, 74, 84, 97, 106, 137, 161, 271 Neonatal Screening, 55, 84, 106, 137, 161, 271 Neoplasms, 231, 271 Nephron, 64, 271 Nephropathy, 264, 271 Nervous System, 193, 227, 228, 234, 254, 257, 268, 271, 272, 287, 291, 292 Neural, 40, 228, 253, 272 Neuromuscular, 227, 272, 296 Neuromuscular Junction, 227, 272 Neuronal, 41, 272
308
Cystic Fibrosis
Neurons, 246, 254, 272, 292 Neuropathy, 190, 272 Neurotransmitter, 227, 228, 236, 248, 257, 259, 263, 272, 286, 288, 291 Neutrons, 229, 272, 283 Neutrophil, 39, 43, 47, 58, 82, 98, 125, 135, 138, 229, 272 Niche, 39, 272 Nitric Oxide, 40, 129, 132, 272 Nitrogen, 228, 229, 252, 257, 264, 272, 275, 295 Norepinephrine, 228, 248, 272, 285 Nosocomial, 28, 272 Nuclear, 18, 31, 39, 58, 141, 171, 249, 252, 255, 271, 272, 273 Nuclear Envelope, 171, 273 Nuclear Pore, 273 Nuclei, 31, 229, 249, 252, 255, 256, 259, 267, 269, 272, 273, 282 Nucleic acid, 234, 245, 255, 259, 261, 271, 272, 273, 283, 286 Nucleic Acid Hybridization, 259, 273 Nucleotidases, 260, 273 Nurse Practitioners, 199, 273 Nursing Care, 105, 273 Nutritional Status, 76, 80, 84, 104, 122, 127, 139, 142, 273 Nutritional Support, 255, 273 O Oculogyric, 69, 273 Odds Ratio, 273, 284 Oestrogen, 147, 273 Oliguria, 264, 274 Omega-3 fatty acid, 122, 133, 138, 145, 147, 274 Oncogenic, 265, 274 Oocytes, 31, 43, 130, 274 Open Reading Frames, 265, 274 Operon, 274, 285 Orderly, 18, 274 Organ Culture, 274, 293 Organelles, 170, 171, 241, 245, 274, 278 Oropharynx, 25, 274 Osteoporosis, 115, 273, 274 Outpatient, 274 Ovaries, 198, 274, 285, 287 Ovary, 273, 274, 291 Oxidation, 125, 132, 227, 231, 235, 245, 257, 265, 274 Oxidative Phosphorylation, 172, 274 Oxidative Stress, 34, 49, 57, 274 Oxygenation, 83, 274
Oxytocic, 269, 274 P Palliative, 55, 125, 155, 273, 275, 293 Pancreatic enzymes, 153, 275 Pancreatic Insufficiency, 138, 147, 148, 149, 153, 156, 275 Pancreatic Juice, 241, 275 Pancreatin, 118, 153, 275 Pancreatitis, 9, 50, 63, 152, 275 Pancrelipase, 71, 153, 275 Paranasal Sinuses, 275, 288 Parenteral, 123, 130, 250, 275 Parotid, 166, 275 Partnership Practice, 275, 280 Patch, 56, 59, 60, 68, 275 Paternity, 198, 275 Pathogen, 13, 14, 16, 18, 28, 37, 53, 57, 60, 61, 62, 65, 100, 261, 275 Pathologic, 33, 40, 67, 232, 244, 275 Pathologic Processes, 232, 275 Pathophysiology, 17, 31, 47, 51, 275 PDQ, 209, 276 Pelvis, 227, 274, 276, 296 Penicillin, 231, 276 Penis, 249, 276, 285 Pepsin, 269, 276, 287 Peptic, 142, 276 Peptic Ulcer, 142, 276 Peptide, 11, 37, 51, 100, 250, 260, 264, 265, 276, 279, 281, 282 Peptide Hydrolases, 260, 276 Perennial, 253, 276 Perfusion, 141, 276 Perinatal, 30, 74, 276 Peripheral blood, 36, 262, 276 Peroxidase, 58, 265, 276 Peroxide, 125, 132, 276 Perspiration, 68, 276 Petrolatum, 250, 276 Phagocyte, 18, 276 Phagocytosis, 19, 38, 276 Pharmaceutical Preparations, 153, 276 Pharmacodynamic, 253, 277 Pharmacokinetic, 277 Pharmacologic, 30, 106, 230, 258, 277, 294 Pharmacotherapy, 76, 106, 115, 140, 277 Pharynx, 274, 277 Phenolphthalein, 250, 277 Phenotype, 10, 11, 30, 33, 37, 38, 42, 44, 58, 87, 139, 243, 277 Phenylalanine, 154, 178, 277, 295 Phenylbutyrate, 113, 135, 277
Index 309
Phorbol, 277, 282 Phorbol Esters, 277, 282 Phospholipases, 16, 277, 288 Phospholipids, 34, 126, 128, 253, 262, 266, 268, 277, 282 Phosphoric Monoester Hydrolases, 260, 277 Phosphorus, 237, 277 Phosphorylase, 100, 277 Phosphorylated, 152, 242, 277 Phosphorylates, 277, 282 Phosphorylation, 42, 44, 45, 47, 65, 152, 172, 228, 277, 282 Photoreceptors, 277 Phylogeny, 59, 277 Physical Examination, 196, 278 Physical Therapy, 165, 278 Physiologic, 21, 44, 59, 64, 87, 229, 235, 258, 268, 269, 278, 281, 284 Pigment, 235, 268, 278 Pilot Projects, 44, 49, 278 Pilot study, 63, 68, 113, 124, 146, 278 Plants, 229, 233, 234, 240, 246, 256, 257, 265, 270, 272, 278, 279, 282, 294 Plaque, 240, 278 Plasma cells, 33, 231, 278 Plasmid, 39, 278, 296 Plastids, 239, 274, 278 Platelet Activation, 278, 288 Platelet Aggregation, 272, 278 Platelet Factor 4, 263, 278 Platelets, 234, 272, 278, 287 Pleated, 264, 279 Pneumonia, 14, 244, 279 Point Mutation, 12, 279 Polycystic, 72, 279 Polymerase, 65, 68, 279, 285, 287 Polymerase Chain Reaction, 68, 279 Polymers, 24, 47, 156, 235, 279, 282 Polymorphic, 89, 279 Polymorphism, 63, 91, 97, 108, 200, 279 Polyneuritis, 247, 279 Polyp, 126, 279 Polypeptide, 51, 230, 242, 251, 259, 279, 282, 298 Polyphosphates, 53, 279 Polyposis, 88, 279 Polysaccharide, 228, 231, 279 Polyunsaturated fat, 116, 121, 279 Polyvalent, 24, 279 Porins, 115, 279 Portal Hypertension, 46, 279
Portal Vein, 279, 280 Portosystemic Shunt, 100, 280 Posterior, 230, 263, 275, 280 Postnatal, 280, 290 Postsynaptic, 280, 288 Post-translational, 13, 280 Postural, 117, 135, 280 Potassium, 21, 126, 280, 288 Potentiates, 117, 280 Potentiation, 280, 288 Practice Guidelines, 212, 218, 280 Precipitation, 280 Precipitins, 165, 280 Preclinical, 53, 280 Precursor, 232, 240, 248, 249, 251, 272, 277, 280, 281, 295, 296 Predisposition, 50, 280 Prenatal, 19, 160, 163, 198, 201, 249, 280 Prenatal Care, 19, 280 Prevalence, 37, 46, 50, 73, 92, 101, 186, 273, 280 Private Practice, 19, 280 Probe, 43, 46, 269, 280 Prodrug, 89, 281 Progression, 14, 59, 101, 162, 230, 281 Progressive, 3, 37, 43, 65, 184, 239, 241, 246, 248, 264, 271, 278, 281, 283, 285 Projection, 246, 272, 281 Proline, 242, 260, 281 Promoter, 11, 28, 58, 97, 152, 281 Prone, 184, 193, 281 Prophase, 274, 281, 292 Prospective study, 266, 281 Prostaglandin, 59, 269, 281 Prostate, 235, 273, 281, 285, 295 Protease, 19, 30, 47, 60, 70, 101, 106, 124, 229, 275, 281, 282 Protease Inhibitors, 124, 282 Protein Conformation, 26, 230, 264, 282 Protein Folding, 27, 33, 52, 282 Protein-Tyrosine Kinase, 256, 282 Proteolytic, 43, 60, 229, 242, 250, 282 Protocol, 84, 204, 282 Protons, 229, 260, 282, 283 Protozoa, 269, 282 Proximal, 248, 282 Psychiatry, 282, 297 Psychic, 268, 282 Public Health, 32, 68, 168, 212, 282 Public Policy, 211, 283 Pulmonary, 11, 14, 15, 18, 23, 25, 30, 34, 36, 37, 39, 43, 46, 50, 53, 54, 55, 60, 61,
310
Cystic Fibrosis
64, 67, 72, 74, 76, 80, 81, 87, 89, 92, 93, 95, 96, 97, 98, 99, 101, 102, 107, 114, 129, 132, 134, 136, 142, 152, 153, 154, 155, 156, 161, 163, 218, 224, 229, 236, 237, 252, 264, 283, 285, 292, 297 Pulmonary Artery, 236, 283, 297 Pulmonary Edema, 264, 283 Pulmonary Fibrosis, 36, 218, 283 Pulmonary hypertension, 81, 283 Pulmonary Ventilation, 283, 285 Pulsation, 254, 283 Pulse, 52, 154, 270, 283 Purines, 234, 283, 287 Pyrimidines, 234, 283, 287 Q Quality of Life, 31, 50, 55, 56, 81, 94, 129, 283, 292 Quaternary, 282, 283 R Race, 264, 283 Radiation, 46, 227, 254, 260, 261, 283, 286, 295, 298 Radiation therapy, 227, 283 Radioactive, 236, 246, 258, 260, 261, 263, 266, 270, 273, 274, 283, 286 Radiolabeled, 53, 283 Radiology, 55, 74, 85, 90, 283 Randomized, 25, 55, 71, 88, 102, 103, 116, 122, 249, 284 Randomized clinical trial, 55, 102, 284 Reabsorption, 64, 284 Reactive Oxygen Species, 11, 58, 284 Reagent, 266, 284 Recessive gene, 55, 284 Recombinant, 18, 204, 284, 296 Recombination, 255, 284 Rectum, 232, 236, 242, 247, 254, 262, 264, 281, 284 Refer, 1, 176, 180, 182, 187, 206, 237, 242, 259, 266, 272, 284, 294 Reflex, 40, 284 Reflux, 86, 284 Refraction, 284, 289 Refractory, 81, 284 Regeneration, 30, 42, 284 Regimen, 53, 249, 277, 284 Relapse, 25, 51, 284 Relative risk, 48, 284 Renal Artery, 260, 284 Renal failure, 77, 103, 285 Repressor, 59, 274, 285
Reproductive cells, 184, 194, 195, 256, 259, 285 Reproductive system, 3, 8, 285 Reserpine, 146, 147, 285 Respiration, 129, 161, 232, 270, 285 Respiratory Burst, 60, 285 Respiratory failure, 23, 65, 285 Respiratory Physiology, 71, 82, 83, 113, 129, 132, 135, 138, 148, 285, 297 Respiratory System, 3, 14, 219, 229, 270, 285 Retina, 265, 285, 286 Retinoblastoma, 186, 285 Retinoids, 285, 297 Retinol, 125, 285 Retrograde, 127, 285 Retroviral vector, 255, 286 Rheology, 24, 66, 144, 286 Ribonuclease, 66, 286 Ribonucleic acid, 178, 286 Ribose, 228, 286 Ribosome, 51, 178, 286, 294 Risk factor, 55, 281, 284, 286 Rod, 234, 241, 282, 286 Role-play, 121, 286 S Saline, 90, 91, 92, 140, 163, 237, 286 Saliva, 8, 46, 67, 96, 286 Salivary, 46, 245, 247, 253, 286, 291 Salivary glands, 46, 245, 247, 253, 286 Satellite, 30, 286 Scans, 43, 286 Scatter, 286, 296 Schizophrenia, 191, 286 Scleroproteins, 264, 286 Sclerosis, 187, 286 Screening, 5, 6, 7, 49, 55, 67, 68, 69, 70, 72, 87, 91, 97, 98, 100, 110, 141, 152, 159, 160, 161, 162, 163, 165, 189, 198, 199, 201, 218, 241, 271, 276, 286, 296 Scrotum, 286, 296 Second Messenger Systems, 41, 286 Secretin, 157, 224, 287 Secretory, 25, 27, 43, 45, 46, 47, 56, 59, 229, 270, 287 Sediment, 287, 296 Selenium, 123, 287 Semen, 8, 9, 249, 281, 287 Seminal vesicles, 287, 296 Sepsis, 28, 48, 287 Sequencing, 31, 50, 206, 279, 287 Serine, 60, 70, 106, 152, 241, 282, 287, 295
Index 311
Serotonin, 232, 272, 277, 285, 287, 295 Serous, 156, 250, 287 Serum, 47, 74, 76, 104, 125, 131, 133, 139, 143, 145, 155, 242, 261, 264, 266, 287 Sex Characteristics, 273, 287 Shock, 239, 287, 295 Side effect, 25, 51, 59, 205, 208, 228, 232, 287, 292, 294 Sigma Factor, 54, 287 Signal Transduction, 15, 238, 258, 262, 288 Signs and Symptoms, 4, 137, 154, 192, 193, 198, 284, 288, 296 Silicon, 68, 288 Silicon Dioxide, 288 Silver Compounds, 61, 288 Sinusitis, 134, 159, 288 Skeletal, 34, 142, 241, 263, 288 Skeleton, 227, 281, 288 Skull, 288, 292 Sleep apnea, 99, 288 Small intestine, 156, 240, 241, 249, 259, 260, 263, 288, 295 Smooth muscle, 237, 259, 288, 291 Soaps, 253, 288 Social Environment, 283, 288 Social Work, 113, 195, 288 Sodium, 8, 15, 60, 64, 70, 105, 120, 126, 130, 152, 156, 165, 284, 288, 289, 292 Soft tissue, 236, 288, 289 Solid tumor, 236, 289 Solvent, 257, 289 Soma, 289 Somatic, 31, 181, 184, 195, 239, 268, 269, 289 Somatic cells, 181, 184, 195, 239, 268, 269, 289 Somatic mutations, 184, 289 Soybean Oil, 128, 279, 289 Specialist, 199, 220, 247, 289 Species, 13, 21, 52, 61, 108, 131, 208, 234, 251, 259, 264, 265, 268, 269, 270, 282, 283, 284, 289, 291, 293, 295, 297, 298 Specificity, 11, 62, 65, 68, 228, 289 Spectrum, 12, 44, 56, 244, 289 Sperm, 4, 8, 9, 180, 181, 184, 193, 194, 195, 198, 205, 240, 256, 259, 285, 289 Spermatozoa, 287, 289, 296 Spinal cord, 30, 240, 271, 272, 284, 289 Spleen, 245, 267, 289, 290 Splenectomy, 80, 100, 290 Splenomegaly, 100, 290 Sporadic, 285, 290
Sputa, 124, 290 Sputum, 24, 43, 81, 106, 108, 109, 144, 290 Squamous, 18, 251, 290 Squamous cell carcinoma, 18, 251, 290 Squamous cells, 290 Stabilization, 43, 290 Staging, 286, 290 Steatorrhea, 71, 290 Steatosis, 134, 290 Steel, 241, 290 Stem Cells, 15, 34, 42, 290 Stent, 107, 290 Sterility, 262, 290 Sterilization, 168, 290 Steroid, 234, 258, 273, 290 Stillbirth, 196, 290 Stimulant, 259, 263, 264, 290 Stimulus, 248, 249, 263, 264, 284, 291, 293 Stomach, 219, 227, 233, 247, 251, 254, 255, 256, 259, 276, 277, 284, 287, 288, 289, 291 Stool, 225, 242, 264, 290, 291 Strand, 91, 171, 279, 291 Stress, 40, 49, 54, 57, 223, 238, 239, 274, 280, 291 Stroke, 30, 189, 210, 238, 291 Stromal, 34, 291 Stromal Cells, 34, 291 Structure-Activity Relationship, 120, 291 Subacute, 262, 288, 291 Subclinical, 262, 291 Submaxillary, 251, 291 Subspecies, 289, 291 Substrate, 26, 28, 58, 62, 65, 100, 260, 291 Substrate Specificity, 62, 100, 291 Sulfides, 74, 291 Sulfur, 252, 291 Superoxide, 285, 291 Support group, 129, 225, 226, 292 Supportive care, 276, 292 Suppression, 19, 24, 108, 292 Surfactant, 36, 292 Surrogate Mothers, 31, 292 Survival Rate, 51, 292 Sweat, 8, 25, 67, 98, 139, 141, 154, 156, 165, 166, 168, 218, 224, 246, 276, 292 Sweat Glands, 156, 246, 292 Sympathomimetic, 248, 251, 263, 272, 292 Symptomatic, 86, 275, 292 Synapse, 228, 272, 292, 295 Synaptic, 272, 288, 292 Synergistic, 144, 292, 293
312
Cystic Fibrosis
Systemic, 28, 60, 154, 232, 236, 247, 251, 262, 283, 292 Systolic, 260, 292 T Taurine, 122, 123, 234, 240, 292 Temporal, 162, 292 Teratogenic, 264, 292 Terminator, 242, 292 Testis, 273, 293 Therapeutics, 16, 18, 20, 22, 34, 62, 82, 103, 112, 118, 127, 133, 142, 293 Thermal, 29, 68, 233, 248, 258, 272, 279, 293 Thermoregulation, 40, 293 Thigh, 23, 293 Threonine, 12, 282, 287, 293 Threshold, 260, 293 Thrombin, 278, 282, 293 Thrombomodulin, 282, 293 Thrombosis, 234, 282, 291, 293 Thyroid, 198, 293, 295 Thyroid Gland, 198, 293 Thyroid Hormones, 293, 295 Thyroxine, 277, 293 Tic, 55, 293 Tissue Culture, 50, 53, 293 Tobramycin, 14, 70, 96, 99, 293 Tolerance, 35, 117, 155, 227, 256, 258, 293 Tomography, 102, 293 Tone, 70, 294 Tonus, 294 Tooth Preparation, 228, 294 Topical, 61, 240, 260, 263, 276, 288, 294 Toxic, iv, 27, 155, 170, 233, 234, 242, 245, 247, 261, 272, 287, 294 Toxicity, 29, 51, 61, 204, 294 Toxicokinetics, 294 Toxicology, 67, 211, 294 Toxin, 18, 247, 250, 293, 294 Toxoplasmosis, 233, 294 Trace element, 236, 288, 294 Trachea, 237, 264, 277, 293, 294 Traction, 241, 294 Transcription Factors, 179, 294 Transduction, 42, 288, 294 Transfection, 18, 235, 255, 294 Transferases, 257, 294 Translation, 15, 178, 179, 251, 255, 294 Translational, 14, 20, 49, 294 Translocation, 127, 241, 251, 294 Transmitter, 40, 227, 248, 263, 268, 272, 295
Transplantation, 31, 42, 56, 73, 78, 80, 86, 89, 92, 95, 96, 97, 105, 109, 218, 241, 264, 295 Transport Vesicles, 27, 295 Trauma, 49, 271, 275, 295 Triage, 104, 295 Trinucleotide Repeat Expansion, 193, 295 Trinucleotide Repeats, 295 Trisomy, 184, 230, 295 Trypsin, 91, 140, 225, 229, 241, 250, 295, 298 Tryptophan, 242, 287, 295 Tuberculosis, 50, 67, 271, 295 Tumor marker, 235, 295 Tyrosine, 47, 144, 248, 264, 282, 295 U Ubiquitin, 13, 22, 27, 154, 295 Ulcer, 269, 295 Ulceration, 276, 295 Ulcerative colitis, 59, 262, 295 Ultraviolet radiation, 181, 295 Unsaturated Fats, 253, 296 Uraemia, 275, 296 Urea, 264, 292, 296 Uremia, 264, 285, 296 Urethra, 276, 281, 296 Urinalysis, 67, 296 Urine, 43, 232, 234, 236, 244, 251, 264, 274, 296 Ursodeoxycholic Acid, 47, 122, 296 Uterus, 198, 239, 274, 275, 285, 296 V Vaccine, 67, 282, 296 Vacuole, 60, 296 Vagina, 239, 285, 296 Vas Deferens, 4, 8, 163, 296 Vascular, 74, 246, 250, 262, 266, 269, 272, 293, 296 Vasculitis, 275, 296 Vasodilation, 40, 296 Vasodilator, 40, 236, 248, 259, 296 Vector, 11, 30, 38, 52, 203, 204, 294, 296 Vein, 230, 263, 273, 275, 279, 280, 286, 296 Venous, 234, 282, 297 Ventilation, 55, 109, 117, 136, 297 Ventricle, 283, 292, 297 Ventricular, 11, 297 Venules, 236, 237, 250, 269, 297 Vertebrae, 289, 297 Vertebral, 101, 297 Vesicular, 40, 259, 297 Veterinary Medicine, 211, 297
Index 313
Viral, 11, 30, 34, 49, 203, 227, 255, 274, 294, 297 Viral vector, 30, 34, 297 Virulence, 12, 16, 28, 57, 60, 65, 294, 297 Virus, 30, 52, 68, 203, 255, 262, 278, 286, 294, 297 Viscera, 289, 297 Viscosity, 49, 155, 227, 286, 297 Vitro, 11, 13, 18, 21, 25, 26, 31, 32, 38, 39, 40, 42, 44, 46, 51, 52, 53, 61, 106, 126, 198, 239, 255, 261, 279, 293, 297 Vivo, 11, 12, 19, 21, 26, 28, 33, 40, 42, 46, 47, 53, 58, 61, 63, 90, 105, 153, 155, 239, 255, 261, 269, 270, 297 Vocal cord, 114, 297
W Weight Perception, 143, 297 Wheezing, 4, 36, 224, 297 White blood cell, 181, 227, 231, 236, 241, 267, 270, 272, 278, 297 Windpipe, 277, 293, 298 Womb, 285, 296, 298 Wound Healing, 267, 298 X Xenograft, 230, 298 X-ray, 45, 74, 111, 126, 224, 225, 238, 243, 254, 273, 283, 286, 298 Y Yeasts, 254, 277, 298 Z Zygote, 243, 270, 298 Zymogen, 241, 282, 298
