HEMOPHILIA
A
3-in-1
Medical
Reference
A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES
HEMOPHILIA 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., 1960Hemophilia: 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: 0-497-11229-9 1. Hemophilia-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail:
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on hemophilia. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the 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 HEMOPHILIA ............................................................................................. 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Hemophilia? ..................................................................................................................... 3 How Common Is Hemophilia?....................................................................................................... 4 What Genes Are Related to Hemophilia?....................................................................................... 4 How Do People Inherit Hemophilia? ............................................................................................. 4 Where Can I Find Additional Information about Hemophilia? ..................................................... 5 References....................................................................................................................................... 7 What Is the Official Name of the F8 Gene?.................................................................................... 8 What Is the Normal Function of the F8 Gene? .............................................................................. 8 What Conditions Are Related to the F8 Gene? .............................................................................. 8 Where Is the F8 Gene Located? ...................................................................................................... 8 References....................................................................................................................................... 9 What Is the Official Name of the F9 Gene?.................................................................................. 10 What Is the Normal Function of the F9 Gene? ............................................................................ 10 What Conditions Are Related to the F9 Gene? ............................................................................ 10 Where Is the F9 Gene Located? .................................................................................................... 10 References..................................................................................................................................... 11 Federally Funded Research on Hemophilia .................................................................................. 12 The National Library of Medicine: PubMed ................................................................................ 70 CHAPTER 2. ALTERNATIVE MEDICINE AND HEMOPHILIA........................................................... 116 Overview.................................................................................................................................... 116 National Center for Complementary and Alternative Medicine................................................ 116 Additional Web Resources ......................................................................................................... 122 General References ..................................................................................................................... 123 CHAPTER 3. PATENTS ON HEMOPHILIA ....................................................................................... 124 Overview.................................................................................................................................... 124 Patent Applications on Hemophilia ........................................................................................... 124 Keeping Current ........................................................................................................................ 128 CHAPTER 4. BOOKS ON HEMOPHILIA ........................................................................................... 129 Overview.................................................................................................................................... 129 Book Summaries: Online Booksellers......................................................................................... 129 The National Library of Medicine Book Index ........................................................................... 136 CHAPTER 5. MULTIMEDIA ON HEMOPHILIA ................................................................................ 139 Overview.................................................................................................................................... 139 Bibliography: Multimedia on Hemophilia.................................................................................. 139 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 142 Overview.................................................................................................................................... 142 The Basics: Genes and How They Work..................................................................................... 142 Genetic Mutations and Health................................................................................................... 153 Inheriting Genetic Conditions ................................................................................................... 159 Genetic Consultation ................................................................................................................. 167 Genetic Testing .......................................................................................................................... 169 Gene Therapy ............................................................................................................................. 175 The Human Genome Project and Genomic Research................................................................. 178 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 181 Overview.................................................................................................................................... 181 NIH Guidelines.......................................................................................................................... 181 NIH Databases........................................................................................................................... 182
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Other Commercial Databases..................................................................................................... 185 The Genome Project and Hemophilia......................................................................................... 185 APPENDIX C. PATIENT RESOURCES .............................................................................................. 189 Overview.................................................................................................................................... 189 Patient Guideline Sources.......................................................................................................... 189 Finding Associations.................................................................................................................. 192 Resources for Patients and Families........................................................................................... 193 ONLINE GLOSSARIES................................................................................................................ 194 Online Dictionary Directories ................................................................................................... 197 HEMOPHILIA DICTIONARY .................................................................................................... 198 INDEX .............................................................................................................................................. 255
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FORWARD In March 2001, the National Institutes of Health issued the following warning: “The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.”1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with hemophilia is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about hemophilia, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to hemophilia, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of hemophilia. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on hemophilia. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to hemophilia, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. We hope these resources will prove useful to the widest possible audience seeking information on hemophilia. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.
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CHAPTER 1. STUDIES ON HEMOPHILIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on hemophilia. For those interested in basic information about hemophilia, 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 hemophilia 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 hemophilia is provided.2 The Genetics Home Reference has recently published the following summary for hemophilia:
What Is Hemophilia?3 Hemophilia is a bleeding disorder that slows the blood clotting process. People with this condition often experience prolonged bleeding or oozing following an injury, surgery, or having a tooth pulled. In severe cases of hemophilia, heavy bleeding occurs after minor trauma or even in the absence of injury (spontaneous bleeding). Serious complications can result from bleeding into the joints, muscles, brain, or other internal organs. Milder forms of hemophilia do not involve spontaneous bleeding, and the condition may only become apparent when abnormal bleeding occurs following surgery or a serious injury.
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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=hemophilia.
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Hemophilia
The major types of this condition are hemophilia A (also known as classic hemophilia) and hemophilia B (also known as Christmas disease). Although the two types have very similar signs and symptoms, they are caused by mutations in different genes. People with an unusual form of hemophilia B, known as hemophilia B Leyden, experience episodes of excessive bleeding in childhood, but have few bleeding problems after puberty. Another form of the disorder, acquired hemophilia, is not caused by inherited gene mutations. This rare condition is characterized by abnormal bleeding into the skin, muscles, or other soft tissues, usually beginning in adulthood.
How Common Is Hemophilia? The two major forms of hemophilia occur much more commonly in males than in females. Hemophilia A is the most common type of the condition; about 1 in 4,000 males worldwide are born with this disorder. Hemophilia B occurs in approximately 1 in 20,000 newborn males worldwide.
What Genes Are Related to Hemophilia? Mutations in the F8 (http://ghr.nlm.nih.gov/gene=f8) and F9 (http://ghr.nlm.nih.gov/gene=f9) genes cause hemophilia. Changes in the F8 gene are responsible for hemophilia A, while mutations in the F9 gene cause hemophilia B. The F8 gene provides instructions for making a protein called coagulation factor VIII. A related protein, coagulation factor IX, is produced from the F9 gene. Coagulation factors are proteins that work together in the clotting process. After an injury, blood clots protect the body by sealing off damaged blood vessels and preventing further blood loss. Mutations in the F8 or F9 gene lead to the production of an abnormal version of coagulation factor VIII or coagulation factor IX. The altered protein cannot participate effectively in the blood clotting process and, in some cases, the protein does not work at all. A shortage of either protein prevents clots from forming properly in response to injury. These problems with blood clotting lead to excessive bleeding that can be difficult to control. Some mutations almost completely eliminate the activity of coagulation factor VIII or coagulation factor IX, resulting in severe hemophilia. Other mutations reduce but do not eliminate the activity of one of these proteins, which usually causes mild or moderate hemophilia. The other, rare form of this condition, acquired hemophilia, results when the body makes specialized proteins called autoantibodies that attack and disable coagulation factor VIII. The production of autoantibodies is sometimes associated with pregnancy, immune system disorders, cancer, or allergic reactions to certain drugs. In about half of cases, the cause of acquired hemophilia is unknown.
How Do People Inherit Hemophilia? Hemophilia A and hemophilia B are inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X
Studies
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chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the altered gene to her children, but usually does not experience signs and symptoms of the disorder. In about 10 percent of cases, however, females who carry one altered copy of the F8 or F9 gene will experience mild problems with bleeding.
Where Can I Find Additional Information about Hemophilia? You may find the following resources about hemophilia 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?tool=bookshelf&call=bv.View..ShowSect ion&searchterm=hemophilia&rid=gnd.section.95
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National Heart, Lung, and Blood Institute: http://www.nhlbi.nih.gov/health/dci/Diseases/hemophilia/hemophilia_what.html
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National Human Genome Research Institute: http://www.genome.gov/20019697 MedlinePlus - Health Information
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Encyclopedia: Hemophilia A: http://www.nlm.nih.gov/medlineplus/ency/article/000538.htm
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Encyclopedia: Hemophilia B: http://www.nlm.nih.gov/medlineplus/ency/article/000539.htm
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Health Topic: Hemophilia: http://www.nlm.nih.gov/medlineplus/hemophilia.html Educational Resources - Information Pages
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Ask the Geneticist: Inheritance of hemophilia: http://www.askthegen.org/question.php?question_id=1702
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Ask the Geneticist: Life with hemophilia: http://www.askthegen.org/question.php?question_id=602
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Centers for Disease Control and Prevention: Hereditary Bleeding Disorders: http://www.cdc.gov/ncbddd/hbd/hemophilia.htm
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Hemophilia
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Centre for Genetics Education: http://www.genetics.com.au/factsheet/38.htm
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Children's Hospital Boston: http://www.childrenshospital.org/az/Site1008/mainpageS1008P0.html
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Cincinnati Children's Hospital Medical Center: http://www.cincinnatichildrens.org/health/info/blood/diagnose/hemophilia.htm
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KidsHealth from the Nemours Foundation: http://kidshealth.org/kid/health_problems/blood/hemophilia.html
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Lab Tests Online: Bleeding Disorders: http://labtestsonline.org/understanding/conditions/bleeding_disorders.html
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Madisons Foundation: http://www.madisonsfoundation.org/content/3/1/display.asp?did=84
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Mayo Clinic: http://www.mayoclinic.org/hemophilia/
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Merck Manual of Medical Information, Second Home Edition: http://www.merck.com/mmhe/sec14/ch173/ch173f.html
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NetWellness: http://www.netwellness.org/healthtopics/bleeding/
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New York Online Access to Health (NOAH): http://www.noah-health.org/en/blood/hemophilia/
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Orphanet: http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=448
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The National Women's Health Information Center: Bleeding Disorders: http://www.4woman.gov/faq/bleed.htm
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The Wellcome Trust: http://genome.wellcome.ac.uk/doc_WTD020862.html Patient Support - for Patients and Families
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Canadian Hemophilia Society: http://www.hemophilia.ca/
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Family Village: http://www.familyvillage.wisc.edu/lib_hemp.htm
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National Hemophilia Foundation: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=0&contentid =1
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National Organization for Rare Disorders: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Hemophilia
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Resource list from the University of Kansas Medical Center: http://www.kumc.edu/gec/support/hemophil.html
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World Federation of Hemophilia: http://www.wfh.org/index.asp?lang=EN
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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://ghr.nlm.nih.gov/condition=hemophilia/show/Gene+Reviews;jsessionid=D0D6 B505BD393BB942BD5E2D18B45C90
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Gene Tests - DNA tests ordered by healthcare professionals: http://ghr.nlm.nih.gov/condition=hemophilia/show/Gene+Tests;jsessionid=D0D6B50 5BD393BB942BD5E2D18B45C90
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Genetic Tools - Teaching cases: http://www.genetests.org/servlet/access?fcn=y&filename=/tools/cases/postpartumHe m-32/
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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22hemophilia%22?recruiting=false
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Online Books - Medical and science texts: http://ghr.nlm.nih.gov/condition=hemophilia/show/Online+Books;jsessionid=D0D6B 505BD393BB942BD5E2D18B45C90
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OMIM - Genetic disorder catalog: http://ghr.nlm.nih.gov/condition=hemophilia/show/OMIM;jsessionid=D0D6B505BD 393BB942BD5E2D18B45C90
References These sources were used to develop the Genetics Home Reference condition summary on hemophilia. •
Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003 May 24;361(9371):18019. Review. PubMed citation
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Franchini M. Acquired hemophilia A. Hematology. 2006 Apr;11(2):119-25. Review. PubMed citation
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Gene Review: Hemophilia A
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Gene Review: Hemophilia B
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Giangrande P. Haemophilia B: Christmas disease. Expert Opin Pharmacother. 2005 Aug;6(9):1517-24. Review. PubMed citation
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Graw J, Brackmann HH, Oldenburg J, Schneppenheim R, Spannagl M, Schwaab R. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet. 2005 Jun;6(6):488-501. Review. PubMed citation
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Oldenburg J, El-Maarri O. New insight into the molecular basis of hemophilia A. Int J Hematol. 2006 Feb;83(2):96-102. Review. PubMed citation
A summary of the genes related to hemophilia is provided below:
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Hemophilia
What Is the Official Name of the F8 Gene?4 The official name of this gene is “coagulation factor VIII, procoagulant component (hemophilia A).” F8 is the gene's official symbol. The F8 gene is also known by other names, listed below.
What Is the Normal Function of the F8 Gene? The F8 gene provides instructions for making a protein called coagulation factor VIII. Coagulation factors are related proteins that are essential for the formation of blood clots. After an injury, clots protect the body by sealing off damaged blood vessels and preventing further blood loss. Coagulation factor VIII is made chiefly by cells in the liver. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.
What Conditions Are Related to the F8 Gene? Hemophilia - Caused by Mutations in the F8 Gene Mutations in the F8 gene cause hemophilia A, the most common form of this bleeding disorder. Hundreds of alterations in this gene have been identified. Some of these mutations change single DNA building blocks (base pairs) in the gene, while others delete or insert multiple base pairs. The most common mutation in people with severe hemophilia A is a rearrangement of genetic material called an inversion. This inversion involves a large segment of the F8 gene.
Where Is the F8 Gene Located? Cytogenetic Location: Xq28 Molecular Location on the X chromosome: base pairs 153,717,259 to 153,904,191
4
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=f8;jsessionid=D0D6B505BD393BB942BD5E2D18B45C90.
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The F8 gene is located on the long (q) arm of the X chromosome at position 28. More precisely, the F8 gene is located from base pair 153,717,259 to base pair 153,904,191 on the X chromosome.
References These sources were used to develop the Genetics Home Reference gene summary on the F8 gene. •
Bicocchi MP, Pasino M, Lanza T, Bottini F, Boeri E, Mori PG, Molinari AC, Rosano C, Acquila M. Analysis of 18 novel mutations in the factor VIII gene. Br J Haematol. 2003 Sep;122(5):810-7. PubMed citation
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Bogdanova N, Markoff A, Eisert R, Wermes C, Pollmann H, Todorova A, Chlystun M, Nowak-Gottl U, Horst J. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. PubMed citation
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Bogdanova N, Markoff A, Pollmann H, Nowak-Gottl U, Eisert R, Wermes C, Todorova A, Eigel A, Dworniczak B, Horst J. Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. Hum Mutat. 2005 Sep;26(3):249-54. PubMed citation
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Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003 May 24;361(9371):18019. Review. PubMed citation
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Bowen DJ. Haemophilia A and haemophilia B: molecular insights. Mol Pathol. 2002 Apr;55(2):127-44. Review. Erratum in: Mol Pathol 2002 Jun;55(3):208. PubMed citation
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Graw J, Brackmann HH, Oldenburg J, Schneppenheim R, Spannagl M, Schwaab R. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet. 2005 Jun;6(6):488-501. Review. PubMed citation
•
Oldenburg J, El-Maarri O. New insight into the molecular basis of hemophilia A. Int J Hematol. 2006 Feb;83(2):96-102. Review. PubMed citation
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Hemophilia
What Is the Official Name of the F9 Gene?5 The official name of this gene is “coagulation factor IX (plasma thromboplastic component, Christmas disease, hemophilia B).” F9 is the gene's official symbol. The F9 gene is also known by other names, listed below.
What Is the Normal Function of the F9 Gene? The F9 gene provides instructions for making a protein called coagulation factor IX. Coagulation factors are related proteins that are essential for the formation of blood clots. After an injury, clots protect the body by sealing off damaged blood vessels and preventing further blood loss. Coagulation factor IX is an enzyme made in the liver. This protein circulates in the bloodstream in an inactive form until an injury that damages blood vessels occurs. In response to injury, coagulation factor IX is activated by another coagulation factor called factor XI. The active protein (sometimes written as coagulation factor IXa) interacts with coagulation factor VIII and other molecules. These interactions set off a chain of additional chemical reactions that form a blood clot.
What Conditions Are Related to the F9 Gene? Hemophilia - Caused by Mutations in the F9 Gene Mutations in the F9 gene cause a type of hemophilia called hemophilia B. Hundreds of alterations in this gene have been identified. The most common mutations change single DNA building blocks (base pairs) in the gene. A small percentage of mutations delete or insert multiple base pairs or rearrange segments of DNA within the gene. Other Disorders - Caused by Mutations in the F9 Gene Mutations in the F9 gene cause a type of hemophilia called hemophilia B. Hundreds of alterations in this gene have been identified. The most common mutations change single DNA building blocks (base pairs) in the gene. A small percentage of mutations delete or insert multiple base pairs or rearrange segments of DNA within the gene.
Where Is the F9 Gene Located? Cytogenetic Location: Xq27.1-q27.2 Molecular Location on the X chromosome: base pairs 138,440,560 to 138,473,282
5
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=f9.
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The F9 gene is located on the long (q) arm of the X chromosome between positions 27.1 and 27.2. More precisely, the F9 gene is located from base pair 138,440,560 to base pair 138,473,282 on the X chromosome.
References These sources were used to develop the Genetics Home Reference gene summary on the F9 gene. •
Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003 May 24;361(9371):18019. Review. PubMed citation
•
Bowen DJ. Haemophilia A and haemophilia B: molecular insights. Mol Pathol. 2002 Apr;55(2):127-44. Review. Erratum in: Mol Pathol 2002 Jun;55(3):208. PubMed citation
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Chu K, Wu SM, Stanley T, Stafford DW, High KA. A mutation in the propeptide of Factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest. 1996 Oct 1;98(7):1619-25. PubMed citation
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Giangrande P. Haemophilia B: Christmas disease. Expert Opin Pharmacother. 2005 Aug;6(9):1517-24. Review. PubMed citation
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Kristensen SR. Warfarin treatment of a patient with coagulation factor IX propeptide mutation causing warfarin hypersensitivity. Blood. 2002 Oct 1;100(7):2676-7. No abstract available. PubMed citation
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Lillicrap D. The molecular basis of haemophilia B. Haemophilia. 1998 Jul;4(4):350-7. Review. PubMed citation
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Oldenburg J, Quenzel EM, Harbrecht U, Fregin A, Kress W, Muller CR, Hertfelder HJ, Schwaab R, Brackmann HH, Hanfland P. Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol. 1997 Jul;98(1):240-4. PubMed citation
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Hemophilia
Federally Funded Research on Hemophilia The U.S. Government supports a variety of research studies relating to hemophilia. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.6 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 hemophilia. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore hemophilia. The following is typical of the type of information found when searching the CRISP database for hemophilia: •
Project Title: AN INTERNATIONAL, RANDOMIZED, CONTROLLED TRIAL OF IMMUNE-TOLERANCE INDUCTION Principal Investigator & Institution: Angiolillo, Anne L.; Children's Research Institute 111 Michigan Avenue, Nw Washington, Dc 20010 Timing: Fiscal Year 2005; Project Start 01-FEB-2005; Project End 30-NOV-2005 Summary: There is no text on file for this abstract.
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Project Title: ASSESSMENT OF HD-AD VECTORS AND FACTOR IX AND APOA-1 Principal Investigator & Institution: Beaudet, Arthur L.; Professor and Chair; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: The overall goals of this project are to further define the safety and toxicity of helper-dependent adenoviral (HD-Ad) vectors, to delineate the pathogenesis of the thrombocytopenia observed with the HD-Ad vectors, to attempt to identify mechanisms to circumvent the thrombocytopenia, to develop experience with these vectors in primates, and to move incrementally towards clinical trials with these very promising HD-Ad vectors. The pathogenesis of the thrombocytopenia will be studied in mice, focusing on direct interactions between platelets and vector and between endothelial cells and vector. One very important aim will be to evaluate safety, toxicity, and shortterm expression using high doses of HD-Ad vectors in juvenile baboons. Because of the desire to initiate clinical trials with maximum safety, we are comparing the expression of factor IX and apolipoprotein A-I (apo A-I) with IM administration utilizing a musclespecific promoter and IV administration aimed at expression in hepatocytes. Another aim will be to put in place all of the necessary reagents and commitments to prepare GMP quality HD-Ad vector suitable for use in pre-clinical and clinical studies. Toxicity
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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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studies with GMP quality vector will be conducted in mice and baboons. In longer-term experiments in baboons, we will test whether over-expression of apo A-I will protect against atherosclerosis in baboons. Finally, we propose to develop a clinical trial to introduce the HD-Ad vectors into the clinic using either IM or IV administration. No IRB-approved protocol is available at present, but the major possibilities under consideration include expression of factor IX in patients with hemophilia B or expression of apo A-I in patients with coronary artery disease and low production of apo A-I. The long-term significance of this project is to attempt to develop HD-Ad vectors designed to increase expression of the LDL receptor and/or apo A-I in humans. If successful, this approach could have a major impact on prevention or reduction of atherosclerosis in the human population. •
Project Title: B-CELL RESPONSES TO CLOTTING FACTOR VIII Principal Investigator & Institution: Thompson, Arthur; Chief of Hematology; Puget Sound Blood Center 921 Terry Ave Seattle, Wa 98104 Timing: Fiscal Year 2005; Project Start 01-MAY-2004; Project End 30-APR-2008 Summary: (provided by applicant): As a pathogenic B cell response, factor VIII inhibitors represent a major clinical challenge including alloantibodies in hemophilia A patients or autoantibodies in acquired hemophilia. Responses are polyclonal to a limited number of major epitopes on different domains and IgG4 responses often predominate. However, most studies to characterize factor VIII inhibitors have been on samples representing single points in time, focusing upon high titer antibodies at their peak response and defining fractions reacting with epitopes throughout entire domains. We propose to study fractions of the polyclonal responses that are directed to clusters of surface epitopes on factor VIIl's C domains to characterize variability between subjects and stability (or changes) across time in individual patients. We will study three sets of patient groups: (1) allo antibodies in severe hemophilia A, (2) auto antibodies in acquired hemophilia A and (3) combined auto and allo antibodies in patients with mild hemophilia A. C domain epitopes remain the most complex and least well understood. Affinity-purified antibody fractions binding to C domain epitope clusters will be characterized. We have expressed C2 and C1C2 and several mutants. Relative amounts of inhibiting and/or binding patient antibodies reacting to C2, its mutants or C1C2 will be assessed as will distribution of IgG isotypes, both between patients and longitudinally in a given patient's samples. Specific hemophilic C1C2 mutants will characterize responses in mildly severe patients with inhibitors. As a final component, we will define structural elements of C1C2's surface, and the extent of flexibility in conformations of residues on C2, surface residues that differ when the entire C domain is present. Results will provide insights into strategies for therapy of bleeding episodes and the induction of tolerance or prevention of alloimmunization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOENGINEERING OF A STENT-GRAFT FOR GENE THERAPY Principal Investigator & Institution: Yu, Hong; Surgery; University of Miami-Medical School 1507 Levante Avenue Coral Gables, Fl 33124 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): A stent-graft is a conduit composed of a polymer membrane supported by a metal stent that is placed in a vessel using catheter technology. We have genetically engineered vascular smooth muscle cells (SMC) and placed them on a stent graft that was specifically designed to shelter the SMC cells from
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implantation trauma. We found that these genetically engineered cells survived and proliferated and that gene expression was maintained at high levels over a long period, indicating the feasibility of this new gene therapy strategy to deliver the gene product directly into the bloodstream. The objective of this project is to explore whether a stentgraft suffused with genetically engineered SMC can be used to deliver functional Factor IX (F.IX) to treat hemophilia B. Hemophilia B is an X-linked bleeding diathesis resulting from a deficiency of blood coagulation factor IX. Hemophilia is an ideal model for gene therapy because precise regulation and tissue-specific transgene expression are not required. We will use a hemophilic dog model to study the feasibility of bioengineering a stent graft for gene therapy. We hypothesize that the intravascular delivery of F. IX using a stent-graft suffused with retrovirally transduced SMC will offer the opportunity for delivery of F.IX at a therapeutic level to correct the coagulation defect. We will first determine how long and how much of the transgene product canine F.IX can be produced from the bioengineered stent grafts after being implanted into the aorta of a hemophilia B dog using catheter technology. We will modulate the level of F.IX production by the length of the implanted stent graft. Then, we will determine whether the secreted F. X at these levels can ameliorate the coagulation defect in a hemophilic dog by measuring coagulation parameters. The host immune response to the transgene product canine F.IX will also be examined. The outcome of the project will have direct applications in the treatment of hemophilia as well as other blood and vascular disorders. •
Project Title: BIOLOGIC AND IMMUNOLOGIC ASPECTS OF TRANSFUSION MEDICINE Principal Investigator & Institution: Slichter, Sherrill J.; Medical Director; Puget Sound Blood Center 921 Terry Ave Seattle, Wa 98104 Timing: Fiscal Year 2005; Project Start 30-SEP-2005; Project End 31-AUG-2010 Summary: (provided by applicant): Our research focuses on several biologic and immunologic aspects of transfusion medicine. Three projects deal with questions related to platelet biology. Specifically, Dr. Slichter's project seeks to define the parameters that must be met to allow extension of platelet storage by evaluating the effects of an initial collection injury that may limit storage duration and the role of storage solutions in facilitating extended platelet storage. Dr. Gilligan and Reems' project expects to identify the optimal methods of growing megakaryocytes in culture with the goal of producing platelets or "platelet-like fragments" that function similarly to platelets in maintaining hemostasis. Dr. Josephson's project focuses on the development of foamy virus vectors as a gene transfer system to deliver therapeutic genes into hematopoietic stem cells. The target disease that he will use as a model for his system is congenital amegakaryocytic thrombocytopenia (CAMT). Two additional projects have an immunologic emphasis. Dr. Nelson's project involves transfusing three different types of blood products [standard (unmodified), leukoreduced, or leukoreduced gamma-irradiated] into immunocompetent patients undergoing open-heart surgery. The differences in serologic and cellular immune responses in the three patient cohorts as well as the influence of HLA Class II sharing between donors and recipients on immunologic outcomes will be evaluated. Dr. S. Pratt and Thompson's project addresses issues related to the prevention or reversal of inhibitor antibody formation in patients with acquired or congenital hemophilia A. Modification of T-cell epitopes in FVIII may lead to nonimmunogenic FVIII replacement therapy while new peptides or recombinant proteins may be useful in tolerance induction for patients with existing antibodies. Finally, an administrative core will be used to maintain an interactive environment among the SCCOR scientists and provide administrative and statistical support. In summary, we
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have utilized the established expertise of our scientists to address several important questions in Transfusion Medicine. In addition, most projects involve the skills of one or more Blood Center scientists working within and between the projects to accomplish the objectives of this SCCOR Program. (End of Abstract) PROJECT 1: Strategies to Extend Platelet Storage (Slichter, Sherrill) (provided by applicant): The primary objective of these studies is to determine whether platelets (plts) can be stored for longer than the currently-licensed 5 days. Furthermore, does the duration of plt storage depend on the type of plt product being stored (apheresis plts, plt concentrates prepared from plt-rich plasma (PRP), or from buffy coats (BC), pre-storage pooled PRP plt concentrates, or pathogen-reduced apheresis or BC plts), and the medium used for storage; i.e., plasma or a storage solution. The four critical questions that will be addressed in our studies are: 1) does the method of plt collection using apheresis procedures versus preparing plt concentrates from whole blood influence storage duration?; 2) does pre-storage pooling of plt concentrates affect plt viability?; 3) do plt storage solutions allow plts to be stored longer than plts stored in plasma?; and 4) can pathogen-reduced plts be stored for extended time periods similar to non-pathogen reduced plts? Although in vitro tests will be performed to document post-storage plt counts as well as a variety of assays to determine post-storage plt function, metabolism and apoptosis, the post-storage quality of the extended stored plts will be based on in vivo measurements in normal volunteers and thrombocytopenic patients. Specifically, radiolabeled plt recovery and survival measurements of extended stored autologous plts in normal volunteers will be used to determine post-storage plt viability for all types of plt products stored in plasma versus a storage solution. For plts that are stored for longer than 8 days and/or are stored in a storage solution, transfusion studies in the thrombocytopenic patients will be used to evaluate plt viability by measuring the radiolabeled recovery and survival of the donors' plts following transfusion. Alternatively, patient responses to transfused donor plts will be determined by measuring post-transfusion plt increments, corrected count increments, and days-to-next transfusion. Plt function (i.e., hemostasis) following the transfusion of extended stored donor plts will be monitored by plt count versus bleeding time measurements and by radiochromium-labeled stool blood loss studies. At the conclusion of these studies, we should know how long each type of plts can be stored in plasma or Plasmalyte, the relative merits of each type of plts, and whether the extended stored plts are both viable and functional when given to thrombocytopenic patients. (End of Abstract) •
Project Title: BIOMOLECULAR INTERACTIONS OF FACTOR VIII AND VON WILLEBRAND FACTOR Principal Investigator & Institution: Montgomery, Robert R.; Professor and Vice Chair for Research; Bloodcenter of Wisconsin, Inc. P.O. Box 2178, 638 N 18Th St Milwaukee, Wi 53233 Timing: Fiscal Year 2006; Project Start 01-DEC-2005; Project End 30-NOV-2010 Summary: Von Willebrand Factor (VWF) and Factor VIII (FVIII) are key central proteins in the initiation and regulation ofhemostasis. Each has its own hereditary deficiency disease, which cause either VWD or hemophilia A, and theycirculate together as a noncovalent complex in plasma. This project explores the requirements for the establishmentof a regulated secretory pathway for one or both VWF and FVIII proteins within endothelial cells andmegakaryocytes. Aim 1 will determine the structural and functional requirements within VWF for the storageof both VWF and FVIII and contrasts these pathways within endothelial cells and platelets. The Weibel-Paladebody has an absolute requirement for synthesis of pro-VWF while the alpha granule is permissive if pro-VWF issynthesized. Specific Aim 2 will determine the in vivo potential
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for synthesis of FVIII in the presence of VWFas a novel therapeutic approach in the treatment of hemophilia A. Transgenic (F8-/-) animals expressing FVIIIonly in either endothelium or megakaryocytes will be studied to determine the therapeutic advantage of expressingFVIII with VWF. Specific Aim 3 will examine the potential for plateletspecific or endothelial cell-specificFVIII expression as a means to bypass the inhibitory activity of FVIII antibodies. Transgenic animalsexpressing FVIII in endothelial cells or platelets will be studied within the context of inhibitory antibodies todetermine if these sites of expression can "bypass" plasma inhibitors by locally releasing active FVIII in the contextof VWF. Specific Aim 4 will determine if the endothelial cell is the physiologic site for expression of FVIII orat least the site synthesizing and storing the FVIII released by the administration of DDAVP. Since thecontroversy continues as to the site of normal FVIII synthesis, these studies will explore whether the DDAVPreleasable pool of FVIII has an absolute requirement for endothelial synthesis of FVIII or whether it can be created inthe absence of specific endothelial cell synthesis. Tissue specific knockouts of FVIII production will be carried outin the hepatocyte or in the endothelial cell to determine if these tissue-specific knockouts caused a marked reductionin plasma FVIII. Therefore, we feel that tiiese aims will definitively explore the function of VWF on the in vivo andin vitro intracellular biology of FVIII and provide potential for new therapeutic approaches to the treatment ofhemophilia A both in patients with and those without FVIII inhibitors. •
Project Title: BOEC IN BIOLOGY Principal Investigator & Institution: Hebbel, Robert P.; Professor and Vice-Chairman; Medicine; University of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070 Timing: Fiscal Year 2005; Project Start 08-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Our preliminary data indicate that molecularly engineered BOEC (blood outgrowth endothelial cells) can be used for effective gene therapy of hemophilia A. The present project will examine several aspects of BOEC biology that are directly relevant to this potential therapeutic use of BOEC. Three Specific Aims will utilize the model of human BOEC (either unmanipulated or engineered to express human factor VIII) given to NOD. SCID mice. In Aim 1 we will identify the marrow "homing" behavior of BOEC. We will determine where BOEC go in the short- and long-terms when given intravenously. We will identify mechanisms underlying BOEC seeding of marrow and spleen. We will determine if BOEC seeding of marrow/spleen can be increase pharmacologically (with histamine, or beta-1-integrin activating antibody, or VEGF, or 1L6 plus stem cell factor). We will determine if the apparently low seeding frequency of BOEC in marrow is a stochastic or preprogrammed characteristic of establishing a BOEC graft. In Aim 2 we will examine certain issues regarding BOEC graft expansion and longevity in vivo. We will confirm our preliminary impression that BOEC expand substantially in vivo after being administered intravenously. We will determine if this in vivo expansion is predicatble and is dependent on the prior passaging history of the BOEC. We will seek to confirm that silencing of our fVIlI transgene expression vector is not a problem in BOEC. in Aim 3 we expect to document that endothelial expansion in vivo after intravenous administration of BOEC is due to a true BOEC cell rather than a contaminating hematopoietic precursor cell. Each of these studies addresses an issue that is necessary to understand before BOEC technology can be applied for therapeutics. Aside from eventual therapeutics, these studies will define aspects of this unique cell type.
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Project Title: CELLULAR IMMUNITY TO HEPATITIS C VIRUS IN HIV Principal Investigator & Institution: Graham, Camilla S.; Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215 Timing: Fiscal Year 2005; Project Start 01-JUL-2001; Project End 30-JUN-2007 Summary: (Provided by Applicant) The epidemics of HIV and hepatitis C virus (HCV) infections meet in individuals with parenteral exposure to blood, including injecting drug users (IDU) and persons with hemophilia, where rates of coinfection range from 60-90 percent. Coinfected individuals have a significantly increased risk of progression to end-stage liver disease, though mechanisms by which HIV modifies the course of HCV are poorly understood. It is paradoxical that HIV, an immunosuppressive state, leads to an accelerated progression of liver disease, and that HAART is associated with liver failure as well. Our central hypothesis is that both peripheral and intrahepatic HCV-specific cellular immune responses are qualitatively and quantitatively different in patients coinfected with HIV compared with those with HCV monoinfection, and that this is not solely a function of the degree of immunosuppression. Our goals are to determine whether coinfected individuals have an altered cellular immune response to HCV, to determine if immune reconstitution impacts HCV-specific cellular immunity, and if cellular immune responses to HCV are associated with improved outcome with anti-HCV therapy. To address these hypotheses we are examining HCV-specific cellular immune responses in three groups: 1) individuals with HCV/HIV versus HCV alone, 2) individuals with HIV/HCV prior to HAART and during immune reconstitution, and 3) individuals with HIV/HCV who are entering a protocol of interferon-ribavirin therapy. We are using ELISPOTS to characterize secretion of interferon-gamma, tumor necrosis factor alfa, and interleukin-10 at the single cell level in peripheral mononuclear cells and liver-infiltrating lymphocytes in these populations. We are complementing these functional assays with flow cytometry to phenotypically characterize lymphocyte populations. Determining alterations in cellular immune responses to HCV in individuals with HIV may help us to understand the pathophysiology underlying the accelerated progression of severe liver disease as well as help define subgroups of persons with HIV who may benefit from treatment of hepatitis C.
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Project Title: CGMP RECOMBINANT FIX FOR IV & ORAL HEMOPHILIA B THERAPY Principal Investigator & Institution: Velander, William H.; Chemical Engineering; University of Nebraska Lincoln Lincoln, Ne 685880430 Timing: Fiscal Year 2005; Project Start 06-SEP-2005; Project End 31-AUG-2010 Summary: (provided by applicant): Hemophilia B is a bleeding disorder resulting from congenital deficiency of coagulation protein Factor IX. Without optimal therapy, patients suffer crippling debilitations, chronic pain, and cognitive impairment. Optimal therapy - frequent dosing with Factor IX to reduce bleeding episode frequency - is currently available to only a small fraction of U.S. patients, largely because of cost and limited supply; 80% of the world's hemophilia patients receive no therapy. The longterm goal of this research is development of an abundant, pure, safe, and effective therapy for the global hemophilia patient population using recombinant human coagulation proteins produced in the milk of transgenic pigs. This proposal describes studies that are based upon innovative bioengineering technologies to refine and scaleup production of clinical grade Factor IX, characterize product formulated for intravenous dosage, complete animal studies required for clinical trials, and ultimately develop an oral dosage form to provide optimal therapy for U.S. hemophilia B patients. This approach capitalizes on existing genetically engineered transgenic pigs that
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synthesize up to 1000 IU/ml (4 g/L) of human Factor IX in milk and preliminary evidence for favorable hemostatic and pharmacokinetic properties of this purified Factor IX in a hemophilia B mouse model. A high probability of success is expected because of the soundness and state of development of the basic research already completed and the breadth and complementarity of the strengths of the team. Dr. J. Cooper of ProGenetics LLC will supply FDA- and USDA-compliant Factor IX milk. At the Univ. NebraskaLincoln, Dr. M. Meagher provides expertise in bioprocess engineering and current Good Manufacturing Practices production of recombinant proteins; Drs. W. Velander and K. Van Cott contribute expertise in transgenic animal engineering and characterization of human Factor IX. Dr. M. Manning of Colorado State University brings expertise in the formulation of stabilized liquid and lyophilized proteins for oral and injectable dosing. Dr. S. Abramson of LifeSci Partners has two decades of biopharmaceutical development experience encompassing clinical, technical, and regulatory expertise, including AlphaNine(r)SD (purified plasma-derived Factor IX). Drs. P. Monahan and T. Nichols of UNC-Chapel Hill have unique preclinical experience with hemophilia B mice and dogs that will be used to test the safety and efficacy of the Factor IX products. •
Project Title: CLINICAL HEMATOLOGY RESEARCH CAREER DEVELOPMENT PROGRAM (K12) Principal Investigator & Institution: Neufeld, Ellis J.; Associate Professor of Pediatrics; Children's Hospital Boston 300 Longwood Ave Boston, Ma 021155737 Timing: Fiscal Year 2006; Project Start 28-SEP-2006; Project End 30-JUN-2011 Summary: (provided by applicant): The Clinical Hematology Research Career Development Program is a Harvard-wide initiative to support training in clinical research for non-malignant hematology. The long-term objective of the program is to attract and retain talented young physician scientists to the field of blood diseases. Current trends in adult hematology/oncology careers are toward oncology. This K12 scholars' program is aimed at reversing that trend. This proposed program is a joint effort of six primary Harvard-affiliated institutes and hospitals with major training and research programs in non-malignant hematology (alphabetically, Beth Israel Deaconess Medical Center (BIDMC), Brigham and Women's Hospital (BWH), Center for Blood Research Institute (CBRI), Children's Hospital, Boston (CHB), Dana Farber Cancer Institute (DFCI), and Mass. General Hospital (MGH)). The administrative home of the program is at CHB. The principal investigator is a pediatric hematologist with a track record of clinical research mentoring and active involvement in NHLBI clinical research networks. The site directors from the member hospitals are distinguished hematologists with strong track records in hematology research. More than 40 potential mentors are available, covering all of the project disciplines. Scholars in the K12 program will receive formal didactic training in responsible conduct of research, in clinical areas of nonmalignant hematology, and in methodology for patient-oriented research. Masters programs of Harvard Medical School available for the latter training are (i) a K30funded Scholars in Clinical Sciences Program; (ii) Program in Clinical Effectiveness (a joint program with the Harvard School of Public Health), and (iii) Clinical Investigator Training Program offered jointly by BWH, BIDMC, HMS and MIT. The initiative includes the major clinical areas of: aplastic anemia/bone marrow failure syndromes; hemoglobinopathies including sickle cell disease and thalassemia; hemophilia and other hemostatic disorders; venous thromboembolism and thrombophilias; myelodysplastic syndromes and myeloproliferative disorders; transfusion medicine, including unique aspects of pediatric transfusion medicine. Together, the member institutions host more than 7,000 annual ambulatory hematology visits. Clinical research resources include three NHLBI clinical trials networks, four large GCRCs, sub-contract sites for the Boston
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Cooperative Sickle Cell Center, the Boston Hemophilia Center, and the resources of the DFCI/Harvard Cancer Center. An advisory committee composed of specialists in each key area, representing all six institutes/hospitals will oversee the project and serve as the admissions committee. Scholar Applicants will be drawn primarily from among the training programs at the member hospitals in Hematology/Oncology and Transfusion Medicine. Typically trainees will spend two years as scholars, pursuing an independent research project along with their didactic training. A colloquium series in non-malignant hematology will bring together scholars, their mentors, program faculty and other hematologists from around the Boston Hematology community. Formal annual evaluation of the program and of trainees' progress will be used for ongoing program improvements. •
Project Title: CORE--CANINE Principal Investigator & Institution: Nichols, Timothy Charles.; Professor; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2010 Summary: The Francis Owen Blood Research Laboratory (FOBRL) will be the location of the Animal Core in this Program Project Grant (PPG) for Gene Therapy of Hemophilia. Our main objective is to use dogs with hemophilia A and hemophilia B to determine the most efficient and least toxic method of gene therapy for these inherited disorders and to monitor the expression and persistence of F.VIII and F.IX. We hypothesize that replacement of F.VIII and F.IX by gene therapy will correct the bleeder phenotype in hemophilia A and B dogs, respectively. The FOBRL, established in 1960 and dedicated to the preservation and study of severely affected animal models of bleeding disorders, has been a resource for the study of canine hemophilia A and B. Both canine hemophilia A and B in the FOBRL colony are inherited as a sex-linked recessive traits; hemophilia A is due to an intron 22 inversion and hemophilia B is due to a point mutation in the catalytic domain of F.IX. Affected dogs have no detectable antihemophilic factor functionally or antigenically. Infusion of canine or human F.VIII and F.IX concentrates corrects prolonged partial thromboplastin times and halts the severe bleeding episodes characteristic of the hemophilias. Correction of canine hemophilia A and B by liver transplantation presaged successful vector-mediated gene therapy. This strain of hemophilia B dogs is the first animal model of hemophilia to enjoy long-term benefit of gene therapy with continuous expression of canine F.IX mediated by AAV-vectors from the High laboratory for over 7 years without production of anti-canine F.IX antibodies. Some dogs have exhibited a lower bleeding rate supporting our hypothesis. Current limitations of hemophilia gene therapy include low levels of transgene expression and the relative paucity of strategies for hemophilia patients with inhibitory antibodies. The Core function, then, is to provide professional and technical personnel and laboratory facilities for the conduct of F.VIII and F.IX gene transfer and vector toxicity studies for this PPG to address these limitations through novel strategies proposed in each of the four projects. Production of the hemophilic dogs dedicated to this PPG is supported by HL63098 "Maintenance of Animal Models of Hemophilia and VWD." This core will support experimental dogs, expert personnel for liver surgery, histochemical and morphological hepatic pathology, and determination of both therapeutic levels and toxic profiles of immunosuppressive agents, transportation of dogs for experimental procedures, and storage of plasmas, gross specimens, preserved tissues, and molecular materials (DNA, RNA, constructs, cell lines, etc.) from experimental and control dogs. These hemophilic dogs with the accompanying professional and technical support are a unique resource for basic studies focused on
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developing methods for gene therapy of hemophilia and testing novel gene expression and transfer vectors. •
Project Title: ECTOPIC F.VIII TREATMENT OF HEMOPHILIA A
EXPRESSION
IN
MEGAKARYOCYTES:
Principal Investigator & Institution: Poncz, Mortimer; Professor; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2010 Summary: Platelets adhere, form a platelet plug and degranulate at sites of vascular injury. We are interested in testing whether ectopically expressed proteins during megakaryopoiesis would be stored within platelets and released at sites of injury, modulating the thrombotic process. Initial transgenic studies suggest that we can accomplish this process, delivering platelet-released (p) Factor VIII (FVIII) to a site of injury to improve the bleeding diathesis in FVIIInull mice. In the following specific aims, we propose to better understand and improve on the transgenic pFVIII model, and to extend these studies to a gene therapy approach. Specific Aim I. Characterize clotting in the platelet delivery of FVIII model. Before human studies can be considered, the advantages and disadvantages of the delivery of FVIII via platelets needs to be better understood. Proposed studies should provide a better understanding of the details of the developing clot and define the efficacy of correcting the bleeding diathesis in FVIIInull mice in various bleeding models. We will address where and how pFVIII Is stored within platelets. Finally, we will test whether pFVIH's directed delivery to sites of injury may be more efficacious than plasma FVIII in the treatment of FVIIInull mice with inhibitors. Specific Aim II. Enhancing the efficacy of platelet-based correction of the hemophilias. The highest level of pFVIII achieved so far in transgenic animals had the equivalent of an approximately 3% plasma activity level. We propose several strategies to enhance the present model including the addition of further gene regulatory elements, the expression of FVIII mutants that either enhance FVIII intracellular processing or resistance to inactivation, and the expression of activated FVII within the platelets. Specific Aim III. Viral delivery of pFVIII. We have successfully extended these transgenic mice studies to bone marrow transplantation studies as a prelude to vectorbased gene therapy. Using a lentiviral approach, we plan to examine lentiviral-based in vivo gene therapy, initially driving megakaryocyte-specific expression of eGFP and then FVIII in mice. If successful, these studies will be extended to FVIIInull dogs, where bleeds are more representative of those seen in patients. We believe that successful application of these ideas may provide new approaches for the management of Hemophilia A and perhaps other diseases affecting thrombus formation. •
Project Title: ENDOGENOUS HNF4 LIGANDS IN PHYSIOLOGY AND DISEASE Principal Investigator & Institution: Sladek, Frances M.; Associate Professor; Cell Biology & Neuroscience; University of California Riverside 900 University Ave Riverside, Ca 92521 Timing: Fiscal Year 2005; Project Start 15-AUG-2005; Project End 31-JUL-2007 Summary: (provided by applicant): Hepatocyte nuclear factor 4 (HNF4) is an essential liver-enriched transcription factor that plays a central role in liver development and differentiation. HNF4 is mutated in an inherited form of type Il diabetes, Maturity Onset Diabetes of the Young 1 (MODY1), and regulates the expression of many genes responsible for liver function, including those in intermediary metabolism - i.e., glucose, lipid, amino acid, xenobiotic and drug metabolism - and blood maintenance as well as other transcription factors. Through its role in the liver and other tissues where it is also
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expressed - pancreas, kidney, intestine and colon - HNF4 is linked to several human diseases in addition to diabetes, including atherosclerosis, hemophilia, hepatitis and possibly cancer. HNF4 is also one of the most highly conserved members of the nuclear receptor superfamily and yet a ligand for h has not yet been identified. In this proposal, we use a novel method to identify an endogenous dietary compound that binds in the ligand binding pocket of HNF4 expressed in mammalian cells and mouse liver. In the two specific aims of this R21 we propose to: 1) determine whether the binding of the compound affects HNF4 function; 2) determine the physiological and pathological conditions under which HNF4 binds the compound. Results from these studies will not only enhance significantly our understanding of how HNF4 regulates transcription in the liver, kidney and the GI track but could also impact the use of HNF4 as a drug target for diabetes and possibly other diseases. •
Project Title: ENHANCING HEPATOCYTE GENE TRANSFER FOR HEMOPHILIA A Principal Investigator & Institution: Mccray, Paul B.; Professor; Pediatrics; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2005; Project Start 27-DEC-2004; Project End 30-NOV-2008 Summary: (provided by applicant): The overall goal of this project is to develop an in vivo gene transfer approach for the treatment of hemophilia A (factor VIII deficiency). Towards this end, we are using a lentiviral vector based on the non-primate feline immunodeficiency virus (FIV) expressing the human FVIII (FVIII) cDNA to correct the phenotype in a mouse model of the disorder. We demonstrated previously that intravenous delivery of an FIV vector encoding FVIII produced sustained protein expression and phenotypic correction in hemophilia A mice. We recently made a series of modifications to the FIV vector constructs, generating a self-inactivating vector containing several additional cis-acting regulatory/boundary elements. Furthermore, we found that the baculovirus GP64 glycoprotein directs efficient gene transfer to hepatocytes. Therefore, we hypothesize that the FVIII expression following in vivo gene transfer will be enhanced by pseudotyping the FIV vector with the GP64 glycoprotein. Aim 1 will investigate the efficacy of the extensively modified, baculovirus GP64 pseudotyped FIV vector in correcting FVIII deficiency in vivo. Studies proposed in Aim 2 seek to identify the cellular receptor(s) for GP64 pseudotyped FIV. Identification of viral receptors lends the ability to predict which cell types that can be transduced and allows a better understanding of vector/host cell biology. We will apply a cDNA microarray-based technique that was recently successfully used to identify the receptor for AAV5 to identify the receptor(s) for GP64/FIV. Aim 3 will investigate the FIV vector integration events in the liver following in vivo delivery. Because persistent expression from an integrated transgene is the desired outcome for this approach, documenting integration and mapping sites of integration are important first steps in understanding the fate of the vector following in vivo gene transfer. Completion of these aims will move us closer to clinical gene transfer application of FIV for the treatment of hemophilia A.
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Project Title: EX VIVO GENE THERAPY OF HEMOPHILIA A Principal Investigator & Institution: Doering, Christopher Bradley.; Expression Therapeutics 1441 Logan Cir Marietta, Ga 300625935 Timing: Fiscal Year 2006; Project Start 01-SEP-2006; Project End 31-AUG-2007 Summary: (provided by applicant): Hemophilia A is a bleeding disorder caused by mutations within the factor VIII (fVIII) gene that result in a deficiency of circulating fVIII
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activity. Current treatment for hemophilia relies on infusion of plasma-derived or recombinant fVIII to restore circulating fVIII activity. This form of therapy is 1) expensive, 2) hard to maintain due to the frequency and intravenous route of treatment, and 3) only offered to 30% of hemophilia A patients worldwide. The mission of Expression Therapeutics is to develop products that will improve the standard treatment of individuals with hemophilia A. Our technology is based on the identification of sequence elements within fVIII that can be modified to increase its biosynthesis. Gene therapy has the potential to cure hemophilia A. However in three previous clinical trials, the levels of circulating fVIII activity achieved were below that required for therapeutic efficacy and all trials ended following phase I. The goal of the studies proposed in this application is to demonstrate the effectiveness of fVIII high expression elements in a gene transfer-based treatment of hemophilia A. We propose to study the expression of several fVIII transgene constructs in vivo using the murine model of hemophilia A. Additionally, we will study fVIII biosynthesis from human stem/progenitor cells that are genetically modified using recombinant lentiviral vectors containing high expression fVIII transgenes. Demonstrating proof-of-concept that fVIII high expression elements are enabling to gene therapy of hemophilia A will represent a major milestone for Expression Therapeutics in the development of improved therapeutic treatments for hemophilia A. PROJECT NARATIVE Hemophilia A is a bleeding disorder caused by genetic mutation of a blood clotting factor, designated factor VIII (fVIII). Current treatment for hemophilia relies on infusion of plasmaderived or recombinant fVIII to restore circulating fVIII activity. This form of therapy is 1) expensive, 2) hard to maintain due to the frequency and intravenous route of treatment, and 3) only offered to 30% of hemophilia A patients worldwide. Therefore, the development of improved therapeutic treatments for hemophilia A, e.g. gene therapy, is warranted. •
Project Title: FACTOR VIII BIOENGINEERED FOR SECRETION EFFICIENCY Principal Investigator & Institution: Pipe, Steven W.; Associate Professor; Pediatrics and Communicable Diseases; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; Project Start 30-SEP-2005; Project End 31-AUG-2009 Summary: (provided by applicant): The inherited bleeding disorder hemophilia A results from a deficiency of plasma clotting factor VIII. Affected patients experience significant morbidity due to repeated joint hemorrhages and subsequent arthropathy and there is increased mortality related to life-threatening bleeding events. The majority of patients are treated with episodic or prophylactic infusions of recombinant FVIII (rFVIII). The ability to bioengineer recombinant clotting factors with improved function holds promise to overcome some of the limitations in current treatment, the high costs of therapy and increase availability to a broader world hemophilia population. These novel molecules partnered with advances in gene transfer vector design and delivery may ultimately achieve persistent expression of FVIII leading to an effective long-term treatment strategy for hemophilia A. In addition, these novel FVIII molecules could be partnered with new advances in alternative recombinant protein production in transgenic animals yielding an affordable, more abundant supply of rFVIII. The long term goal of the proposed research is to advance several novel bioengineered forms of rFVIII developed in our laboratory to readiness for a clinical trial in hemophilia A. Our research in the past has focused on the limitations of rFVIII synthesis, secretion and regulation of activity. This has given us insights to successfully make targeted modifications to rFVIII to overcome these limitations. The major goals of this proposal are to characterize the in vitro and in vivo properties or rFVIII bioengineered for
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improved secretion efficiency (Specific Aim 1) and rFVIII bioengineered to be resistant to inactivation (Specific Aim 2). The proposed experiments will use established biochemical assays to characterize the unique properties of these novel molecules as well as murine and canine hemophilia A animal models to characterize their control of bleeding. These novel rFVIII molecules will be produced by standard mammalian cell culture technology as well as in transgenic animals. We will also test whether the bioengineered modifications will increase the risk for antibody formation and adverse clotting events. Findings from the proposed experiments will provide insights into the FVIII secretion pathway, FVIII structure and function and intermolecular interactions in vivo. The results will directly impact on the future of rFVIII therapeutics for hemophilia. •
Project Title: FIX TOLERANCE IN HEMOPHILIA GENE THERAPY Principal Investigator & Institution: Chao, Hengjun; Assistant Professor; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 100296574 Timing: Fiscal Year 2005; Project Start 16-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Hemophilia B is an X-linked hemorrhagic disorder due to factor IX (FIX) deficiency. Hemophilia B patients suffer from recurrent spontaneous bleeding episodes and the severely affected patients become crippled resulting from recurrent bleeding in the major joints. Current treatment for hemophilia B consists of infusion of FIX concentrates in response to the bleeding episode. This approach is non-prophylactic and up to 5 percent of hemophilia B patients develop anti-FIX antibody after exposure to FIX. Continuous infusion of FIX concentrates can induce FIX tolerance, although the underlying mechanism is not clear. However, the huge cost of continuous infusion therapy makes it prohibitive to apply this treatment to the majority of hemophilia patients, even in developed western countries. Gene therapy based on direct intramuscular injection of recombinant adeno-associated virus serotype 2 (AAV2) can provide sustained expression of FIX, but is complicated by generation of anti-FIX inhibitory antibodies in immune competent animals. The applicants recently reported that direct intramuscular injections of AAV serotype one vectors (AAV1) effected sustained and complete hemophilia B phenotype correction without formation of anti-FIX inhibitory antibody in immunocompetent hemophilia B mice. Understanding the mechanism accounting for immune tolerance to FIX is crucial for the development of successful hemophilia therapy. We hypothesize that sustained expression of high levels of FIX expressed from AAV1 in skeletal muscle induces FIX tolerance by mechanism(s) of helper T lymphocyte energy or clonal deletion, and/or generation of regulatory T lymphocytes. The hypothesis will be tested by completing two specific aims: 1) investigating the effects of sustained high level FIX expression on induction of FIX tolerance, and 2) investigating the state of maturation of antigen presenting cells and helper T cell responses after antigen presentation in an AAV1based gene transfer protocol. The applicant's long-term goal is to develop a successful gene therapy approach for hemophilia B. The objective of this proposal is to elucidate the mechanism(s) accounting for FIX tolerance after direct intramuscular injection of AAV1, developing a novel approach not only to prevent generation of inhibitory FIX antibody but also to induce tolerance to pre-existing inhibitory FIX antibody in hemophilia B patients.
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Project Title: FLUOROGENIC ASSAYS FOR FACTOR VLLA AND TISSUE FACTOR Principal Investigator & Institution: Jenny, Richard J.; President and Scientific Director; Haematologic Technologies, Inc. 57 River Rd Essex Junction, Vt 05452 Timing: Fiscal Year 2005; Project Start 08-MAY-2003; Project End 31-AUG-2007 Summary: (provided by applicant): Factor VIIa and tissue factor (TF) are essential proteins for the initiation of blood coagulation. Blood coagulation is initiated when cryptic TF becomes exposed on the surface of vascular cells where it can bind circulating factor VIla. The factor Vlla/TF complex catalyzes the activation of certain blood zymogens that propagate the coagulation event. The amount of circulating factor VIla has been shown to be a good indicator of hemostatic potential, and for this reason is a potential risk factor indicator for the development of cardiovascular disease. In addition, over the past decade recombinant factor VIla has become the drug of choice for treating hemophilia A and B patients who have developed inhibitors to factors VIII and IX respectively. Formation of the factor Vlla/TF complex is also the basis of specific coagulation assays. The prothrombin time (PT assay) utilizes either natural or synthetic thromboplastin reagents to initiate coagulation in-vitro. Thus in addition to its in-vivo role, TF also has in-vitro applications. Furthermore, TF is not only present in the vasculature, but also in numerous other tissues and cells including brain, lung, placenta, monocytes and tumor cells. In addition to its "normal" role in hemostasis, it is also known to be involved in the metastasis of tumor cells. The fact that factor VIla and TF play such important roles both in vivo and in vitro, indicates that rapid and direct assays for these proteins could be of great utility. At the present time, reliable assays for factor VIla and TF that can be applied to simple and well as complex biological samples do not exist. During the Phase-l project period we demonstrated the feasibility of developing sensitive fluorogenic assays that can directly measure functional factor VIla and TF in simple and complex biological systems. Phase-ll funding will be used to support the further development, refinement, optimization, validation and field-testing of these assays. It is anticipated that by the end of the Phase-ll project period these assays will be ready to market for research and pre-clinical applications.
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Project Title: GENE THERAPY FOR BLOOD PROTEIN DEFICIENCIES Principal Investigator & Institution: Ponder, Katherine P.; Associate Professor of Internal Medicine; Internal Medicine; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2005; Project Start 01-SEP-2003; Project End 31-DEC-2006 Summary: Hemophilia B occurs in 1:30,000 males and is associated with a life-long bleeding diathesis. Although IV injection of Factor IX can prevent or stop bleeding, this treatment is inconvenient, expensive, and can transmit infections. Hepatic gene therapy could permanently correct the clinical manifestations of hemophilia. Retroviral vectors (RV) can result in long-term and therapeutic levels of expression of coagulation factors from the liver in rodents, and are currently being used in a clinical trial for Hemophilia A in humans. However, there are two major problems that must be solved before RVmediated hepatic gene therapy will be used routinely: 1) identify ways to achieve a higher efficiency of stable gene transfer without major toxicity; and 2) identify methods for blocking an immune response to the therapeutic gene in the context of RV-mediated hepatic gene therapy. This project will address both of these issues. The first aim is to determine if delivery of an RV expressing the canine Factor IX (cFIX) cDNA into the liver can reduce the bleeding manifestations of Hemophilia B dogs obtained from a colony that rarely makes antibodies to the canine protein. This should allow us to quantify gene expression without the confounding issue of an immune response. Initial
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studies will use neonatal dogs, as their high baseline level of hepatocyte replication allows transduction of 9 percent of liver cells. Subsequent studies will use hepatocyte growth factor to induce replication in young adult dogs. Animals will be evaluated for cFIX levels, development of antibodies, bleeding, and for other adverse effects. The second aim will address the second major problem of RV-mediated hepatic gene therapy, that of immune responses to the therapeutic gene product. In this aim, we will try to block immune responses to the de novo expression of a transgene from an RV in mice by either performing neonatal gene transfer, or by injecting immunoinhibitory agents at the time of gene therapy in young adults. Although mice are optimal for initial studies due to cost considerations, approaches that function in inbred mice sometimes fail in outbred larger animals. We will therefore test any immunomodulatory approaches that function in mice for their efficacy in normal and Hemophilia B dogs in Aim III. Success in this project might lead to a safe, effective, and permanent therapy for Hemophilia B. •
Project Title: GENE THERAPY FOR CORRECTION OF PIZ MUTATION Principal Investigator & Institution: Song, Sihong; Professor; Pharmaceutics; University of Florida 219 Grinter Hall Gainesville, Fl 32611 Timing: Fiscal Year 2005; Project Start 01-JUL-2005; Project End 30-JUN-2007 Summary: (provided by applicant): Alpha 1-antitrypsin (AAT) is normally secreted from hepatocytes and circulates in the plasma, protecting lung elastin from degradation by neutrophil elastase. Deficiency of AAT can lead to emphysema. In a subset of patients homozygous for the PI*Z mutation, liver disease may also develop, apparently related to accumulation and polymerization of the mutant protein within the endoplasmic reticulum of affected hepatocytes. Gene therapy for AAT deficiencyrelated emphysema requires producing high level of circulating AAT, which has been achieved by muscle and liver gene delivery in mouse models (Song et al 1998 PNAS, Song et al 2001 Gene Therapy). However, gene therapy for the liver disease requires decreasing mutant AAT and producing sufficient wt AAT. It will be beneficial for both liver and lung diseases from AAT deficiency, if we can turn the mutant mRNA into the wt mRNA of AAT. Recent studies have shown the correction of inherited skin diseases, and phenotype correction of hemophilia A mice by spliceosome-mediated RNA transsplicing (Chao et al 2003 Nature Medicine). In this proposal, we will test the feasibility of correction of mutant AAT RNA by spliceosome-mediated RNA trans-splicing in vitro and in vivo. In the specific aim 1, we will optimize the efficiency of mutant hAAT correction in vitro. 4 pre-trans-splicing RNA molecules (PTMs) will be designed for targeting introns (1, 2, 3 or 4) of hAAT (PiZ) pre-mRNA and evaluated by plasmid transfection into transformed liver cells from PiZ transgenic mouse. In the specific aim 2, we will evaluate the effect of recombinant adeno-associated virus serotype 8 (rAAV8) mediated PTM-gene therapy in PiZ transgenic mouse model. Serum levels of wt hAAT and Z-form hAAT will be monitored. The reduction of Z-form AAT accumulation in the liver will be evaluated. Liver pathology will be examined. We anticipate achieving the therapeutic correction in PiZ transgenic mouse model. The success of this project may lead to a novel gene therapy for clinical treatment of human AAT deficiency.
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Project Title: GENE THERAPY FOR HEMOPHILIA Principal Investigator & Institution: High, Katherine A.; William H. Bennett Professor of Pediatri; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 22-FEB-2000; Project End 30-APR-2010
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Summary: (provided by applicant): This is a competitive renewal application for a Program Project Grant entitled Gene Therapy for Hemophilia. The PPG consists of 4 projects and 3 cores. Three of the projects are continued from the previous PPG and one is new. Project 1, directed by Dr. Valder Arruda, analyzes the efficacy of two novel methods for delivering large doses of vector to skeletal muscle. Both methods rely on intravascular delivery of vector, and have resulted in transduction of extensive areas of skeletal muscle in large animals after a single intravascular injection. Project 1 will examine dose-response, the efficacy of alternate serotypes, and the possibility of readministration of vector, for both approaches. Project 1 will also examine the role of variant F.IX molecules with better egress from skeletal muscle or higher specific activity. Project 2, directed by Dr. Katherine High, examines critical safety issues that must be addressed before the intravascular delivery approach can be translated to clinical use. She will explore the immune response to the transgene product, and the risk of germline transmission of vector DNA, in both approaches. She will also determine the maximal levels of fully functional F.IX that can be synthesized in a given mass of skeletal muscle. Project 3, directed by Dr. Haig Kazazian, will explore AAV-mediated, liver-directed gene transfer approaches for hemophilia A, with an emphasis on analysis of novel AAV serotypes, in mice and dogs with hemophilia A. Project 4, directed by Dr. Mortimer Poncz, will continue his highly successful work of the previous funding period, in which he demonstrated that expression of F.VIII in megakaryocytes (and thus in circulating platelets) could correct the bleeding diathesis of hemophilia A mice. In particular he will explore the kinetics of clot formation in the presence of F.VIII-expressing platelets, and will define the cell biology of F.VIII storage and secretion from the gene-modified platelet. He will also examine variant F.VIII molecules with increased specific activity, and will develop lentiviral vectors to allow pursuit of this strategy in megakaryocytes of large animals. These projects will be supported by three cores. Core A, the Administrative Core, will support and co-ordinate scientific interactions among the group. Core B, the Vector Core, will provide research grade AAV and lentiviral vectors for the investigators. Finally, Core C, the Large Animal Models Core at UNC-Chapel Hill, will provide access to hemophilic dogs and will provide expertise in coagulation testing in these animals. •
Project Title: GENE THERAPY FOR HEMOPHILIA Principal Investigator & Institution: Kay, Mark A.; Professor; Pediatrics; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2005; Project Start 28-SEP-2000; Project End 31-AUG-2007 Summary: (provided by applicant): The following application is to continue support an inter-institutional Program of Excellence in Gene Therapy (PEGT). The participating institutions include: Stanford University, The Children's Hospital of Philadelphia, and The University of Pennsylvania and investigators with a well-documented history of collaboration including the successful implementation of an AAV- liver based gene therapy trial. We have used the information learned from this trial to develop new preclinical clinical trials. In this application, there are 3 preclinical gene therapy proposals 2 clinical trials. There are three "local" core proposals (for the investigators of this PEGT), a Research Grade AAV, Administrative, and Clinical Core. We also propose a unique training program to offer post-doctoral candidates research training in gene therapy. A National Morphology core is designed to provide all NHLBI investigators with unique services to further advance the study of gene transfer and/or transgene expression in animal models. The common theme of this proposal is AAV-mediated gene based therapies for hemophilia: (#1) Dr. Katherine High will test the hypothesis that the bleeding diathesis in hemophilia patients with inhibitory antibodies can be
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treated with a gene therapy approach. This grant builds on a decade of clinical experience with recombinant Vila and on the investigator's expertise with coagulation proteins and their expression using AAV vectors. (#2) Dr. Haig Kazazian and colleagues will build on their success in treating hemophilia A mice using new AAV serotypes. They will determine optimal conditions for liver-based gene transfer in fetal monkeys, and validate these conditions in neonatal monkeys and neonatal hemophilia A dogs. (#3) Dr. Mark Kay plans to develop novel AAV pseudotyped vectors that may evade immunological parameters that have limited efficacy in human trials. His group will use non-mammalian primate AAVs and snuffled capsid libraries to make novel vectors and test them in the appropriate animal models. (#4) Dr. Catherine Manno will continue an AAV-2 liver based trial using transient immunosuppressive therapy to attempt to eliminate a T cell mediated elimination of transduced hepatocytes in humans. (#5) Dr. Bertil Glader is proposing a clinical trial using AAV-8 vectors that based on preclinical studies suggesting that this vector pseudotype has advantages over AAV-2. Nonetheless, as has been learned during the previous funding period, even the best animal models and preclinical studies cannot always predict the outcome in humans, supporting the need for multiple approaches. The combined efforts of this group of investigators have a long and productive history that will further research towards a cure for hemophilia. INDIVIDUAL PROJECTS AND CORE UNITS: Project 1: Novel Therapeutic Approach for Hemophilia Using Engineered Secreted FVIIa. (High, Katherine) (provided by applicant): The goal of Project 1 is to determine the feasibility of expression of FVIIa as the transgene in a gene therapy approach for hemophilia. Work with recombinant proteins has established that hemophilia, caused by mutations in genes encoding Factors VIII or IX in the intrinsic pathway of coagulation, can be treated by infusion of activated Factor VII, an enzyme of the extrinsic pathway. In the previous funding period, we created an engineered FVIIa variant, expressed it in a recombinant AAV vector, introduced the vector into the livers of hemophilic mice, and demonstrated long-term expression of activated FVII and amelioration of the hemophilic phenotype. We propose to build on this proof-of-concept by 1) defining precisely the minimum level of VIla required for improvement in hemostasis, and the maximum safe tolerated levels. This will be accomplished by studying hemostatic endpoints in both vectortreated and transgenic Vila-expressing mice. We will use state-of-the-art methods to examine kinetics of clot formation, clot stability, and clot composition as a function of circulating levels of FVIIa in hemophilic mice. 2) In the second aim, we will extend this work to the large animal model of hemophilia. In these experiments we will infuse an AAV vector expressing activated canine FVII into the liver of dogs with severe hemophilia, and determine levels that are safely tolerated and that result in improved hemostasis. 3) Finally, we will capitalize on a novel vector delivery method that we have developed during the previous funding period. This route of administration exploits the extensive capillary network of skeletal muscle to effect transduction of large areas of skeletal muscle. We will determine whether regional intravascular delivery allows us to achieve adequate levels of FVIIa expression using a target organ skeletal muscle) that is accessible for nearly all hemophilia patients, even those with severe liver changes due to viral hepatitis. Successful development of a Vila-based gene transfer strategy would be applicable for both -VIII and FIX deficiency, would avoid problems of immune response to the transgene product (FVIII or FIX) identified in preclinical gene transfer studies, by using a transgene to which the recipient is fully tolerant, and would circumvent problems of short half-life and need for IV infusion that characterize therapy with the recombinant Vila protein. (End of Abstract)
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Project Title: GENE THERAPY PULMONARY & HEMATOLOGIC DISORDERS Principal Investigator & Institution: Samulski, Richard J.; Director, Gene Therapy Center; Pharmacology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2005; Project Start 30-SEP-2001; Project End 31-JUL-2007 Summary: ABSTRACT (provided by the applicant) The goal of this PPG, Gene Therapy for Pulmonary and Hematologic Disorders, is to facilitate translation of basic knowledge of gene delivery to safe and rigorous human clinical trials. The long-range goal is to provide novel therapeutic modalities for treating monogenetic diseases such as Hemophilia and Cystic Fibrosis. The major objectives in the UNC PPG are: (1) the development of highly efficient and high titer viral vectors, optimum expression, and safe persisting delivery systems, and (2) development of novel animal models for better defining rate limiting steps involved in target cell transduction, analysis of long term high level vector gene expression, and expression of normal and mutant human genes (e.g. FIX, CFTR). Four basic science projects and four cores are proposed. The basic research projects are proposed to focus on understanding rate-limiting steps in effective gene transfer. Projects 1 and 2 focus on AAV (Samulski) and Lentivirus (Olsen and Kafri), respectively. These projects are aimed at understanding and overcoming inefficient gene delivery related to virus entry and persistent transgene expression. The goal of the proposed studies is to generate new knowledge about the safety and biological efficacy of gene delivery, which will provide information important to the design of future clinical trials. Projects 3 and 4 involve animal models for airway (Boucher) and hemophilia (Stafford) disorders, respectively. These studies aim to define the host-associated rate limiting step(s) for understanding of the cell biology of the target tissue for efficient in vivo gene delivery and translating improvements in vector development. Specifically, goals include increasing access to airway epithelia (Project 3), development of novel models (e.g. a humanized hemophilia mouse, Project 4). This work will be supported by four cores, Administrative (Core A), Vector (Core B), Animal (Core C), and Morphology (Core D). The PPG is a highly interactive program comprised of clinical investigators and expert basic laboratories designed to optimize vectors and to test their interactions with target cells in vitro and in vivo. The ultimate goal of the UNC PPG is to achieve safe, effective, gene delivery in humans.
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Project Title: GENERATION OF INTERFERING RNA MOLECULES BY TRANSSPLICING Principal Investigator & Institution: Cote, Colette A.; Intronn, Inc. 9700 Great Seneca Hwy, Ste 210 Rockville, Md 20850 Timing: Fiscal Year 2006; Project Start 01-FEB-2006; Project End 31-JAN-2007 Summary: (provided by applicant): Although RNA interference (RNAi) technology has revolutionized the process of rapidly and efficiently generating models to study disease, it has been limited by the lack of robust control over short interfering or micro RNA (siRNA/miRNA) expression. The need for better regulation has prompted the development of novel, conditional siRNA/miRNA expression systems, all of which currently rely on the use of transcriptional controls. While these offer some advantages, it would be desirable to have siRNA expression under tighter and more versatile control. Here we propose such a system that promises exquisite regulation by integrating two dynamic and naturally occurring processes, RNAi and spliceosomemediated RNA trans-splicing (SMaRT). SMaRT takes advantage of the native mammalian splicing machinery to reprogram the sequence of a targeted pre-mRNA through the activity of a Pre-Trans-splicing Molecule (PTM). PTMs and SMaRT have
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been used to correct genetic disorders in mice (e.g. hemophilia A), to image tumor cells in living animals, and to attempt suicide gene therapy of virally infected cells in culture. We propose to use SMaRT to generate novel pri-miRNAs, which will be created by the specific trans-splicing of a PTM and a unique pre- mRNA. Because the pri-miRNA is only generated upon trans-splicing to the correct pre-mRNA, these methods will prevent ectopic RNAi. To develop this SMaRT RNAi methodology we propose the following specific aims: In specific aim 1 we will develop PTMs that form novel primiRNAs capable of generating alpha-1 antitrypsin (AAT)-, human papillomavirus-16 (HPV16)- or TATA box binding protein (TBP)-specific miRNAs in tissue culture cells. In specific aim 2 we will develop and optimize the conditional expression of the miRNAs by altering the availability of the trans-splicing pre-mRNA. In specific aim 3 we propose to broaden the application of SMaRT RNAi by developing PTMs that upon transsplicing to human papillomavirus-16 pre- mRNAs lead to the synthesis of miRNAs that knockdown the essential gene product TATA binding protein. This conditional silencing of TBP should result in the death of cells harboring papillomavirus genomes but not of normal cells. Thus the regulation provided by SMaRT RNAi establishes the groundwork for a new generation of conditional knockdown model systems and potential therapeutic modalities with global applications in human disease. •
Project Title: GENETICS & BIOCHEMISTRY OF A MURINE RETROPOSON Principal Investigator & Institution: Martin, Sandra L.; Professor; Cell and Developmental Biology; University of Colorado Denver/Hsc Aurora P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2005; Project Start 01-JUL-1988; Project End 30-JUN-2006 Summary: (provided by applicant): LINE-1 (long interspersed repeated sequence one, or L1) is a major dynamic force in the mammalian genome. Retrotransposition deposits the progeny of L1 throughout the genome, sometimes leading to gene disruption, modified expression of adjacent genes, and/or transduction of neighboring DNA. In addition, L1, as interspersed, repetitive DNA, provides a substrate for homologous recombination of mispaired sequences, leading to gene duplication, deletion, chromosome translocation and, potentially, exon shuffling. All of these dynamic events can lead to disease; in fact, LINE-1 insertional mutagenesis has been found to be responsible for hemophilia and muscular dystrophy, as well as breast and colon cancer in humans. Thus, it is extremely important to understand the details of the intermediates involved in retrotransposition and the mechanisms used to control their expression and movement in vivo. If the normal control mechanisms of L1 expression and retrotransposition become deranged either during development (gametogenesis or early embryogenesis) or in somatic cells in response to environmental insults, movement and rearrangement of L1 sequences could be instrumental in the generation of genetic diseases, birth defects and cancer. LINE-1 retrotransposition begins with transcription of a full-length, sense-strand L1 RNA and requires two L1-encoded polypeptides. These proteins probably also catalyze the reverse transcription and integration of SINEs (short interspersed repeated sequences) and processed pseudogenes, thereby amplifying the effects of LINE-1 in mammalian genome dynamics. Our long-range goal is to understand the retrotransposition process in detail, including the biochemical intermediates involved as well as its control in genetic and evolutionary time. Specifically, the studies proposed here are designed to: 1) elucidate the role of the L1-encoded ORF1 protein during retrotransposition by investigating the nucleic acid and protein-protein interaction activities of wild-type and mutant proteins in detail; 2) identify cellular proteins that interact with ORF1p then determine whether they facilitate and/or inhibit L1 retrotransposition, and; 3) determine whether translation of ORF2 and/or ORF1
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involves cap-independent mechanisms for initiation that contribute to the control of L1 retrotransposition. •
Project Title: HDAD-MEDIATED GENE THERAPY FOR HEMOPHILIA B Principal Investigator & Institution: Brunetti-Pierri, Nicola; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2007; Project Start 01-DEC-2006; Project End 30-NOV-2008 Summary: (provided by applicant): HDAd are attractive gene therapy vectors that can mediate long-term, high level FIX expression from transduced hepatocytes leading to sustained phenotypic correction of FIX-deficiency in mice and dogs with no chronic toxicity. However, systemic high dose administration, required for efficient hepatic transduction, results in activation of an acute inflammatory response with potentially severe and lethal consequences. The mechanism responsible for Ad-mediated activation of the acute inflammatory response is not known, however, it is clearly dose-dependent. We have developed an in vivo gene therapy delivery approach for HDAd which has proven to be very successful in a large animal model. This method entails the use of balloon occlusion catheters to deliver HDAd preferentially to the liver of nonhuman primates. During the mentored phase, I propose to complete the nonhuman primate studies already initiated to establish dose-response relationship and vector biodistribution following vector delivery with this novel method. In Specific Aim 1, I will investigate the dose-response relationship ranging from 1x1010 to 1x1011 vp/kg of HDAd expressing baboon (-fetoprotein (bAFP) under the control of a liver specific promoter. In Specific Aim 2, I will investigate the biodistribution of HDAd vector delivered through balloon catheter-assisted delivery in nonhuman primates and to carry out formal toxicity studies, both performed under conditions to satisfy the requirements of the FDA for a phase I clinical trial. In the independent phase, I propose to investigate safety and efficacy of the balloon catheter-assisted delivery of HDAd into the clinically relevant animal model of hemophilia B. The proposed experiments are designed to generate the data necessary to progress towards human clinical trials for the treatment of hemophilia B (Specific Aim 3). In Specific Aim 4, I will investigate HDAd expressing genetically engineered FIX molecules with greater catalytic activity. This strategy is specifically designed to achieve therapeutic FIX levels using low vector doses. If superior, these catalytically enhanced FIX molecules will not only increase the safety and efficacy of HDAd-mediated hemophilia B gene therapy, but will also be valuable for other vector systems as well as for recombinant protein replacement therapy. During the independent phase I also propose to investigate, in nonhuman primates, the efficacy and safety of liver-directed gene therapy using naked plasmid DNA vector (pDNA) delivered through the balloon catheter-assisted delivery (Specific Aim 5).
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Project Title: HEMOSTASIS CLINICAL RESEARCH NETWORK PROTOCOLS Principal Investigator & Institution: Leissinger, Cindy A.; Medicine; Tulane University of Louisiana 6823 St Charles Ave New Orleans, La 70118 Timing: Fiscal Year 2005; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Patients with disorders of hemostasis are subject to long term problems and risks, difficult treatment decisions and risks associated with treatment itself. Many of these risks and complications can be lessened or prevented by appropriate intervention strategies. Advances in the management of patients with bleeding disorders of relatively low incidence require: 1) that clinical studies utilize a multi-institutional cooperative network in order to accrue sufficient numbers of patients to achieve meaningful answers; and 2) that patients be educated on the vital importance
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of participation in such studies. The purpose of this project is to develop a Hemostasis Core Clinical Research Unit at Tulane University as part of the NIH Transfusion Medicine/Hemostasis Clinical Research Network. This Unit will be developed using some of the basic infrastructure and services of the Tulane Center for Bleeding Disorders, which is dedicated to the care and advancement of patients with disorders of hemostasis. Once established, this Core Research Unit will provide access to clinical trials for hemostasis patients from the Center for Bleeding Disorders, the Bone Marrow Transplant Unit and from throughout the network of Tulane affiliated hospitals and clinics. In addition, two clinical trial protocols have been developed as part of this proposal. The first, A prospective randomized crossover study of activated prothrombin complex concentrates (aPCCs) as prophylactic therapy in hemophilia A patients with inhibitors, is a long-term protocol designed to evaluate the efficacy of aPCCs in the prevention of bleeds in this very complicated group of patients. The second, short-term protocol, A prospective study of ribavirin for the treatment of HIVassociated immunopathic thrombocytopenic purpura (ITP), was developed to test a novel pharmacologic agent in the management of HIV-ITP. •
Project Title: IMMUNE Principal Investigator & Institution: Terhorst, Cornelis; Wistar Institute 3601 Spruce Street Philadelphia, Pa 191044265 Timing: Fiscal Year 2005; Project Start 05-AUG-2005; Project End 30-JUN-2010 Summary: The central hypothesis of this proposal is that controlling the function of CD4+25+ reguhatory T cells (Treg) invivo will abrogate cellular and humoral immune responses to human coagulation factor IX (hF.IX) antigen,which is administered by adeno-associated viral (rAAV) gene transfer. Because markers of Treg cells haveonly recently become available, it is now possible to enhance the number of activated Treg cells in vivo.The experiments proposed in this application are designed to examine the contributions and limitations ofGITR and GITR-Ligand based on/off switches of Treg cell suppression of cell-mediated and humoral immune responses elicited by rAAVhF.IX gene transfer. Secondly, adoptive transfer based cell therapy with Treg cells will be applied to control the rAAV-hF.IX induced cell-mediated responses. Third a strategy that targets activated cytopathic reactive T cells and spares immunoregulatory networks will be adapted from the transplantation field.The experiments proposed in this application are grouped in the following specific aims:Specific Aim #1: To test the hypothesis that administering a soluble GITR-Ligand-Fc fusion protein [Fc-GITR-L] inactivates Treg cell functions and thus enhances humoral and cellular immune responses to rAAV-hF.IX.Specific Aim #2: To test the hypothesis that treatment with a monoclonal antibody directed at mouse GITR-L enhances Treg cell suppression and immune tolerance to hF.IX antigens and AAV capsid antigen.Specific Aim #3: To test the hypothesis that suppression and/or deletion of potentially pathogenic T cells facilitates Treg mediated immunologic tolerance towards hF.IX.Together these experiments should clarify the role of Treg cell controlled pathways in rAAV hF.IX genetherapy. The results of these studies should suggest therapeutic strategies that can immediately be appliedto hemophilia patients.
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Project Title: IMMUNE RESPONSE FOR HEMOPHILIA AFTER REPLACEMENT THERAPY Principal Investigator & Institution: Miao, Carol H.; Research Assistant Professor; Children's Hospital and Reg Medical Ctr 4800 Sand Point Way Ne Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 27-SEP-2005; Project End 31-AUG-2009
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Summary: (provided by applicant): The goal of this study is to develop strategies to reduce/eliminate inhibitory antibodies in hemophilia A patients following repeated factor VIII infusion or gene therapy. Formation of inhibitory antibodies is a major problem in protein replacement therapy and expected to be a problem in gene therapy for hemophilia A patients. Approximately 25-50% of hemophilic patients develop antiFVIII antibodies after repeated infusion of recombinant or pooled hFVIII protein. Following successful transfer of the factor VIII gene into the livers of hemophilia A mice by hydrodynamic-based nonviral gene transfer of a liver-specific, high-expressing FVIII plasmid, resulting in Supra-physiological levels of FVIII. We observed a robust immune response against FVIII two weeks post-treatment. This led to complete inhibition of circulating FVIII activity. This inhibitory response was mediated by a Th2-dominant human immune response. This inhibitory response completely ablated FVIII activity despite continued (essentially lifelong) FVIII production. This animal model is an ideal system for developing strategies to ameliorate the immune responses against FVIII. Recent data have demonstrated a critical role that CD4+CD25* regulatory T (Treg) cells in the regulation and suppression of autoimmune and alloimmune responses. Clinical trials of Treg infusion in BMT patients to prevent graft-versus-host disease (GVHD) are under way. Furthermore, Foxp3 which encodes the transcription factor Scurfin, is a master regulatory gene for the development and function of CD4+CD25+ regulatory T cells. In mice, ex vivo retroviral gene transfer of Foxp3 can convert peripheral CD25CD45RO-CD4+ naive T cells into a regulatory T cell phenotype similar to CD4+CD25+ regulatory T cells. In addition, Treg type 1 cells (Tr1 cells) which can be induced by specific antigen and IL-10 have also been shown to maintain peripheral tolerance. We anticipate that an effective method to produce FVIII-specific CD4+CD25+ Treg cells (and/or Tr1) cells could provide a novel strategy to eliminate existing inhibitory antibodies and potentially induce long-term tolerance for hemophilia A patients with inhibitors. In this proposal we will test the hypotheses that: 1) Overexpression of Foxp3 in hemophilia A mice will modulate the immune responses against FVIII following gene transfer; 2) Lentiviral-based Foxp3 expression within FVIII-specific CD4+ T cells will induce CD4+CD25+Foxp3+ Treg cells. Further we predict that transplantation of such FVIII-specific Treg cells into hemophilia A mice will induce tolerance against FVIII; and 3) Lentiviral-based Foxp3 expression within FVIII-specific CD4+ T cells isolated from human hemophilia A patients with inhibitors can be used to generate FVIII-specific CD4+CD25+Foxp3+ Treg cells. This cell population could potentially be utilized in the future for cellular therapy in this disease setting. •
Project Title: IMMUNE RESPONSES TO AAV-MEDIATED FIX GENE TRANSFER Principal Investigator & Institution: Ertl, Hildegund C J.; 215-898-3863; Wistar Institute 3601 Spruce Street Philadelphia, Pa 191044265 Timing: Fiscal Year 2005; Project Start 05-AUG-2005; Project End 30-JUN-2010 Summary: (provided by applicant): The goal of this application is to further characterize immune responses that can cause the elimination of recombinant adeno-associated virus (rAAV) transduced cells. Most humans are naturally exposed to AAV-2 together with a helper virus and thus have immunological memory to AAV-2. Memory T cells can be triggered more readily than naive lymphocytes, which was not taken into account by pre-clinical animal experiments conducted thus far. Concerns about immunological consequences of rAAV-mediated gene transfer were substantiated by the outcome of a clinical trial in which human hemophilia B patients were infused into the liver with rAAV-2-F.IX vectors. Only one patient achieved therapeutic levels of F.IX, which were sustained for 4 weeks and then started to decline. At the same time the patient developed a transaminitis, which resolved after F.IX levels decreased to baseline levels.
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Overall, the patient's clinical course was compatible with immune-mediated destruction of rAAV-transduced hepatocytes. Additional data generated since substantiated our hypothesis that AAV-2-specific T cells induced by a natural infection can cause elimination of rAAV-transduced hepatocytes. To further define immune responses to AAV and rAAV-encoded transgenes under conditions thai mimic those of human hemophilia patients and to then devise informed strategies to circumvent such problems we are proposing 4 interlinked Projects supported by 2 Cores. Project by High will define T cell responses to AAV capsid proteins in humans and in non-human primates and assess their effect on hepatic rAAV-mediated gene transfer. Project by Ertl will elucidate the effect of pre-existing AAV-2-specific T cell-mediated immunity on hepatic rAAV vector-mediated gene transfer in mice. Project by Herzog will define regulatory immune responses that prevent induction of CD8+ T cell responses to a rAAV-encoded transgene product. Project by Terhorst will focus on the potential use of regulatory T cells to ablate unwanted immune responses to rAAV-mediated gene transfer. The projects will be supported by an Administrative Core, which will provide the needed oversight, and a Vector Core, which will provide the investigators with purified and quality controlled vectors. •
Project Title: IMMUNOLOGY OF FACTOR IX GENE TRANSFER TO LIVER Principal Investigator & Institution: Herzog, Roland W.; Associate Professortant Profess0r; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 01-APR-2002; Project End 30-JUN-2005 Summary: Hemophilia B is the X-linked bleeding disorder caused by absence of functional coagulation factor IX (F.IX). Pre-clinical studies in animal models have shown that gene transfer mediated by an adeno-associated viral (AAV) vector results in sustained expression of F.IX and partial correction of the coagulation deficiency. A Phase I clinical trial has been carried out based on intramuscular administration of vector to patients with severe hemophilia B, and a Phase I trial for liver-directed gene transfer (by infusion of the vector into the hepatic circulation) is now approved. Currently, the most serious complication of treatment for hemophilia by protein-based therapy is the formation of inhibitory antibodies against the coagulation factor. Using murine and canine models, we have demonstrated sustained F.IX expression with the muscle-directed approach in the context of a F.IX missense mutation, while expression in the context of a F.IX gene deletion/null mutation was limited by inhibitor formation. However, in animals of the same strain, sustained expression without inhibitor formation has been accomplished using liver-directed gene therapy. Thus, the immunological outcome of gene transfer is dependent on the combination of vector and target tissue. We found that AAV-mediated gene transfer to the liver can induce immunological unresponsiveness to F.IX, which may be explained by either a tolerance or a suppression mechanism. Anti-F.IX formation is dependent on CD4+ T helper cells. Therefore, we are proposing a gene transfer model based on mice transgenic for an ovalbumin CD4 about-restricted T cell receptor in order to define the events leading to antigen-specific immunity or unresponsiveness after AAV-mediated gene transfer of a secreted protein. We will investigate potential mechanisms of tolerance induction (clonal deletion, T cell anergy) or suppression/immune deviation (e.g. by activation of regulatory cells) in hepatic gene transfer as opposed to T cell priming associated with a neutralizing antibody response in lymph nodes of injected muscle. For both the ovalbumin and the F.IX system, we will perform adoptive lymphocyte transfer experiments to distinguish tolerance and suppression mechanisms in liver-directed gene transfer. In recently generated transgenic mice expressing liver-derived variants of
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human F.IX, the risk of inhibitor formation in liver-directed gene therapy can be directly compared to other treatment modalities after mice have been crossed with hemophilia B mice on the appropriate genetic background. Finally, the risk of inhibitor formation may be further reduced by a combination of liver-directed gene transfer and transient immune modulation. Taken together, these studies will provide a detailed analysis of transgene product-specific T cell responses following AAV-mediated hepatic gene transfer. •
Project Title: IMPACT OF HIV ON HEPATITIS C INFECTION IN HEMOPHILIA Principal Investigator & Institution: Ragni, Margaret V.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 11-APR-2001; Project End 31-MAR-2007 Summary: (provided by applicant) The purpose of this study is to determine the impact of HIV infection on hepatitis C virus (HCV) liver disease outcome, and the prevalence, risk factors, and viral and immunologic characteristics of liver disease in HCV-infected hemophiliacs, both HIV(+) and HIV(-). Approximately 826 HCV-infected hemophiliacs from 10 U.S. hemophilia treatment centers will be available for study. This group is unique in that patients are well characterized, closely followed, the time of HCV infection is known, HCV infection duration is greater than 20 years, and the incidence of liver disease progression is increasing. The specific objectives of this study include: (1) a cross-sectional cohort study in which hemophiliacs with HCV infection, both HIV(+) and HIV(-), are enrolled and undergo transjugular liver biopsy to determine the prevalence of cirrhosis and fibrosis progression rate. (2) a cross-sectional study comparing HCV-infected patients, both HIV- and HIV+, to determine clinical, life-style, and laboratory, e.g. biochemical, serologic, molecular biologic, and immunologic characteristics associated with development of cirrhosis and stage of fibrosis progression. (3) a cytokine study, comparing cytokine mRNA levels, interleukin-6 (IL-6), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta 1 and TGF-beta 2) in liver tissue, cytokine immunoassay levels in plasma, and cytokine expression genotypes with liver histopathologic score and with fibrosis progression rate in prospectively-biopsied hemophiliacs.
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Project Title: IN UTERO STEM CELL TRANSPLANTATION FOR HEMOPHILIA A Principal Investigator & Institution: Almeida-Porada, Graca; Associate Professor; Animal Biotechnology; University of Nevada Reno 204 Ross Hall Mailstop 325 Reno, Nv 89557 Timing: Fiscal Year 2005; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Hemophilia A is an X-linked recessive bleeding disorder caused by the deficiency/abnormality of Factor VIII. Currently, treatment of hemophilia involves factor replacement using fresh frozen plasma, cryoprecipitate, or Factor VIII concentrate. While this greatly improves the quality of life of hemophiliacs, it is less than ideal, since regular treatments are required throughout the life of the patient. Treating hemophilia in utero would enable correction prior to disease onset, thus allowing the birth of a healthy baby who requires no further treatment. Our laboratory has developed and optimized a unique sheep model for in utero stem cell transplantation (IUSCT) that allows the engraftment and differentiation of human stem cells in the absence of preconditioning, by virtue of the early gestational recipient's preimmune status. This model has proven to be an accurate and valuable pre-clinical system for evaluating approaches to IUSCT, and the data generated in this model was used to conduct the first successful clinical IUSCT in a patient with X-SCID. In addition
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to the durable hematopoietic engraftment, transplanted hematopoietic stem cells (HSC) and marrow-derived mesenchymal stem cells (MSC) also give rise to other tissues in this model, including significant numbers of functional hepatocytes. These results suggest that adult marrow-derived stem cells may be ideally suited for cellular therapy to correct disorders such as the hemophilias in which a liver-derived factor is defective or absent. In the present proposal we will test this hypothesis by utilizing cryopreserved semen to re-establish a line of sheep that exhibited spontaneous factor VIII deficiency with symptomology closely mimicking that of human hemophilia A, while simultaneously transplanting normal sheep fetuses with adult HSC and MSC to determine the optimal stem cell population(s) for generating functional hepatic cells in vivo. We will then transplant the affected fetuses in utero with the optimal stem cell population(s) and assess whether this in utero cell therapy approach produces therapeutic benefit in this clinically relevant large animal model of hemophilia A. We will also examine the liver and other tissues of the recipient hemophilic sheep to establish a correlation between the degree of clinical improvement and the levels of Factor VIII-producing cells generated by the transplanted adult human HSC and MSC. It is hoped that these studies using adult BM-derived stem cells will lead to the development of a successful stem cell-based therapeutic approach to treat hemophilia prior to birth, thus obviating the need for lifelong factor therapy with its inherent risks/shortcomings. •
Project Title: INDUCTION OF TOLERANCE TO FACTOR VIII IN HEMOPHILIC Principal Investigator & Institution: Scott, David W.; Professor; Surgery; University of Maryland Balt Prof School Professional School Baltimore, Md 21201 Timing: Fiscal Year 2005; Project Start 30-SEP-1998; Project End 30-JUN-2007 Summary: (provided by applicant): The focus of our lab has been to use our knowledge of tolerance mechanisms to develop novel approaches for the prevention or reversal of undesirable immune responses, including inhibitor formation in hemophilia. Up to 2530% of hemophilia patients produce antibodies (inhibitors) to therapeutic clotting factor VIII (FVIII), presumably because tolerance has not been adequately induced. Therefore, the induction of tolerance to FVIII is an important goal. We have utilized immunoglobulin (Ig) fusion proteins delivered via retroviral vectors in B-cells for the induction of tolerance. The multiple epitopes so expressed via B-cell MHC class II antigen presentation have been shown to lead to immunologic tolerance at both T-cell and B-cell levels. Data in several experimental autoimmune models (uveitis, EAE for multiple sclerosis and diabetes) are promising in that significant clinical efficacy has been achieved, even in immunized recipients. While effects on antibody-mediated responses have been obtained with model antigens, extension to modulation of undesirable T-cell dependent antibody responses in a mouse model for hemophilia has not been tested. The novelty of this system is that the target antigen, FVIII, is well defined, as are the major domains recognized by inhibitors. Herein we propose to apply this technology for the prevention and/or elimination of FVIII inhibitors in murine hemophilia. Our initial goal is to induce tolerance to major domains of FVIII, to evaluate the requirement for the Ig scaffold, and to analyze the cellular basis of tolerance, including the role of CD25 + regulatory T cells. Specifically, we will engineer multiple domains of FVIII (A2, C2) into retroviral fusion protein constructs delivered singly or in concert via B-cells for effective tolerance induction, as measured by both Tcell and B-cell responsiveness. Importantly, we will determine whether this approach will lead to the elimination of responses not only to those domains, but also to the entire therapeutically delivered molecule. Later, we will apply this approach to reverse ongoing immune responses to FVIII in primed FVIII knockout (-/-) mice, and determine
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whether anti-CD40L treatment enhances the tolerogenicity in this model. The fate, activation state and responsiveness of domain-specific primed T cells will be followed to assess the mechanisms of tolerance. Using modified lentiviral vectors, we will test whether expression of B-domain less FVIII may be necessary to achieve effective tolerance, and if the IgG carrier enhances this process. These studies are an important step toward future pre-clinical testing in non-human primates. •
Project Title: INTEGRATED PROGRAM FOR PERSONS WITH HEMOSTATIC DISORDERS Principal Investigator & Institution: Ortel, Thomas L.; Associate Professor; Medicine; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2005; Project Start 01-JUL-2004; Project End 30-JUN-2007 Summary: Recent advances in diagnostic testing and therapeutic management have greatly improved our ability to deliver care to patients with disorders of hemostasis. Many individuals remain inadequately evaluated or treated, however, for a variety of reasons, including incomplete or incorrect diagnostic testing, inadequate management strategies, and patient lack of access to the healthcare system. We implemented the Duke Comprehensive Hemostasis & Thrombosis Center to integrate existing areas of clinical expertise in the Duke University Health System into a coordinated service. The Center also provides access to clinical research 3rotocols, emphasizes patient education, and has provided the groundwork for developing a training program for healthcare providers interested in disorders of hemostasis. The following Aims will enhance the activity and mission of the Duke Hemostasis & Thrombosis Center. (1) Determine the efficacy of integrated multi-disciplinary care and prevention services for persons with hemophilia, other hereditary bleeding disorders including women with bleeding disorders, and thrombophilia to reduce morbidity and mortality associated with bleeding and clotting diseases. Monitoring strategies will focus on clinical outcomes, patient access, and patient satisfaction. (2) Assess unmet needs for service delivery and identify outreach strategies designed to improve access to care. Unmet needs will be identified at a local level as well as at regional and national levels. (3) Develop effective messages aimed at disease management and prevention. Internet-based as well as paper-based educational messages will be developed to promote patient awareness and education. (4) Foster the development of training programs to enhance provider skills for the delivery of care to persons with disorders of hemostasis. We will use the information obtained through these Aims to enhance the quality of the clinical services that are provided through the Duke Hemostasis & Thrombosis Center, as well as developing exceptional training opportunities for healthcare providers, clinical researchers, and basic investigators.
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Project Title: INTEGRATING PREVENTION SERVICES FOR BLEEDING & CLOTTING Principal Investigator & Institution: Philipp, Claire S.; Medicine; Univ of Med/Dent NjR W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 088548021 Timing: Fiscal Year 2005; Project Start 01-JUL-2004; Project End 30-JUN-2007 Summary: The Division of Hematology of UMDNJ-Robert Wood Johnson Medical School sponsors three combined adult and pediatric programs in hemostasis and thrombosis serving the entire state of New Jersey. The New Jersey Regional Hemophilia Program was established in 1976 for the comprehensive care of hemophilia and related bleeding disorders and has strong collaborative relationships with the Hemophilia Association of New Jersey (HANJ) and the New Jersey State Department of Health and
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Human Services (NJ-DOHHS). The Thrombosis Center, established in 1992, serves as a referral center for the prevention, diagnosis, and treatment of thrombotic disorders. The Women with Bleeding Disorders program was established in 1997 in close collaboration with the Division of General Gynecology, the Women's Health Initiative at RWJMS and the Women with Bleeding Disorders Committee of HANJ. There is a need to develop systematic and comprehensive approaches, clinical as well as investigational, to diagnose, treat and prevent clotting and bleeding disorders across gender and all age categories and to fully evaluate the benefits of such an approach. The goals of this project are to integrate Thrombophilia, Women with Bleeding Disorders, and comprehensive Hemophilia care programs under an organizational umbrella and to evaluate feasibility, outcomes, and benefits of such an approach-particularly in preventing long-term complications. The specific goals are: I) to implement uniform data collection to demonstrate scope and effectiveness of existing comprehensive care in thrombophilia and women with bleeding disorders population, 2) to determine an optimal and effective comprehensivecare model in thrombophilia and women with bleeding disorders populations, including effective prevention components, 3) to develop effective training and outreach programs for subspecialty providers, other related specialties, and locally based consumer organizations. The programs will be integrated through structured collaborative relationships with the New Jersey State Department of Health and the Hemophilia Association of New Jersey. •
Project Title: INTRAVASCULAR DELIVERY OF AAV TO SKELETAL MUSCLE Principal Investigator & Institution: Arruda, Valder R.; Assistant Professor; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2010 Summary: In previous work, we showed that intramuscular (IM) injection of a recombinant adeno-associated viral (AAV) serotype 2 vector expressing F.IX resulted in long-term expression of F.IX in mice and hemophilic dogs. Phase I clinical studies demonstrated that IM injection of AAV-F.IX in humans was safe and resulted in gene transfer and expression as judged by biopsy of injected muscle in all patients tested. Although access to skeletal muscle is easily performed by direct IM injections, achievement of AAV therapeutic target doses in humans has proved impractical because of the large number (> 300 sites) of injections required. Thus there is a great interest in exploiting techniques that allow transduction of large numbers of muscle fibers without requiring hundreds of intramuscular injections. Skeletal muscle contains a rich network of capillaries that can be chemically and/or mechanically modified to ensure vascular leakage of fluid containing vectors. The overall goal of this work is to establish the efficacy and safety of novel regional intravascular delivery methods of vectors to extensive areas of the skeletal muscle of a limb. In aim 1 we will determine the efficacy and safety of two different regional intravascular delivery methods. The first method is isolated limb perfusion (ILP) in which the vector is delivered through the femoral artery. The second approach is anterograde limb perfusion (ALP) in which the vector is injected through a superficial vein in the distal part of the limb under elevated hydrostatic pressure. This goal is encouraged by our preliminary data on these techniques documenting widespread transduction of muscle tissue of the hind limb in normal dogs and by the improvement of the hemophilia B phenotype in a canine model of severe hemophilia B. In aim 2 we will determine whether AAV vectors of alternate serotypes result in higher levels of F.IX expression. These results will have clinical implications in terms of (a) dose-response advantage of non-AAV-2 vectors, and (b) treatment of patients with high titer neutralizing antibodies to AAV-2 (about 20% of general population). In aim 3 we will test whether the use of F.IX variants could
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improve the efficacy in terms of the amount of F.IX required for the correction of the hemophilia B phenotype. For a disease category in which a substantial percentage (>80%) of severely affected adults have iatrogenic underlying liver disease, a muscledirected strategy is very attractive. The results of this translational study will establish an experimental basis for clinical studies of this delivery method in humans with hemophilia B and also for gene transfer for other diseases such as muscular dystrophy. •
Project Title: INVESTIGATION OF PROTEIN INTERACTIONS IN INTRINSIC BLOOD COAGULATION PATHWAY Principal Investigator & Institution: Venkateswarlu, Divi; Chemistry; North Carolina Agri & Tech St Univ 1601 E Market St Greensboro, Nc 27411 Timing: Fiscal Year 2007; Project Start 01-FEB-2007; Project End 31-JAN-2009 Summary: (provided by applicant): We propose to employ computational protein modeling and aqueous-phase molecular dynamics methods to develop threedimensional solution structural models based on partial X-ray crystal structural data and comparative homology modeling techniques. During the requested funding period, we propose to develop structural assembly of multi-domain proteins associated with intrinsic blood coagulation pathway. The specific objectives of the project are: (Aim I): to develop the dynamically equilibrated structural models for factors VIIIa, IXa and FX (Aim II) to model the binary complex between co-factor FVIIIa and factor FIXa (also known as intrinsic Xnase complex). (Aim III) to build the ternary complex among factors FVIIIa, FIXa and zymogen factor FX in an effort to delineate the protein recognition sites during FX activation. (Aim IV) to develop the binary complex between enzyme FIXa and zymogen FX to understand co-factor independent association of FIXa:FX By providing a structural understanding, we hope to address the following questions: i) What specific domains of the individual proteins, i.e., FVIIIa and FIXa, are involved in the intrinsic Xnase complex formation? Ii) How different are the domain-domain interactions and conformations upon co-factor binding? iii) What is the activation mechanism for zymogen FX proteolysis in intrinsic pathway? And iv) Can we decipher the structure-function correlation between the vast amount of hemophilia A and B patient mutational database and the proposed structural models, and if yes, can one use the protein- protein interaction data at the atomic details to engineer the therapeutic proteins? PHS 398/2590 (Rev. 09/04) Page 9 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Venkateswarlu, Divi PROJECT NARRATIVE This research project, under NIH's Academic Research Enhancement Award (AREA) program, is to apply modern computational modeling and simulation methods to understand the dynamic nature of the protein- protein interactions associated with the intrinsic pathway of blood coagulation cascade. The complex process of coagulation involves a series of enzymatic reaction mechanisms that are autoregulated by various activation-deactivation pathways. At least twenty proteins are known to play a major role in the cascade (Davie et al, 1991). Intrinsic pathway of blood coagulation involves the proteolytic activation of zymogenic factor X by serine protease IXa in the presence of phospholipids and divalent metal ions. Factor IXa is known to activate factor X at biologically significant rate only in association with co-factor VIIIa (Duffy & Lollar, 1992). The importance of co-factor FVIIIa-factor FIXa enzyme complex and its role in FX activation is illustrated by hemophilia in which the absence of either protein causes life-threatening bleeding disorders. Deficiency or defect in FVIIIa results in hemophilia-A which occur in 1 per 5000 patients. Currently, there is no cure for hemophilia and the existing therapy includes administration of recombinant FVIII or Bdomain deleted rFVIII (Abshire et al, 2000). Similarly, genetic mutations in FIXa are associated with the bleeding diatheses hemophilia B. In contrast, high levels of FVIII
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activity have recently been reported to be associated with an increased risk of thrombosis (Kraaijenhagen et al, 2000). Thus, there is a great deal of interest in understanding the molecular structure of the three proteins VIIIa,IXa and FX and to develop a structure-function relationship among the three proteins and correlate with the known genetic mutations in FVIIIa (about 270 are known so far) with the structure. We plan to develop a complete molecular mapping of protein interaction sites among the human forms of enzyme (FIXa), substrate (FX) and co-factor (FVIIIa) proteins associated with the intrinsic pathway. We propose to employ computational protein modeling and aqueous-phase molecular dynamics methods to develop threedimensional solution structural models based on partial X-ray crystal structural data and comparative homology modeling techniques. During the requested funding period, we propose to develop structural assembly of multi-domain proteins associated with intrinsic blood coagulation pathway. The specific objectives of the project are: (Aim I): to develop the dynamically equilibrated structural models for factors VIIIa, IXa and FX (Aim II) to model the binary complex between co-factor FVIIIa and factor FIXa (also known as intrinsic Xnase complex). (Aim III) to build the ternary complex among factors FVIIIa, FIXa and zymogen factor FX in an effort to delineate the protein recognition sites during FX activation. (Aim IV) to develop the binary complex between enzyme FIXa and zymogen FX to understand co-factor independent association of FIXa:FX (Aim V) to train graduate and undergraduate students in learning and applying modern computational protein modeling/bioinformatics methods to the problems in biochemical sciences. The training program is expected to provide a vehicle for the students at the Investigator's Institution, which is a predominantly minority serving HBCU, enter the biomedical research programs at research-intensive universities for doctoral and other higher studies. By providing a structural understanding, we hope to address the following questions: i) What specific domains of the individual proteins, i.e., FVIIIa and FIXa, are involved in the intrinsic Xnase complex formation? Ii) How different are the domain-domain interactions and conformations upon co-factor binding? iii) What is the activation mechanism for zymogen FX proteolysis in intrinsic pathway? And iv) Can we decipher the structure- function correlation between the vast amount of hemophilia A and B patient mutational database and the proposed structural models, and if yes, can one use the protein-protein interaction data at the atomic details to engineer the therapeutic proteins? •
Project Title: LENTIVIRAL VECTOR BASED GENE THERAPY FOR LIVER DISEASES Principal Investigator & Institution: Kafri, Tal; Assistant Professor; Microbiology and Immunology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2005; Project Start 01-APR-2001; Project End 31-JAN-2007 Summary: (Copied from Applicant Abstract): The overall goal of this study is to validate our hypothesis that lentivirus vectors can serve as an efficient and safe platform for therapeutic gene delivery to the liver tissue. The ability of HIV-1 and other lentiviruses to transduce non-dividing cells prompt the development of an HIV-l based gene delivery system. The novel lentivirus vectors proved efficient at transducing various tissues in vivo (brain, liver, muscle, retina, and hematopoietic stem cells) without any detectable pathology. Recently, we showed that a single intraperitoneal injection of hemophilic mice with lentivirus vectors resulted in long term expression of therapeutic levels of canine factor IX. The treated mice demonstrated aPTT values equivalent to those obtained from heterozygous littermates. In addition our preliminary results indicated that cis-regulatory sequences in the lentivirus down-regulate transgene
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expression. These studies are most encouraging, however we believe that further improvements in: vector production, trsansgene expression, and regulation, and better characterization of the mechanism responsible for the development of inhibitory antibodies are required before we can consider the use of the lentiviral system as a safe and efficient viral vector for liver gene therapy. To facilitate safe vector production we propose to generate a novel third generation packaging cell line, which will be devoid of the Tat and all HIV-l accessory proteins. As an additional measurement of safety, we will separate the new packaging system into four stably integrated plasmids (vector, envelope, packaging, and rev). To improve transgene expression from the lentivirus vector cassette we will attempt to identify and delete inhibitory sequences from the lentivirus vector genome. To improve regulation of transgene expression we will generate an improved new inducible lentivirus vector which will exhibit minimal basal inducible promoter activity. Testing the proposed improvements in hemophilic mouse and canine animal models will allow us to characterize potential immune response against the newly synthesized factor IX. We believe that the ability to maintain therapeutic levels of factor IX in these animal models will determine the feasibility of using lentivirus vector based gene therapy to cure hemophilia B and other hepatic metabolic diseases. •
Project Title: LENTIVIRAL VECTORS FOR GENE THERAPY FOR BETATHALASSEMIA Principal Investigator & Institution: Malik, Punam; Associate Professor of Pediatrics and Pa; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2005; Project Start 08-MAY-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The B-thalassemias are the most common single gene defect in humans and result from absent or decreased B-globin synthesis, leading to severe anemia. Patients with B-thalassemia major are treated with life-long transfusions. Bone marrow transplantation can be curative, but is limited to a few with matched donors, and has potentially serious complications. Replacement of a normal Bglobin gene into hematopoietic stem cells (HSCs) can potentially correct the disorder permanently, avoiding the complications associated with a transplant. With the advent of better vectors, improved gene transfer techniques and a better understanding of stem cell and vector biology, gene therapy is going from the bench to the bedside, in diseases like SCID and hemophilia B. 'Globin' gene therapy has suffered from problems of vector instability, low titers and variable expression. The recently developed lentiviral vectors transduce the non-dividing HSCs and stably export large genomic fragments by unique RNA export mechanisms, imparting stability to globin vectors. Self-inactivating (SIN) lentiviral vectors are even more advantageous: the viral LTR is deleted upon integration into cells, completely inactivating viral transcription. This feature is ideal for the expression of a highly lineage-restricted gene such as globin, and additionally improves their bio-safety. We have recently shown remarkably lineage-specific and long-term expression of GFP and gamma-globin from SIN lentiviral vectors in mouse erythroleukemia (MEL) cells, primary murine and human cells. We propose to capitalize on these findings by examining the capabilities of SIN lentiviral vectors to carry the human B-globin gene and erythroid regulatory elements for gene transfer into HSCs that results in stable, lineage-specific and sustained expression of B-globin in RBCs. The aims of the study are to: 1) Develop SIN-lentiviral vectors carrying the human B-globin gene under control of erythroid regulatory elements, and screen them in MEL cells for stable transmission and high level expression. 2) Determine the efficacy, lineage specificity and long term expression of B-globin SIN lentiviral vectors in vivo, in thalassemic mice. 3) Determine the gene transfer capacity and efficacy of B-globin SIN
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lentiviral vectors in the RBC progeny of human thalassemia progenitor cells, using a unique model of human RBC production developed in our laboratory from hematopoietic progenitor cells. Together, these aims comprise a focussed research program to produce therapeutic and sustained levels of B-globin in human thalassemia RBCs, and form the basis for future preclinical studies. •
Project Title: LENTIVIRAL VECTORS FOR GENE TRANSFER Principal Investigator & Institution: Verma, Inder M.; Professor; Salk Institute for Biological Studies 10010 N Torrey Pines Rd La Jolla, Ca 920371099 Timing: Fiscal Year 2005; Project Start 30-SEP-1994; Project End 31-MAR-2009 Summary: (provided by applicant): Gene therapy is a form of medicine which can have a major impact on human health in this century. The scope of gene therapy ranges from correcting a myriad of genetic diseases to acquired diseases like cancer, neurodegeneration, and infectious diseases. The concept of gene therapy is disarmingly simple-introduce the gene, and its product should alleviate the defect, slow down progression of the disease, or ameliorate the disease. Why then has gene therapy not been proven to be a greater success and the answer lies in the execution of the concept of gene therapy? How do you introduce genes in the liver with a billion cells or the brain with a trillion neurons? Much of the effort, not surprisingly in the field of gene therapy, has remained in generating suitable delivery vehicles. We propose to improve lentivectors based delivery system by utilizing more efficient tissue-specific transcriptional units, which can be regulated by external manipulation. Because viruses are usually foreign to the body, we want to identify the cellular factors that may hinder the production or transduction by delivery vehicles. Since lentiviral vectors have the ability to efficiently introduce foreign genes in fertilized mouse eggs, we plan to use this property to generate mouse disease models, which will mimic the human disease. We specifically want to generate mouse models, which faithfully recapitulate human hemophilia due to factor IX and factor VIII deficiency. The methodology also allows us to explore the possibility to generate transgenic nonhuman primates. We also propose to use the emerging RNA interference technology (SiRNA) for combination with lentiviral vectors to generate recombinant viruses capable of silencing gene expression in cells, tissues and whole organisms. Finally ability of lentiviral vectors to efficiently introduce genes in mouse or human embryonic stem (ES) cells will allow us to manipulate their differentiations to desired lineages. We strongly believe that continued improvement of lentiviral vectors for gene transfer is an important and challenging goal to pursue.
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Project Title: LOW ANTIGENICITY FACTOR VIII Principal Investigator & Institution: Mueksch, Josef; Octagen Corporation Bala Cynwyd, Pa 19004 Timing: Fiscal Year 2006; Project Start 01-JUL-2000; Project End 31-JUL-2008 Summary: (provided by applicant): Octagen's broad, long-term objective is to complete the clinical development and secure FDA approval of its b-domain deleted recombinant factor VIII (OBI-1), a low antigenicity version of factor VIM (fVIII). OBI-1 is designed for the treatment of patients with inhibitory, neutralizing antibodies to human fVIII. Such "inhibitor" patients include congenital hemophiliacs who are refractory to human fVIII, as well as patients with "acquired hemophilia." The development of an inhibitor to human fVIII is a serious, potentially life-threatening condition. Current treatment options are not always effective and there is a need for improved therapies. The specific aims of this application are to conduct: 1. an open-label, non-comparative phase II study of the hemostatic efficacy, pharmacokinetics and safety of OBI-1 in non-life and non-
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limb-threatening bleeding episodes in congenital hemophilia A inhibitor patients, 2. an open-label, non-comparative phase III study of the efficacy and safety of OBI-1 in longterm repeated treatment of hemorrhages congenital hemophilia A inhibitor patients, 3. an open-label, non-comparative phase III study of the efficacy and safety of OBI-1 in the treatment of hemorrhages in patients with acquired hemophilia A, 4. an open-label, non-comparative phase III study of the efficacy and safety of OBI-1 in prophylaxis during surgery in patients with congenital hemophilia A inhibitor patients, 5. an openlabel, non-comparative phase III study of the efficacy and safety of OBI-1 in prophylaxis during surgery in patients with acquired hemophilia A, 6. an open-label, noncomparative phase III study of the efficacy and safety of OBI-1 in the treatment of hemorrhages in hemophilia A inhibitor patients and in acquired hemophilia A patients in whom all approved products have failed to control the hemorrhage. •
Project Title: MODEL GENE THERAPY OF HEMOPHILIA A VIA LIVER DIRECTED Principal Investigator & Institution: Kazazian, Haig; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2005; Project Start 29-SEP-2005; Project End 31-AUG-2006 Summary: In the previous four years of this PEGT, we carried out AAV-mediated gene delivery of FVIII cDNA to hemophilia A mice and dogs. Recently, we found that use of the new AAV capsid serotypes, AAV8 and AAV9, to deliver canine FVIII heavy and light chain sequences in either two separate vectors or a single vector led to complete long-term correction of hemophilia A mice. This result was obtained with either intraportal or intravenous delivery. However, results from intraportal delivery of canine heavy and light chain cDNAs to hemophilia A dogs in an AAV8 vector have been disappointing. One dog in three has had partial correction of 4-8% activity for 18 months, while the other two had only 1% FVIII activity. Since the best animal model and best developmental stage for FVIII gene therapy are unknown, we now have decided to turn to a non-human primate, the rhesus macaque, and to carry out gene delivery in the fetus and neonate. In Specific Aim 1, we develop the tools for monkey studies, cloning human FVIII cDNA in two separate constructs and developing a human-specific FVIII antibody. In Specific Aim 2, we study the effectiveness of three different AAV serotypes, AAV8, AAV9, and the best available hybrid AAV vector, at two different doses of vector. In this Aim, two fetal monkeys will be evaluated for each of the six conditions with all fetuses undergoing intrahepatic delivery of vector in late first trimester. In Specific Aim 3, we will validate the optimal conditions for effective FVIII gene delivery discovered in Specific Aim 2 using neonatal monkeys and neonatal hemophilia A dogs. Thus, in this renewal we will find conditions for safe, long term FVIII expression in early development as a model for a useful treatment option for hemophilia A.
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Project Title: MOLECULAR & CELLULAR MECHANISMS IN TRANSFUSION MEDICINE Principal Investigator & Institution: Newman, Peter J.; Vice President for Research; Bloodcenter of Wisconsin, Inc. P.O. Box 2178, 638 N 18Th St Milwaukee, Wi 53233 Timing: Fiscal Year 2006; Project Start 01-MAY-1997; Project End 30-NOV-2010 Summary: (provided by applicant): This is a revised competitive renewal application for years 16-20 of Program Project Grant HL-44612, which provides support for a coordinated, multi-disciplinary investigation of molecular and cellular mechanisms important to the field of transfusion medicine - a discipline that, despite its obvious importance to the nation's health, has historically been underrepresented in both
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training and research resources. Our application reflects ongoing, close collaborative ties that have existed amongst the Project Leaders for more than a decade, and who remain committed to interrelated research projects centered around the biology of blood and vascular cells. In the first Project, Peter and Debra Newman propose four interrelated aims that seek to further our understanding of the cell surface receptors and associated signaling pathways that regulate platelet activation and adhesion. In the second Project, Dick Aster proposes to continue his investigation of pre-existing, "naturally-occurring" antibodies that cause acute platelet destruction in patients exposed to abciximab or ligand-mimetic GPIIb/IIIa inhibitors, and may have important implications for other immune disorders. The third Project, led by Cheryl Hillery, seeks to define how blood coagulation pathways contribute to sickle cell-induced organ damage, and to explore potential therapies that limit both acute episodes of vaso-occlusion and the accompanying chronic organ damage. The fourth Project, led by Bob Montgomery continues to explore the structural requirements for VWF biosynthesis that lay the foundation for an entirely novel replacement therapy approach for the treatment of patients with severe hemophilia A. The Shared Instrumentation Core will continue to provide centralized instrumentation and expertise for DNA sequence analysis, peptide synthesis, microscopy/digital image analysis, histology, flow cytometry and cell sorting, BIAcore analysis, and monoclonal antibody production. The Transgenic/Knockout Mouse Core will assist with vector design, transgenic mouse production, embryonic stem cell growth and transfection, breeding, and animal husbandry. Taken together, the overall scientific synergy of ideas, reagents and expertise afforded by these multiple collaborations should enable this Program Project in Transfusion Medicine Research, to advance our understanding of the biology of blood and vascular cells, and to apply findings made toward treating blood diseases and enhancing the effectiveness of transfusion therapy. •
Project Title: MOLECULAR AND CELLULAR CHARACTERIZATION OF AAV1 VECTOR Principal Investigator & Institution: Xiao, Weidong; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2005; Project Start 01-DEC-2001; Project End 30-NOV-2006 Summary: Adeno-associated virus (AAV) has been studied extensively as a gene therapy vector. Results from both preclinical studies and clinical trials using recombinant AAV (rAAV) vector suggest that this vector would be safe and effective for muscle gene delivery. Currently, the most widely used rAAV vector is based on AAV serotype 2 because it is the most extensively characterized serotype. Recently, characterization of AAV serotype 1 demonstrated that AAV1 based vectors are approximately 10 to 20-fold more effective than AAV2 for delivery into muscle. Such dramatic differences suggest that AAV1 vector is not merely an alternative vector for AAV2 but has distinctive advantages over the AAV2 vector. Scientifically, AAV1 offers an excellent tool to study the biology and vectorology of AAV. As a continuation of my previous work, the following studies are proposed to characterize AAV1 as a gene therapy vector using hemophilia B as a disease model. 1). To identify the tissue tropism determinants of AAV1 for muscle. The hypothesis to be tested in this specific aim is that some dissimilar amino acid clusters between AAV1 and AAV2 account for the differences in affinity for muscle. Such dramatic differences in transducing muscle provide a reliable assay for the tissue tropism determinants. 2). To characterize the biological properties of AAV1/2 hybrid helpers, and to identify the cellular receptors for AAV1 virus. 3). To explore the effectiveness of AAV 1 and its hybrid derivative vectors
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in correcting the phenotype in hemophilic mice, and to administer these vectors to animals with neutralizing antibodies against AAV. •
Project Title: MOLECULAR CHIMERISM THERAPY FOR HEMOPHILIA A Principal Investigator & Institution: Hawley, Robert G.; Head; Anatomy and Cell Biology; George Washington University Office of Research Services Washington, Dc 20052 Timing: Fiscal Year 2006; Project Start 01-JUL-2000; Project End 30-JUN-2010 Summary: (provided by applicant): Hemophilia A is an X-linked recessive genetic bleeding disorder caused by a deficiency or functional defect in coagulation factor VIII (FVIII). There is currently no cure for hemophilia A and patients receive infusion of FVIII concentrates or recombinant proteins at the time of bleeding. Although this treatment regimen has increased the life expectancy of hemophiliacs significantly, it is inconvenient and has potentially serious complications such as the development of inhibitory antibodies to FVIII, which occurs in approximately 25% of patients, rendering them refractory to further treatment. The objective of this research is to evaluate the curative efficacy of retroviral vectors encoding modified human FVIII transgenes targeted to hematopoietic stem cells (HSCs) in a murine hemophilia A model. HSCs are an attractive target cell population for hemophilia A gene therapy because they are readily accessible for ex vivo genetic modification and allow for the possibility of sustained expression of a FVIII transgene in circulating peripheral blood cells for the recipient's lifetime. Moreover, a potential benefit of targeting HSCs is the possibility of inducing immunological tolerance to the FVIII transgene product. For almost two decades, our laboratory has been designing and optimizing retroviral vectors for gene transfer studies of HSC biology and gene therapy modeling. In particular, our MSCV (murine stem cell virus) retroviral vector is in use in several HSC gene therapy trials currently underway in the United States. However, the emergence of adverse events in a French clinical trial for X- linked severe combined immunodeficiency disease demands a reevaluation of the risks of retroviral-induced mutagenesis. Therefore, building upon our recent success at achieving clinically-relevant FVIII plasma levels in hemophilia A mice by MSCV-based HSC-directed gene delivery, our Specific Aims are: (1) To further optimize FVIII transgene sequences for more efficient secretion in hematopoietic cells and decreased immunogenicity of the protein; (2) To develop nonmyeloablative HSC transplant conditioning regimens that allow sufficient levels of transgene molecular chimerism for long-term therapeutic FVIII production and tolerance induction; and (3) To create biologically safer FVIII retroviral vectors - devoid of transcriptional regulatory elements within their long terminal repeats and flanked by enhancer/promoterblocking elements - displaying reduced HSC genotoxicity.
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Project Title: MOLECULAR THERAPUETICS FOR EPITHELIAL DISORDERS Principal Investigator & Institution: Khavari, Paul A.; Professor; Dermatology; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2005; Project Start 01-JUL-1998; Project End 30-JUN-2007 Summary: (provided by applicant): While functional correction of genodermatoses has been demonstrated using retroviral mediated ex-vivo gene therapy, the cost and traumatic features of this procedure has led to the search for additional non-viral technologies for gene therapy. Non-viral vector gene transfer vectors have been plagued by the inability to get both therapeutic and persistent levels of gene expression in vivo. We have recently described a non-viral vector system based on DNA transposons that integrates an expression cassette into the chromosomal DNA of hepatocytes in vivo.
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Stable gene transfer is achieved by transient expression from the transposase gene resulting in the integration of transposon DNA flanking an expression cassette. As a result, life-long and therapeutic concentrations of human factor IX have been achieved in hemophilia B mice. Moreover, there is no toxicity and secondary transposition if it occurs is extremely rare. The two major limitations of this system are the limited gene transfer capacity (-5.0 kb), and the efficiency of integration, which is ~5% of transfected: hepatocytes in vivo and varies between different cell types in culture. While the effectiveness of this transposon has been demonstrated for diseases like hemophilia, there are other diseases in which the efficiency and size of the -DN A insert will need to be increased. We have made progress in that we have identified hyperactive transposase mutants that are >8x more efficient than the original transposase that in Combination with a new transposon increases integration by 14x and allows for efficient transposition of DNA molecules of at least 14 kb. We have recently shown that transposon-based vectors work well in skin models and plan to test current and newly obtained hyperactive transposons hi skin models of gene transfer. Moreover, we will use our new chimeric transposase-helper dependent adenoviral vector system in preclinical gene therapy studies. •
Project Title: NOVEL THERAPEUTIC APPROACH FOR HEMOPHILIA USING ENGINERED SECRETED FVIIA Principal Investigator & Institution: High, Catherine; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2005; Project Start 29-SEP-2005; Project End 31-AUG-2006 Summary: The goal of Project 1 is to determine the feasibility of expression of FVIIa as the transgene in a gene therapy approach for hemophilia. Work with recombinant proteins has established that hemophilia, caused by nutations in genes encoding Factors VIII or IX in the intrinsic pathway of coagulation, can be treated by infusion of activated Factor VII, an enzyme of the extrinsic pathway. In the previous funding period, we treated an engineered FVIIa variant, expressed it in a recombinant AAV vector, introduced the vector into the livers of hemophilic mice, and demonstrated long-term expression of activated FVII and amelioration of the hemophilic phenotype. We propose to build on this proof-of-concept by 1) defining precisely the minimum level of VIla required for improvement in hemostasis, and the maximum safe tolerated levels. This will be accomplished by studying hemostatic endpoints in both vector-treated and transgenic VIIa-expressing mice. We will use state-of-the-art methods to examine kinetics of clot formation, clot stability, and clot composition as a function of circulating levels of FVIIa in hemophilic mice. 2) In the second aim, we will extend this work to the large animal model of hemophilia. In these experiments we will infuse an AAV vector expressing activated canine FVII into the liver of dogs with severe hemophilia, and determine levels that are safely tolerated and that result in improved hemostasis. 3) Finally, we will capitalize on a novel vector delivery method that we have developed during the previous funding period. This route of administration exploits the extensive capillary network of skeletal muscle to effect transduction of large areas of skeletal muscle. We will determine whether regional intravascular delivery allows us to achieve adequate levels of FVIIa expression using a target organ (skeletal muscle) that is accessible for nearly all hemophilia patients, even those with severe liver changes due to viral hepatitis. Successful development of a VIla-based gene transfer strategy would be applicable for both FVIII and FIX deficiency, would avoid problems of immune response to the transgene product (FVIII or FIX) identified in preclinical gene transfer studies, by using a transgene to which the recipient is fully tolerant, and would
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circumvent problems of short half-life and need for IV infusion that characterize therapy with the recombinant VIla protein. •
Project Title: NOVEL THERAPIES IN HEMOSTASIS AND TRANSFUSION MEDICINE Principal Investigator & Institution: Bussel, James Bruce.; Associate Professor of Pediatrics; Pediatrics; Weill Medical College of Cornell Univ 1300 York Avenue New York, Ny 10021 Timing: Fiscal Year 2005; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): This application is in response to RFA HL-02-001 entitled Transfusion Medicine/Hemostasis Clinical Network and is a consortium of the New York Presbyterian Hospital - Weill Cornell College of Medicine-Columbia College of Physicians and Surgeons. It provides health care to > 20% of the New York City metropolitan area and has access to > 20 million people within 2 hours. It is an amalgam of physicians and scientists involved in clinical research in Hemostasis and Transfusion Medicine with expertise in Pediatrics, Internal Medicine, Pathology, and Surgery. The group has both the patient population and the clinical expertise required to participate in clinical trials proposed by other centers in the Network. Specific Aim 1 is a clinical trial of refractory ITP, defined as children and adults with ITP who have failed to respond to splenectomy. It intends to focus on the pathophysiology of refractory ITP by comparing two novel treatments. One, rituximab, is an anti-CD20 which depletes the recipient of B cells and should be an effective immunosuppressant in a "pure" autoantibody disease like ITP. There is preliminary data describing its effectiveness which should optimize its use. The other arm intends to use thrombopoietin or mimetic (TPO) to increase the platelet count by stimulating platelet production. This arm hypothesizes that a critical element in refractory ITP is a decreased production of platelets which can be rectified by stimulation with TPO. A registry of splenectomy will be included to facilitate enrollment of eligible patients. Specific Aim 2 intends to optimize granulocytes for transfusion. This would be of great potential benefit to patients with prolonged, severe neutropenia who suffer considerable morbidity and occasional mortality from infection. There is also the high cost of prolonged hospitalizations. In the past, studies of granulocyte transfusion showed little benefit and significant toxicity. The current study will explore different methods of preparation of granulocytes and also novel techniques for evaluation of their efficacy. Specific Aim 3 demonstrates that the consortium is able to participate in protocols for a wide variety of disorders of hemostasis and transfusion medicine. The consortium includes Dr. Grima of the NY Blood Center who annually phereses approximately 20 TTP patients; a leading center, Cornell, for management of patients with alloimmune thrombocytopenia;and a large hemophilia center.
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Project Title: PATHOGENESIS OF HIV AND HCV IN HEMOPHILIA: HGDS Principal Investigator & Institution: Gomperts, Edward D.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2004; Project Start 25-SEP-2001; Project End 31-AUG-2007 Summary: (provided by the applicant) This study will define host and immune factors that influence HCV and HIV-1 infection. Understanding the immunopathogenesis of HIV-1 is vital to vaccine development and the establishment of new treatment strategies. In addition, HCV infection is recognized as a major worldwide threat with significant implications for HIV-1-coinfected individuals. The specific aims of this application are: 1) to investigate the role of viral specific immunologic responses in controlling HIV-1
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and HCV infection, 2) to investigate the relationship between CD4+ and CD8+ cellular activation with HIV-1 viral load, HCV viral load, and HIV-1 clinical progression, 3) to investigate how host genetic factors that modulate the expression of intracellular cytokines affect the levels of HCV RNA, HIV-1 RNA and HIV-1 clinical progression, and 4) to investigate the mechanism by which HCV infection affects HIV-1 clinical progression. This study will utilize biologic specimens stored from participants in the Hemophilia Growth and Development Study (HGDS), a U.S. multi-center natural history study that enrolled subjects between 1989 and 1990 with 7-8 years of follow-up. The HGDS included those who were HCV infected (n=126) and those HIV-1/HCV coinfected (n=207). The first aim will utilize tetramer and ELlSPOT assays on longitudinally collected specimens to determine the relationship between HIV-1 specific responses and the control of viral replication and clinical progression. Similar studies will be performed to test the relationship between HCV-specific responses and HCV viral load in both cohorts. The second aim will determine if cellular activation, as measured by expression of activation markers on longitudinally collected CD4+ and CD8+ cells, is associated with HIV-1 and HCV RNA levels, as well as HIV-1 clinical progression. The third aim will determine if genetic polymorphisms in the promoter region of various Th1 and Th2 cytokines predicts HIV-1 clinical progression, and/or the quantity of inducible intracellular cytokines. The final aim of this study will explore the mechanism underlying recent observations that HCV infection and viral load adversely affect HIV-1 clinical progression. Two potential explanations for these observations will be tested. First, to determine if systemic cellular activation, that may occur in the setting of chronic HCV replication, accounts for the enhanced risk of HIV-1 progression, after controlling for CD4+ cell number and HIV viral load. Second, to explore the possibility that chronic HCV infection, previously shown to occur in the setting of waning HCVspecific immune responses, is associated with down-regulation of HIV-1 specific cellular responses and clinical progression. This study will utilize state-of-the-art technology in a well-characterized cohort to expand the current understanding of host and immune factors that influence viral replication and clinical disease progression. •
Project Title: PEGT ADMINISTRATIVE COORDINATING CENTER AT WEILL CORNELL Principal Investigator & Institution: Zalaznick, Robert; Medicine; Weill Medical College of Cornell Univ 1300 York Avenue New York, Ny 10021 Timing: Fiscal Year 2005; Project Start 29-SEP-2000; Project End 31-AUG-2007 Summary: (provided by applicant): The following application is to continue support an inter-institutional Program of Excellence in Gene Therapy (PEGT). The participating institutions include: Stanford University, The Children's Hospital of Philadelphia, and The University of Pennsylvania and investigators with a well-documented history of collaboration including the successful implementation of an AAV- liver based gene therapy trial. We have used the information learned from this trial to develop new preclinical clinical trials. In this application, there are 3 preclinical gene therapy proposals 2 clinical trials. There are three "local" core proposals (for the investigators of this PEGT), a Research Grade AAV, Administrative, and Clinical Core. We also propose a unique training program to offer post-doctoral candidates research training in gene therapy. A National Morphology core is designed to provide all NHLBI investigators with unique services to further advance the study of gene transfer and/or transgene expression in animal models. The common theme of this proposal is AAV-mediated gene based therapies for hemophilia: (#1) Dr. Katherine High will test the hypothesis that the bleeding diathesis in hemophilia patients with inhibitory antibodies can be treated with a gene therapy approach. This grant builds on a decade of clinical
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experience with recombinant Vila and on the investigator's expertise with coagulation proteins and their expression using AAV vectors. (#2) Dr. Haig Kazazian and colleagues will build on their success in treating hemophilia A mice using new AAV serotypes. They will determine optimal conditions for liver-based gene transfer in fetal monkeys, and validate these conditions in neonatal monkeys and neonatal hemophilia A dogs. (#3) Dr. Mark Kay plans to develop novel AAV pseudotyped vectors that may evade immunological parameters that have limited efficacy in human trials. His group will use non-mammalian primate AAVs and snuffled capsid libraries to make novel vectors and test them in the appropriate animal models. (#4) Dr. Catherine Manno will continue an AAV-2 liver based trial using transient immunosuppressive therapy to attempt to eliminate a T cell mediated elimination of transduced hepatocytes in humans. (#5) Dr. Bertil Glader is proposing a clinical trial using AAV-8 vectors that based on preclinical studies suggesting that this vector pseudotype has advantages over AAV-2. Nonetheless, as has been learned during the previous funding period, even the best animal models and preclinical studies cannot always predict the outcome in humans, supporting the need for multiple approaches. The combined efforts of this group of investigators have a long and productive history that will further research towards a cure for hemophilia. (End of Abstract) •
Project Title: PHASE I/II SAFETY STUDY IN PATIENTS WITH SEVERE HEMOPHILIA B Principal Investigator & Institution: Glader, Bertil; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2005; Project Start 29-SEP-2005; Project End 31-AUG-2006 Summary: AAV-2 mediated liver gene transfer for hemophilia B has been used to safely cure dogs of the disease in preclinical trials. While we have shown that AAV-2 vectors can transduce efficacious amounts of the factor IX gene into human hepatocytes, unpredicted human immune response has limited efficacy. While the promise of gene therapy for this disease is real, we plan a trial, which we believe addresses the limitations of the previous trial and will ultimately lead to a successful therapy for hemophilia. To do this, we plan to use pseudotyped vectors based on AAV-8. The potential advantages of AAV-8 over AAV-2 are: (1) Greater efficiency; (2) Simpler delivery route; (3) Lack of pre-existing humoral immunity; (4) Potential for lack of a T cell mediated immune response directed against capsid containing hepatocytes. The structure of the trial is similar in design to the previous AAV-2 liver based approach funded during the previous PEGT granting period. During the first two years, we plan to perform the appropriate preclinical studies that will allow for FDA approval to begin the phase I/II clinical trial in the beginning of year 03. During this period we anticipate treating 9 patients. We believe that hemophilia B may be treatable using AAV-8 vectors and the information learned from the proposed trial will provide data relevant for treating many hepatodeficiency states.
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Project Title: PLATELETS AS MODIFIERS OF PHENOTYPE IN HEMOPHILIA A Principal Investigator & Institution: Yee, Donald L.; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-JUL-2009 Summary: (provided by applicant): Platelet function varies considerably between individuals, as does bleeding tendency in patients with hemophilia A. Platelets contribute significantly to thrombin generation and fibrin formation, processes that are deficient in hemophilic individuals. We hypothesize that inherent variations in platelet
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reactivity (that are presumably genetically based) underlie much of the heterogeneity in clinical phenotype observed in hemophilia patients. We will address this hypothesis through the following specific aims: (1) characterize the range of bleeding tendency demonstrated by a local and national cohort of patients with hemophilia A (via a prospective cohort study and a secondary data analysis, respectively), and (2) study the local cohort with a select panel of assays of platelet function, platelet receptor genotyping and other hemostatic parameters so that bleeding tendency can be modeled as a function of platelet reactivity (via linear regression techniques). This local cohort of hemophilia patients (and corresponding specimens of banked plasma and DNA) will not only enable us to access platelet modifiers of bleeding in hemophilia, but will also serve as a valuable basis for future studies pertaining to the applicant's long-term goal of identifying genetic and functional modulators of bleeding and thrombotic risk. Identifying parameters associated with an increased bleeding tendency is important for establishing an individual patient's prognosis, optimizing allocation of costly medical resources and illuminating future studies of the biology and mechanisms underlying these associations. The research work proposed in this application forms the basis for an integrated career development plan that also incorporates expert mentoring, intensive scientific and clinical exposure, focused coursework and specialized training at centers with distinctive expertise in the applicant's area of focus. These efforts are intended to develop the applicant into an independent clinical investigator of the highest caliber, focused on problems encountered by patients with bleeding and clotting disorders. •
Project Title: PREVENTING BLEEDING DISORDER COMPLICATIONS THRU HEMOPHILIA TX CTRS IN REGION IX Principal Investigator & Institution: Nugent, Diane J.; Professor and Chair; Children's Hospital of Orange County 455 S Main St Orange, Ca 928683874 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The purpose of this application is to measurably prevent and reduce the complications of inherited bleeding disorders among residents of Region DC - California, Hawaii, Nevada and Guam. This will be accomplished by continued implementation of diagnostic, clinical management, education, outreach, standardized surveillance, and prevention services that reduce hemophilia morbidity and mortality by 40%. Services will be conducted by the Region DCs 14 multidisciplinary Hemophilia Treatment Centers (HTC), and its regional administrative office. These entities have been part of the nearly 30-year-old U.S. bleeding disorder infrastructure that is organized into 12 regions and provide services per federal CDC, HRSA and Healthy People 2010 priorities for Americans with disabilities to live longer healthier lives. Our HTCs and regional office will: (1) Expand clinical assessment, prevention, surveillance, outreach, education, consultation, and management services for people of all ages and racial/ethnic backgrounds who have hemophilia, von Willebrand Disease and other inherited bleeding and clotting disorders in our catchment area that are directed at attaining and measuring specific outcomes to reduce complications; (2) Expand the cohort through continued recruitment and standard data collection; (3) Transition the national database from paper to electronic, from email to web-based; (4) Expand the database to collect new data related to women's ssues in coagulation, rare bleeding disorders, prophylaxis, factor utilization, thrombophilia, inhibitors, and other important clinical outcomes; (5) Design and pilot additional studies aimed at further characterizing these populations through the expanded access to a) gene-based diagnosis and b) more precise definition of the biochemical phenotype; (6) Design prevention messages and strategies, clinical trials and data sharing with other
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relevant agencies; and (7) Maintain a regional office which will support the HTC network and assess the efficacy of prevention services. •
Project Title: PREVENTION OF COMPLICATIONS IN HEMOPHILIA THROUGH HTCS Principal Investigator & Institution: Manco-Johnson, Marilyn J.; Professor of Pediatrics and Pathology; Pediatrics; University of Colorado Denver/Hsc Aurora P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The purpose of this proposal is to continue the direct patient care family-centered, community-based comprehensive hemophilia and thrombophilia services by supporting the successful existing structure of the five Hemophilia Treatment Centers (HTCs) in MCHB Region VIII serving Colorado, Montana, Wyoming, Utah, New Mexico and Arizona. Challenges: Providing care to persons with a rare, chronic disease in a large geographic area presents significant challenges. This region of the country has realized unprecedented growth over the past decade and this has strained existing health care resources at a time of level funding. In addition, there is over 90% penetration of managed care in the payer market providing challenges to the HTC staff in coordinating care within those systems. Supplementing unreimbursed care for patients is a primary response to this challenge. There are large groups of ethnic and racial minorities in some of the states providing language and culture challenges. Goals and objectives: The goals of this project are as follows: (a) Foster direct patient services including comprehensive care systems that provide culturally sensitive, family-centered care coordinated through a regional system of hemophilia diagnostic and treatment centers. Provide access to comprehensive call for all currently served, underserved, or newly identified patients with hemophilia/HIV and their families by providing direct services not reimbursed by third party payers; (b) Place care emphasis on prevention to educe the complications and morbidity associated with hemophilia; (c) Provide services to women with congenital bleeding disorders; (d) Coordinate services with State Title V MCH programs, prevention, education and peer support activities of the NHF and prevention and education initiatives of the CDC. Methodology: Continue the existing structure of HTCs in Region VIII using past successes of treatment center approaches including direct patient care service provision of comprehensive care and diagnosis of patients, education, outreach to underserved populations, outreach to women with bleeding disorders and preventions of morbidities associated with hemophilia. Expand services to persons with clotting disorders within the same HTC structure. Experience to date: The HTCs in Region VIII have a history of excellent care and organizational coordination, and each center has developed a strong referral network for all patients within their catchment area that assures access to care for these patients. This region has strong leadership and a history of successful clinical research that enhances patient care.
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Project Title: PREVENTION OF COMPLICATIONS OF HEMOPHILIA THROUGH HTCS Principal Investigator & Institution: Ingram-Rich, Robina; None; Oregon Health & Science University 3181 Sw Sam Jackson Pk Rd Portland, or 972393098 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): Comprehensive hemophilia treatment centers (HTCs) received their first federal funding from the Maternal and Child Health Bureau, Health Resources and Services Administration in 1975. Regional networks developed
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enabling and strengthening intra- and inter-state cooperation and collaboration. In 1995, the CDC provided direct funding to the twelve hemophilia regions following a Congressional mandate to monitor blood product safety and hemophilia disease progression, including arthropathy. During the past ten years funds from the Hematologic Disease Branch has assisted Region X (Alaska, Idaho, Oregon and Washington) with building center and regional infrastructure including expanded data collection capabilities for surveillance. Funds have also enhanced inter-regional collaboration in the US West. The Universal Data and Serum Specimen collection System for Hemophilia and other bleeding disorders has been enrolling participants since 1997/98 and has provided a robust data bank. During the next five years, Region X in collaboration with other federal regions will begin more focused public health research with the hemophilia and bleeding disorders community that may be extrapolated to other populations with chronic conditions and diagnoses. Region X is an area of the United States with urban, rural and frontier counties. The majority of the population in this region lives north of the 45th parallel. The region also has an incidence of obesity and overweight in hemophilia patients and the general region that mirrors the national averages. The Region X research interests include: 1) whether the health disparities experienced by rural and frontier citizens also extends to persons with bleeding disorders or does care for a bleeding disorder provided by HTCs decrease the health disparities; 2) whether persons living in counties without physicians and/or hospitals have poorer physical and health outcomes compared to others with similar diagnosis, especially persons with milder severity; 3) the impact of less ambient vitamin D on joint disease and bone health/density; and 4) the relationship between perceived ability to engage in activity, actual level of activity, unemployment due to disability, pain and quality of life. •
Project Title: PREVENTION DISORDER THROUGH HTCS
OF
THE
COMPLICATIONS
OF
BLEEDING
Principal Investigator & Institution: Monahan, Paul E.; Pediatrics; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The purpose of this program is to prevent complications of hemophilia and other bleeding disorders through assessment, surveillance, outreach, education, consultation, and management. A regional network of ten hemophilia treatment centers in Kentucky, North Carolina, South Carolina, and Tennessee will be coordinated by the University of North Carolina at Chapel Hill and provide comprehensive care and prevention services to persons with hemophilia and other bleeding disorders. In 2005, Region IV-North (comprising nine hemophilia treatment centers [HTCs] in North Carolina, South Carolina, Kentucky, and Tennessee) had a total of 1,848 active patients with hemophilia and other bleeding disorders. Hemophilia patients constitute 61.5% of the total patients, while 27.6% have von Willebrand disease and 10.9% have other bleeding disorders. In 2005, there were 380 active female patients, an increase of 25.2% over the 2004 total. Almost 22% of the active patients are from ethnic minority groups, with an explosive increase in Hispanics. In comparison to U.S. averages, there are higher poverty rates and lower educational levels within the region, predisposing individuals to suboptimal behaviors in relation to diet, exercise, and use of health care services. The network will collaborate with regional lay organizations and the four non-federally funded centers in the region to deliver appropriately tailored prevention messages aimed at reducing complications of bleeding disorders and improving health across the lifespan, with the intention of attaining and measuring specific outcomes to reduce complications. Further, the region
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will redouble its outreach to underserved populations, such as women and minorities, to integrate them into the HTC system. All of these efforts will be systematically evaluated to assess their efficacy. Surveillance of patients enrolled in the CDC's Universal Data Collection (UDC) project, which has collected samples and data from over 18,000 individuals nationally since 1998, will continue in order to monitor the safety of the blood supply. The network will also expand upon the UDC program to collect data that could be used for clinical research projects leading to improved health outcomes for individuals with bleeding disorders, accelerated adoption of healthy behaviors, the reduction or elimination of health disparities among various ethnic and racial groups and between genders, and the achievement of greater efficiency in the core public health infrastructure. •
Project Title: DISORDERS
PREVENTION
OF
THE
COMPLICATIONS
OF
BLEEDING
Principal Investigator & Institution: Brettler, Doreen B.; Univ of Massachusetts Med Sch Worcester Worcester, Ma 01655 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The objective of this application is to prevent the complications of hemophilia and other bleeding disorders by prevention programs in the eight multidisciplinary centers in New England. This proposed program will be performed in conjunction with the national network of twelve federally funded regional networks. During the past ten years the regional networks, in conjunction with the Centers for Disease Control and Prevention (CDC), established a national network of treatment centers that have the capacity to serve as prevention centers. Multidisciplinary teams have been trained to implement prevention programs and research. A national database has been developed that collects demographic, clinical and quality of life data. This is the largest clinical database of rare bleeding disorders in the world. The regional program's overall goal for the next five years is in conjunction with the national network design prevention messages, strategies, and clinical trials and share the data with other relevant agencies, such as HRSA, MCHB, NHLBI, NHF and researchers and care providers of individuals. This will be accomplished by: 1) expanding the cohort through continued recruitment and observations of individuals with bleeding disorders including hemophilia A and Hemophilia B, von Willebrand disease, rare bleeding disorders, and women with bleeding disorders: (2) transition from paper submission of data to web-based (3) expand the database to collect data relevant to Woman's issues in coagulation, prophylaxis, inhibitor formation, utilization of treatment products and treatment regimes, obesity, and other important clinical information (4) maintain a regional administration that will support the established infrastructure and foster collaboration, (5) perform regional and national research utilizing the national database and (6) expand the current database to include relevant data on women's issues, obesity issues, rare bleeding disorders, and prophylaxis. •
Project Title: PREVENTION OF THE COMPLICATIONS DISORDERS THROUGH HEMO TMT CENTERS
OF
BLEEDING
Principal Investigator & Institution: Dominic, Patricia A.; Hemophilia of Georgia, Inc. 8800 Roswell Rd, Ste 170 Atlanta, Ga 303501844 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The Region IV South Bleeding Disorders Program is a network of nine federally funded Hemophilia Treatment Centers (HTCs) that provide comprehensive care and prevention services to persons with bleeding disorders in the
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states of Alabama, Florida, Georgia, and Mississippi. The Regional Core Center (RCC) office is located in Atlanta, Georgia and shares an office with Hemophilia of Georgia, Inc. The RCC emphasizes a pro-active orientation toward bleeding disorder care. This program will further the mission of the CDC in promoting heath and quality of life in persons with bleeding disorders by preventing and controlling disease, injury and disability. The goals and objectives of this regional program were designed to reduce the complications and morbidity associated with bleeding disorders, as well as to promote access to integrated and family-centered services for individuals with bleeding disorders in Region IV South. Comprehensive systems of care are necessary, as those receiving care outside of an HTC have a 60% higher mortality rate than those receiving care in federally funded HTCs (CDC). Objectives will focus on those patients from traditionally underserved populations. Prevention programs will strive to reduce the impact on the public health system by, for example, decreasing the number of days missed from work and school. The RCC will be responsible for program evaluation and monitoring through required affiliate reporting, data reports, assessment of Universal Data Collection (UDC) Project participation, site visits, needs assessments, and consumer input. Other specific project objectives include: (1) provide continuous screening for HIV and Hepatitis A, B, and C; (2) facilitate improved regional information management systems, data collection and evaluation; (3) expand the UDC cohort through recruitment of individuals with genetic bleeding disorders; (4) transition the national database to a web-based application; (5) expand the database with additional relevant date related to women's issues and other important clinical outcomes; and (6) address areas of concern unique to Region IV South regarding healthcare disparities. This hemophilia care program strives to improve the quality and years of healthy lives for those living with bleeding disorders in Region IV South. Prevention and outreach efforts aimed at the traditionally underserved will eliminate the region's health disparities by providing quality healthcare services, regardless of an individual's race, ethnicity, age, or gender. Particular attention will be paid to the leading health indicators: physical activity, overweight and obesity, immunization and access to health care. •
Project Title: PREVENTION OF DISORDERS THROUGH HTCS
THE
COMPLICATIONS
OF
BLEEDING
Principal Investigator & Institution: Konkle, Barbara A.; Associate Professor of Medicine; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): Hemophilia is an inherited bleeding disorder resulting from a deficiency of coagulation factor VIII or factor IX and von Willebrand Disease (VWD) is an inherited bleeding disorder resulting from decreased or abnormal von Willebrand protein. These bleeding disorders result in both spontaneous and trauma-induced bleeding. The purpose of this project is to prevent complications of bleeding disorders through the network of Region hemophilia treatment centers (HTCs). Consisting of 15 HTCs in DE, MD, PA, VA, WV, and DC Region III serves 3,061 individuals with bleeding disorders. The principal investigator and significant contributors for this project have extensive experience in caring for individuals with bleeding disorders and are supported by a multi-disciplinary team. Each HTC is a specialty, prevention, diagnostic and treatment program providing assessment, education, research, surveillance, outreach, consultation, and management to children, adolescents, and adults with bleeding disorders. Comprehensive care has been shown to decrease mortality n men with hemophilia. Building on this success and using data through the CDC's Universal Data Collection study, this network is poised to answer
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Hemophilia
key questions related to optimal care and prevention strategies for patients with inherited bleeding disorders. Working collaboratively with the nationwide system of HTCs, the Region III network will foster the understanding of health promotion and prevention of disease, injury and disability by the following Specific Aims: 1) To enhance prevention activities and improve outcomes by: expanding Region III HTC participation in the UDC study and utilizing data collected to address research questions, including: a) Does rural or urban residence impact UDC participation and utilization of HTC resources? b) Do patients with moderate hemophilia have worse joint function than patients with severe disease on primary or modified primary prophylaxis? 2) To maintain the regional network of HTCs to allow data collection and implementation of prevention strategies by: providing comprehensive care to reduce complications from bleeding disorders; developing programs to expand the HTC patient populations, including women and minorities; facilitating training resources for new and established HTC staff; and providing educational resources for other medical providers. 3) To implement DC supported regional activities through the University of Pennsylvania Core Center to collaborate with a national network of Core Centers to implement the objectives of these project activities and studies by: facilitating communication between the HTCs; maintaining a Regional Executive Committee; organizing an annual Regional Meeting; providing oversight to the subcontracting HTCs; serving as a liaison between the DC, Maternal and Child Health Bureau, National Hemophilia Foundation and HTCs; sharing research data throughout the nationwide HTC network; and participating in the CDC Coordinating Committee. •
Project Title: PREVENTION OF THE COMPLICATIONS DISORDERS THRU HEMOPHILIA TREATMENT.
OF
BLEEDING
Principal Investigator & Institution: Hoots, W. Keith; Pediatrics; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The objective of this application is to prevent complications of hemophilia by implementing prevention programs based on knowledge gained in clinical research in multidisciplinary comprehensive care clinics. The specific aims are (1) expand the provision of comprehensive prevention services to persons with bleeding disorders, (2) increase the number of individuals served and recruited to the UDC and other prevention studies, (3) facilitate access to appropriate training resources for HTC personnel, (4) coordinate the development program plans, goals, objectives, monitoring and reporting for the HTCs in the Region; and develop appropriate management and evaluation systems to ensure that the HTCs implement the activities of this program, (5) continue to collect data related to infectious and bleeding complications that could be used for clinical research leading to improved care for the patients using these centers and develop local research protocols, and (6) participate fully in the Coordinating Committee. To meet these specific aims, the Region will (1) maintain a core staff and relationships with other providers and have these available at clinics where the UDC study is being conducted, (2) complete the implementation of the Lab Tracker database and use it and the UDC to target underserved areas, (3) offer several opportunities for staff training, (4) continue the use of two evaluation tools to measure the effectiveness of the HTCs, (5) continue to make efforts to enroll patients focusing on the annual reevaluation and the enrollment of children under the age of two, and (6) the principal investigator will take an active role in the coordinating committee as they work to expand the reach of the research activities of the HTCs. This research will significantly improve the lives of individuals with hemophilia and other bleeding disorders by leading to the development of better
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treatment regimens. The knowledge gained can also be of benefit to others with chronic disorders as we better define the impact of these disorders on the individual and their family. Lastly it may have a more global impact as we design interventions in the bleeding disorders community to address common problems such as obesity which has added impact to the joints of individuals with bleeding disorders. •
Project Title: PREVENTION THROUGH HTCS
OF
THE
COMPLICATIONS
OF
BLEEDING
Principal Investigator & Institution: Roach, Kathleen J.; Great Lakes Hemophilia Foundation C/O Jack Lazerson, Milw Chld Hos Milwaukee, Wi 53233 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The objective of this application is to prevent complications of hemophilia by proactive implementation of prevention programs in the states of Wisconsin, Illinois, Minnesota, North Dakota, and South Dakota. The Great Lakes Hemophilia Foundation, the Regional Grantee for this five-state region, will enhance the capacity of regional centers as a public health prevention network by: 1) developing and coordinating a plan for multi-disciplinary, comprehensive prevention services for persons with bleeding disorders; (2) developing programs to identify underserved populations including minorities and women; (3) facilitating access to appropriate training and technical assistance; (4) promoting referral and access to educational and support services; (5) promoting and facilitating the exchange of information and collaboration among health care providers; (6) developing appropriate management and evaluation systems to track treatment center achievement of program plans, goals and objectives, and assess compliance with federal regulation; and (7) participating in surveillance for complications of bleeding disorders including data collection for the Universal Data Collection (UDC) and clinical research utilizing that data. The specific aims of this application include the following: 1) To expand the cohort through continued recruitment of individuals with genetic bleeding disorders; 2) To complete a transition of the database from paper to electronic and then from email to web-based; 3) To design prevention messages and strategies to share research findings; and 4) To utilize exising/expanded UDC data to address clinical issues such as these proposed by V-West: a. Joint disease progression in hemophilic patients with established hemophilic arthropathy: Evaluation of risk factors and the effect of secondary prophylaxis. b. Hemorrhagic and vascular complications of von Willebrand disease. c. An evaluation of the efficacy of a transition protocol in preparing adolescents with a bleeding disorder for self-sufficiency. It is anticipated that the proposed research will help to accelerate the adoption of healthy behaviors and that lessons leaned from this research will have application for broader populations. •
Project Title: PREVENTION OF THE COMPLICATIONS OF HEMOPHILIA THRU HEMOPHILILA TREATMENT CENTERS Principal Investigator & Institution: Walsh, Christopher E.; Associate Professor; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 100296574 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The overall objective of this application is to prevent the complications of hemophilia and bleeding disorders through the expansion and acquisition of clinical data sets. These data sets will include both disease-specific and general-health related information. The data acquired will be used for proactive implementation of prevention programs throughout the network of multidisciplinary
56
Hemophilia
comprehensive Hemophilia Treatment Centers (HTC) throughout the United States. HTC's are designed to treat patients with hemophilia A and B, von Willebrand Disease and rare factor deficiencies. Utilizing the comprehensive care model, therapeutic interventions based on previously collected data and changes in therapy based on new research continues to enhance the care of the bleeding disorders community. Chronic genetic disorders often require complex and multidisciplinary care for optimal diagnosis, treatment and management. The consequences of bleeding disorders include severe medical, financial, vocational, psychological and familial repercussions when the condition is not properly managed. The lack of proper treatment has general public health consequences such as increased costs of care caused by increased hospital and emergency utilization and patient disability that may require welfare and other government entitlements. A regional approach to planning, coordination and allocation of funds is vital to ensure that services are available to treat this and other complicated bleeding disorders in Region II, New York, New Jersey, Puerto Rico and the US Virgin Islands. The proposed program will continue a national network of federally funded HTCs organized through 12 regional core centers and funded by the CDC. Aim 1: To provide comprehensive prevention services to persons with bleeding disorders directed at attaining and measuring specific outcomes through research and surveillance aimed at reducing complications using a multidisciplinary approach. Under this aim we propose to expand the cohort through continued recruitment and observation individuals with genetic bleeding disorders including hemophilia A and B, von Willebrand disease, rare bleeding disorders and women with bleeding disorders; and expand the current Universal Data and Serum Specimen Collection System (UDC) database to collect additional relevant data related to women's issues in coagulation, rare bleeding disorders, prophylaxis, factor utilization, inhibitors, genetic mutations, and other important clinical outcomes. We plan to design and pilot additional studies aimed at further characterizing the bleeding disorders population through the expanded access to a) gene-based diagnosis and b) more precise definition of the biochemical phenotype (e.g. global assays) with the ultimate goal of genotype - phenotype correlation; utilize the UDC BMI data to evaluate the cost impact on the health care system from conditions with weight-based dosing; test interventions that could facilitate weight loss; and design and pilot a study to evaluate effects of rising annual out- ofpocket expenses and co-payments on the use of elective/preventive services provided by the HTC. Aim 2: Maintain A Regional Network Of Comprehensive Prevention Services Through Hemophilia Treatment Centers to Persons With Hemophilia and Related Disorders Including Women, Minorities and the Underserved. Under this broad aim we will lay out our comprehensive, culturally sensitive, family-centered care services and their expansion, our communication within the region and administrative mechanisms. These include outreach and education, orientation and training programs, maintenance of appropriate management and evaluation systems, maintenance of a prevention evaluation network to assess the efficacy of prevention services by increasing the capacity for data collection, moving from paper to electronic and our participation in the coordinating committee. Our plan as stated will promote health and quality of life by preventing and controlling disease, injury, and disability. Many of our aims will facilitate reducing health disparities and accelerate the adoption of health behaviors while improving prevention effectiveness through cost-based studies. Some aims will be directly transferable to other chronic disease populations in the general public such as the evaluation of obesity and menorrhagia.
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Project Title: PROLONGATION OF FACTOR VIII LIFETIME IN CIRCULATION Principal Investigator & Institution: Saenko, Evgueni L.; Biochemistry and Molecular Biology; University of Maryland Balt Prof School Professional School Baltimore, Md 21201 Timing: Fiscal Year 2005; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Genetic deficiency in factor VIII (fVIII), an essential component of the intrinsic pathway of blood coagulation, results in a life-threatening bleeding disorder Haemophilia A, which is treated by repeated infusions of expensive recombinant and plasma-derived fVIII products. The goal of the current application is to develop recombinant fVIII with a prolonged lifetime in circulation for more efficient therapy of Haemophilia A based on the breakthrough knowledge on the mechanisms of fVIII catabolism. We have established that fVIII clearance from circulation is mediated by low-density lipoprotein receptor-related protein (LRP), a member of LDL receptor superfamily, and facilitated by cell surface heparan sulfate proteoglycans (HSPGs). Simultaneous blocking of LRP and HSPGs in a mouse model, led to a significant, 5.5fold prolongation of fVIII half-life. We have localized the major LRP- and HSPGsbinding sites within residues 484-509 and 558-565, respectively, of the A2 subunit of fVIII. These sites are exposed within fVIII complex with von Willebrand factor (vWf), in which fVIII is present in circulation. We propose to find an optimal combination of mutations within LRP- and HSPGs-binding sites and in their proximity, which would substantially reduce the corresponding components of fVIII clearance and will not affect the functional properties of fVIII. We will perform comprehensive site-specific mutagenesis using the isolated A2 subunit as a model of fVIII based on the identity of catabolism of A2 to that of fVIII from it complex with vWf. An optimal combination(s) of A2 mutations found to maximally reduce LRP- and HSPGs-mediated components of catabolism in a cell model without affecting the functional activity and stability of reconstituted activated fVIII, will be next introduced into fVIII constructs. We plan to use a construct encoding B domain-deleted fVIII, which provides high fVIII expression levels, and a fVIII construct carrying the B domain region 741-956, which is required for efficient fVIII secretion from the cell. We will apply a variety of methods to assess the ability of generated mutant fVIII to maintain interactions critical for its normal functioning, including ability for complex formation with vWf, interaction with components of the Xase complex, and normal activation/inactivation kinetics. We will also examine whether repeated use of mutant fVIII is not associated with increased immune response in fVIII-deficient mouse model of Haemophilia A. To obtain prognosis of the use of mutant fVIII in Haemophilia A patients, we will compare the ability of mutant and wild-type fVIII to stimulate in vitro proliferation of peripheral blood T lymphocytes from patients with severe Haemophilia A. Accomplishment of the current project will result in generation of mutant fVIII with prolonged lifetime in circulation, which will meet major functional, biochemical and immunological criteria.
•
Project Title: RAAV-MEDIATED GENE THERAPY FOR HEMOPHILLIA B Principal Investigator & Institution: Davidoff, Andrew M.; Division Chief; St. Jude Children's Research Hospital 332 N Lauderdale St Memphis, Tn 381052794 Timing: Fiscal Year 2005; Project Start 01-MAY-2005; Project End 30-APR-2010 Summary: (provided by applicant): Hemophilia B is an inherited bleeding disorder that is due to a defect in blood coagulation factor IX (FIX) synthesis. A gene therapy mediated approach to the replacement of FIX has a number of advantages, particularly the potential for sustained expression. The overriding hypothesis to be tested in this project is that liver-targeted delivery of recombinant adeno-associated virus (rAAV)
58
Hemophilia
vectors encoding the cDNA for human factor IX (hFIX) can safely mediate long-term expression of therapeutic levels of hFIX. This approach has been used successfully to generate normal levels of hFIX in mice but has not yet consistently been successful in a relevant nonhuman primate model or in humans. Optimal delivery methods need to be established to ensure efficient rAAV transduction of the primate liver with persistent, high-level transgene expression, and with minimal procedure or vector-related toxicity. In addition, the impact of naturally acquired and iatrogenic immunity to AAV on transduction efficiency with rAAV vectors and the ability to manipulate these potential immunologic obstacles to successful gene transfer is unknown. Finally, demonstrating the safety of this gene therapy mediated approach is of critical importance prior to initiating a clinical trial. This proposed study is designed to address these critical issues in a context that is relevant to humans. The following hypotheses will be tested: (1) rAAV particles of an alternative serotype, rAAV-8, can generate systemic levels of hFIX that are greater than those obtained by rAAV-5 particles, and equivalent transduction efficiency can be achieved whether using the mesenteric or peripheral venous route of vector administration. (2) Equivalent transduction efficiency can be achieved with vector re-administration either when an alternate rAAV serotype is used or when transient immunosuppression is utilized at the time of initial vector administration. (3) rAAV mediated transfer targeting the liver is safe, will not lead to germ line transmission, and will be free of long term toxicity, including organ damage, and the development of malignancy. Data generated from these studies will provide insight and preclinical data for a gene therapy trial not only for hemophilia B, but also for other potential trials in which AAV-mediated liver-targeted gene therapy might be employed. •
Project Title: REGION V-EAST HTC NETWORK FOR THE PREVENTION OF BLEEDING DISORDERS COMPLICATIONS Principal Investigator & Institution: Harner, Ivan C.; Hemophilia Foundation of Michigan Ypsilanti, Mi 48197 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The objective of this application is to secure support for the ongoing development and maintenance of the Region V-East network of multidisciplinary comprehensive clinics to conduct surveillance and implement programs to prevent the complications of hemophilia and other bleeding disorders. Building on previous federal funding for staff and clinical infrastructure, the first two five-year periods of CDC funding focused on the development of a national database to collect critical data that enabled outcome assessment including blood-borne viral transmission, joint disease, inhibitor formation, and mortality. This database is now the largest clinical outcomes database of a rare chronic disease in the world. This third fiveyear period will focus on expansion of the cohort and the refinement of data collected to continue to characterize sub-populations, including hemophilia A and B, women with bleeding disorders, von Willebrand disease, and rare bleeding disorders. Major efforts have begun to increase the sophistication of data collection methodologies and to finalize the transition from a paper to an electronic system that is currently being converted to a web-based interface with the CDC. This infrastructure will greatly increase our capacity for national clinical research to improve care, support outcomesbased standardization, and defend against efforts by payers to cut costs by denying access to therapeutic regimens and products. Data collected to date has shown decreased mortality and morbidity among patients who receive care at federally funded HTCs. Care is accessible and patients have many resources to overcome traditional barriers that face families with chronic diseases, including linkages with other specialists, community based social services and patient advocacy and support. This
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model of care, which is coordinated in response to agreed upon national and regional objectives, is a successful model of a comprehensive and collaborative public health approach to the management of a chronic disorder that may be applicable to other rare and/or expensive chronic diseases. The regional network infrastructure and data collection capacity may also provide fertile ground for the assessment of prevention and intervention strategies for broad public health concerns like nutrition and obesity and compliance that affect the general population. •
Project Title: REGION VII HEMOPHILIA PROGRAM Principal Investigator & Institution: Wicklund, Brian M.; Children's Mercy Hosp (Kansas City, Mo) 2401 Gillham Rd Kansas City, Mo 641084619 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 29-SEP-2011 Summary: (provided by applicant): The long-term objective of this application is to prevent complications of hemophilia through assessment, surveillance, outreach, education, consultation, and management in multidisciplinary comprehensive hemophilia treatment centers (HTCs) in Region VII (Iowa, Kansas, Missouri and Nebraska). In addition to work toward the national aims of the project for this 5-year period of funding to expand the UDC cohort, transition the national database from paper to electronic, and from email based to web-based, to expand the database to collect additional relevant data, and to design prevention messages and strategies, clinical research and data sharing with other relevant agencies and lay organizations such as the National Hemophilia Foundation and the National Alliance for Thrombosis and Thrombophilia, the regional project looks at the hypothesis that with increased physical activity, persons with hemophilia or von Willebrand disease will have fewer complications. The proposed study, "Adding Physical Activity/Subtracting Complications" will include designing, implementing and evaluating a new program aimed at increasing physical activity in persons ages 13-21 with bleeding disorders as part of comprehensive care through HTCs. The significance of this project is clearly evident through the data previously collected through UDC. 24% of the 926 patients from Region VII who have participated in UDC are categorized as being overweight, 17 % report using canes, crutches, or walkers, 3.4% use wheelchairs, and 26% of the total patients reported restrictions in their activity level. During their annual comprehensive clinic visit, participants in the proposed study would receive educational materials describing physical activity plans for the upcoming year from which to choose. Data will be collected during the comprehensive clinic visit as it is currently being done. Additional data would be collected at three, six and nine months of participation from questionnaires, and at twelve months, when the participants return for their annual visit. The expected results for persons who maintained frequency of activity within 25% of the goal would be decreases in BMI, number of target joints, activity restrictions, and use of assistive devices, and an increase in range of motion. Results can be applied to the general population regarding the benefit of increased physical activity to health status as described in Healthy People 2010 goal to "Improve health, fitness, and quality of life through daily physical activity."
•
Project Title: REGULATION OF FACTOR VIII SECRETION Principal Investigator & Institution: Kaufman, Randal J.; Professor; Biological Chemistry; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; Project Start 01-AUG-1995; Project End 30-NOV-2005
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Hemophilia
Summary: (provided by applicant): FVIII (FVIII) is the plasma protein deficient or functionally defective in hemophilia A, an X-chromosome linked bleeding disorder affecting 1/5,000 males. Affected patients experience significant morbidity and mortality related to repeated and/or life-threatening bleeding events. Protein replacement therapy with recombinant-derived FVIII is presently the preferred therapy. However, the cost of recombinant FVIII and the continued problem ofimmunogenicity remain significant problems. The long term goal of the proposed research is to provide fundamental insight into the regulation of FVIII synthesis and secretion with the ultimate goal of developing improved therapies for hemophilia A. The specific aims of this proposal are to test the following three hypotheses: FVIII secretion is limited by transient aggregation immediately after its translation. We will characterize the requirements for ATP-dependent dissociation of FVIII aggregates. FVIII expression is toxic to cells by activation or ER stress-response signaling kinases. We will determine whether accumulation of FVIII within the ER activates protein kinases to inhibit protein synthesis and induce transcription of genes encoding ER stress proteins. ERGIC-53 is a molecular chaperone that interacts with the B domains or FV (FV) and F VIII and facilitates their transport to the Golgi compartment. We will elucidate the requirement of ERGIC-53 in the transport of FV and FVIII to the Golgi compartment. These studies will identify folding pathways of FVIII, improve FVIII secretion efficiency and limit toxicity associated with FVIII expression. In addition, these studies will identify how deficiency in ERGIC-53 causes combined deficiency of FV and FVIII. They will provide fundamental new insights into FVIII protein synthesis and secretion. The information will be vital to the future development of improved gene therapy protocols for hemophilia A. The ER provides an essential function to promote folding of proteins destined for the cell surface. Elucidating the mechanisms of protein folding, retention, and transport through the ER will have impact on the ability to therapeutically intervene in disease states that are associated with defective protein folding in the ER. •
Project Title: REGULATION OF TARGETED GENE CORRECTION Principal Investigator & Institution: Kmiec, Eric B.; Professor; Biological Sciences; University of Delaware Vice Provost for Research Newark, De 19716 Timing: Fiscal Year 2006; Project Start 01-DEC-2000; Project End 30-APR-2011 Summary: (provided by applicant): The ultimate form of gene therapy for inherited diseases is to reverse the phenotype by correcting the genetic mutation at its endogenous location in the chromosome. We have been developing a gene repair strategy that relies on DNA oligonucleotides to enter the cell, hybridize to the mutant sequence and direct single base exchanges in the target gene. During the initial grant period, we created several model systems in yeast and mammalian cells that enabled the elucidation of pathways that control the frequency of gene correction. The data indicate that the gene repair process is controlled by the activation of homologous recombination and rate at which DNA replication takes place. We now propose to transition from model systems to a clinically relevant cell type that is likely to serve as a target in the initial clinical application. Results from several laboratories indicate that liver cells, particularly hepatocytes, are highly responsive to this technique and enable gene correction to take place at robust levels. We shall target a integrated, mutant eGFP gene and the endogenous HPRT gene in clonal isolates of HepG2 and THLE cells, two established hepatocytic cell lines that have been used in the development phase of therapies aimed at liver diseases. Guided by the results of our first grant term, we will focus on the activation of homologous recombination as a means to support enhanced levels of correction in a reproducible and sustainable fashion. The experiments outlined in this grant will address the following questions; 1) are random ds breaks required for
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attaining high levels of gene correction?; 2) do lesions at replication forks or stalled forks themselves provide enough stimulus for elevating the levels of gene correction in the absence of DNA damage; 3) is the process of gene repair itself mutagenic at nontargeted sites and are cells undergoing gene repair more prone to genome rearrangement?; 4) how does the cell respond to the intemalization of the ssODN in terms of DNA damage response pathways. The key to developing this technique in the long term, even for liver disease and cancer, lies in the ability to regulate, predict and reliably attain correction efficiencies that have therapeutic effects. These goals support the choice of liver as a target for clinical applications of gene repair but there are other important reasons for focusing on hepatocvtes: they are the target cell for gene therapy for Alpha-1 Antitrypsin Deficiency. Crigler-Naiiar. OTC. MPSVII. Hemophilia A and B and many lysosomal storage disorders among others. Our work will uncover restrictions or limitations for gene repair in hepatocvtes with the goal of treating hepatic cancer and genetic diseases of the liver. •
Project Title: REPAIR OF FACTOR VIII BY TARGETED RNA TRANS-SPLICING Principal Investigator & Institution: Mansfield, S Gary.; Intronn, Inc. 9700 Great Seneca Hwy, Ste 210 Rockville, Md 20850 Timing: Fiscal Year 2005; Project Start 15-APR-2003; Project End 30-APR-2007 Summary: (provided by applicant): Successful gene therapy will revolutionize the treatment of the inherited bleeding disorders hemophilia A and B. Hemophilia A is caused by deficiency of coagulation factor VIII (FVIII) and is a prime disorder for genetic correction. The disease constitutes 80% of all hemophilia patients and is the focus of this proposal. The requirements for successful FVIII gene include: the persistent expression of therapeutic levels of FVIII, the lack of significant toxicity to the gene transfer vehicle (vector), the lack of host immune response to the normal FVIII protein, and reduced ectopic expression of the normal product. Gene therapy through the use of Intronn's platform technology, spliceosome mediated RNA trans-splicing (SMART), can potentially circumvent some of these problems. Intronn has developed and patented constructs called pre-trans-splicing molecules (PTMs) that are capable of modifying mRNA in vivo. PTMs work by promoting trans-splicing reactions between the PTM and a targeted pre-messenger RNA. The product of a SMART reaction is a novel chimeric or composite RNA that can encode virtually any desired gene product. The product of a SMART reaction contains one or more exons of the target endogenous pre-mRNA and an exonic or cDNA sequence delivered by the PTM. We propose studies to target mutant factor VIII in cell and animal models of hemophilia A with PTMs that can perform repair of endogenous transcripts to generate full length functional FVIII. In this application we will plan to 1) optimize an adeno-associated virus (AAV) delivery system for correction of FVIII in the mouse model of hemophilia A, 2) demonstrate functional long term correction of endogenous FVIII in a knockout mouse model of hemophilia using AAV delivered PTMs and identify a lead AAV delivery system for use in clinical work, 3) identify a lead human FVIII PTM that can efficiently repair FVIII using in vitro screening models, and 4) perform biodistribution and clearance studies in mice using the lead AAV vector and lead human PTM. This work will be performed in collaboration with a key university site(Mt. Sinai School of Medicine) with extensive experience in hemophilia A biology, gene transfer and experimentation with murine and canine models of hemophilia A. The research proposed in this application will form the groundwork for a Phase I clinical trial in humans.
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Project Title: SLEEPING BEAUTY GENE THERAPY FROM LIVER TO BOECS Principal Investigator & Institution: Steer, Clifford J.; Professor; Medicine; University of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 30-JUN-2009 Summary: (provided by applicant): Gene therapy using viral vectors has had limited success in the treatment of the various types of hemophilia. Both the host response and the unique characteristics of the vector systems have made it difficult to achieve persistent long-term transgene expression. An additional complication in the treatment of hemophilia by replacement therapy is the development of inhibitory antibodies to the clotting factor. In fact, this has prompted the use of rFVIIa in an effort to induce hemostasis via tissue factor (TF) independent FX activation at the platelet surface. The main objective of this research project is to evaluate the nonviral Sleeping Beauty transposon (SB-Tn) vector for gene therapy in a mouse model of factor IX deficiency. This objective tests our hypothesis that separate or combined expression of FIX, rFVIIa and soluble TF (sTF) transgenes will improve the disease phenotype. The first specific aim is designed to optimize in cell culture (i) the Tn design for maximal transposition and persistent gene expression of the coagulation factors IX, an engineered rFVIIa and sTF; and (ii) the nonviral delivery systems to hepatocytes via the asialoglycoprotein receptor by several different ligand moieties. The second specific aim evaluates the capacity of the best Tn vectors/delivery systems to promote Tn insertion and persistent transgene expression in vivo. The therapeutic effects in vivo for expression of FIX, rFVIIa, and/or sTF will be monitored and quantitated by the relevant metabolic parameters. The dosing regimen, the delivery vehicle and route of administration will be optimized for efficiency of transposition and safety. The third specific aim is designed to evaluate the potential use of blood outgrowth endothelial cells (BOECs) as a vehicle of transgene expression via SB transposition. The transposition and expression characteristics of the different SB-Tns expressing FIX, TF and/or rFVIIa will be examined in BOECs both individually and in pair wise combinations. The ex vivo engineered BOECs will be infused back into hemophilia B mice, and analyzed for longterm expression and effect on the bleeding diathesis of the FIX deficient animals. The major goals of this research proposal are to (i) optimize Tn designs and nonviral delivery systems that provide therapeutic levels of FIX, rFVIIa and/or sTF with SBmediated gene transfer; (ii) identify the best in vivo conditions for correction of the clotting disorder in animal models of | hemophilia B; and (iii) characterize the BOECs potential as an autologous vehicle for persistent transgene expression.
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Project Title: HEMOPHILIA
SLEEPING
BEAUTY-MEDIATED
GENE
THERAPY
FOR
Principal Investigator & Institution: Hackett, Perry B.; Professor; Discovery Genomics, Inc. 614 Mc Kinley Pl Ne Minneapolis, Mn 55413 Timing: Fiscal Year 2005; Project Start 01-FEB-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Hemophilia A is a bleeding disorder caused by the absence of clotting factor VIII (FVIII). This disease is inherited in an X-linked recessive manner. There are 15,000 affected individuals in the U.S. Treatment of Hemophilia A is based on frequent delivery of recombinant FVIII (recombinate). However, the high expense of this treatment (as much as $100,000 per year in severe cases) and variable levels of FVIII maintained in the circulation compromise the effectiveness of this therapy. FVIII gene therapy represents a more efficacious and cost-effective treatment of the disease. We propose continued development of the Sleeping Beauty (SB) transposon system in a Phase II study of non-viral FVIII-gene transfer and expression in the liver as
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a therapeutic approach for hemophilia A. This approach is based on results from our Phase I studies of long-term, SB transposon-mediated FVIII gene expression in livers of FVIII-deficient mice. We hypothesize that the FVIII gene can similarly be delivered and expressed in the livers of larger animals (ultimately, humans), providing long-term and curative expression of FVIII. These goals are addressed in four Specific Aims. In Aim 1 we will test for SB-mediated long-term expression of reporter genes and the FVIII gene in the livers of mice after delivery of transposon and transposase components directly to the hepatic circulation via retroductal delivery. In Aim 2 we will determine the efficacy of using DNA, DNA-polycation complexes or other DNA complexes for delivery of transposons to liver. These conditions will then be used in Aim 3 to test for SB-mediated long-term expression of reporter genes in the livers of dogs as a large animal model for in vivo gene transfer. In Aim 4, results from the experiments in normal dogs will be used to evaluate the SB system for transposition and long-term expression of the canine FVIII gene in a dog model of hemophilia A, testing for improved clotting and correction of the bleeding disorder. At every stage we will examine animal tissues for histopathological indications of adverse events. Results from these preclinical studies will position DGI for submission of an Investigational New Drug application (IND) to the FDA, with subsequent initiation of a clinical trial testing the effectiveness of the SB system FVIII gene therapy in human subjects. Technological Innovation: Sleeping Beauty is a novel gene transfer system with potential application in gene therapy. The market size for the inherited-diseases market niche, to which this technology applies is about $5.8 billion. •
Project Title: SONORHOEMETRY FOR THE IN VITRO ASSESSMENT OF VISCOELASTIC PROPERTIES Principal Investigator & Institution: Walker, William F.; Assistant Professor; Biomedical Engineering; University of Virginia Charlottesville Box 400195 Charlottesville, Va 229044195 Timing: Fiscal Year 2006; Project Start 06-SEP-2006; Project End 30-JUN-2010 Summary: (provided by applicant): Soft tissue mechanical properties indicate organ health and impact tissue function. This is perhaps nowhere more obvious than in the blood, where the transition from a fluid to a solid (coagulation) can preserve life during trauma and end life during heart attack, stroke, and pulmonary embolism. While a failure to coagulate (hemophilia) is easily identified and fairly effectively treated, inappropriate coagulation remains responsible for 35% of all deaths in the U.S. Diagnosis of coagulation disorders is critical for identifying those at risk and implementing appropriate treatment and prophylaxis. The goal of this proposal is refinement and clinical validation of an ultrasound radiation force based approach for measuring soft tissue mechanical properties. In this proposal we focus on sonorheometry for coagulation assessment, however the proposed developments will support other future applications. By inducing displacements of only a few microns, sonorheometry avoids disrupting clot formation and therefore provides a fundamentally better measure of overall coagulation risk than existing methods. Sonorheometry will be developed, enhanced, and evaluated through the following specific aims: 1. Implement and Optimize Sonorheometry on the Ultrasonix Sonix RP System 2. Utilize Theory, Simulations, and Experiments to Validate Sonorheometry with High Strain Rates 3. Enhance Algorithms to Improve Accuracy and Reduce Processing Time 4. Test the Ability of Sonorheometry to Identify Hypercoagulability among Human Subjects A successful outcome in assessing hypercoagulability could have a large and immediate clinical impact as it would quantify the magnitude of acquired hypercoagulability (such as that from tobacco smoking and oral contraceptive use). Our
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collaboration with B. Gail Macik, M.D. of the UVA Division of Hematology and Medical Oncology will identify additional applications and ensure that our work remains clinically relevant. •
Project Title: STABILIZED FACTOR VIIIA AS THERAPY FOR HEMOPHILIA A Principal Investigator & Institution: Gale, Andrew J.; Scripps Research Institute 10550 North Torrey Pines Road La Jolla, Ca 920371000 Timing: Fiscal Year 2005; Project Start 27-SEP-2005; Project End 31-AUG-2009 Summary: (provided by applicant): The long term goal of this project is to characterize recombinant variants of activated factor Villa (FVIIIa) that have increased stability resulting in improved therapeutic characteristics as agents for treatment of hemophilia A. Recombinant stabilized FVIIIa with improved therapeutic properties could improve the quality of life and long term health of numerous hemophilia A sufferers in the United States. This is potentially a very significant medical benefit. Basic knowledge of the structure and function of FVIIIa allowed us to create FVIII variants stabilized by a disulfide bond and we propose to characterize these stabilized FVIII variants with respect to functional activity, inactivation, and correction of hemophilia in vivo. The primary hypothesis is that a disulfide bond-stabilized form of FVIII and other stabilized variants of FVIII that we may develop provide FVIIIa that will last longer in vivo and thereby allow correction of the FVIII deficiency of hemophilia A with less FVIII. We also hypothesize that these variants will have a normal half-life before they are activated and that they won't create a prothrombotic state at concentrations that are effective in correcting bleeding. Further, we hypothesize that the immunogenicity of these variants will not be altered. The Specific Aims are: [1] Analyze and characterize disulfide crosslinked recombinant FVIII and FVIIIa. We will use biochemical and chemical methods to characterize variants. [2] Determine the half-life of disulfide crosslinked FVIII in vivo and the effects of FVIIIa stabilization on in vivo bleeding correction. We will characterize the properties and function of disulfide bond-stabilized FVIIIa in vivo in a mouse model of hemophilia A. [3] Characterize the thrombogenicity of disulfide crosslinked FVIII. We will use an intravital model of arterial and venous thrombosis in hemophilia A mice using video microscopy visualization of thrombus formation. [4] Characterize the immunogenicity of disulfide crosslinked FVIII. It is important that modified variants of FVIII are not more immunogenic than normal FVIII. Therefore, we will quantify immune responses in mice. Relevance - One in 5000 males suffer from hemophilia A, a deficiency of coagulation factor VIII. The purpose of this project is to develop recombinant factor VIII with improved therapeutic properties as a new treatment for hemophilia A patients. This treatment could improve the quality of life and overall health of the hemophilia A sufferers.
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Project Title: STRUCTURAL STUDIES OF BLOOD COAGULATION PROTEINS Principal Investigator & Institution: Stoddard, Barry L.; Full Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 981091024 Timing: Fiscal Year 2005; Project Start 01-APR-1999; Project End 30-APR-2007 Summary: (provided by applicant): Factor VIII (fVIII) is a serum protein that acts as a critical cofactor and regulator of the intrinsic blood coagulation pathway. Factor VIII acts by nucleating the assembly of a membrane-bound proteolytic complex that contains the factor IXa protease on the surface of activated platelets. This complex activates factor X as part of a proteolytic cascade that generates fibrin polymers. Prior to its own activation, factor VIII circulates in a tight, stable complex with von Willebrand Factor. A wide variety of inheritable coagulation deficiencies are associated with mutations in
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factor VIII (hemophilia A), factor IX (hemophilia B) and von Willebrand Factor (von Willebrand Disease). Recent studies have reported the high resolution structure of the C2 membrane-binding domain of factor VIII, the structural characterization of hemophilia-associated missense mutations found in the fVIII C domains, the structure of a complex between fVIII and a hemophilia patient-derived antibody inhibitor, and a detailed analysis of the structural genomic relationships throughout the discoidin fold superfamily (of which the fV and fVIII C domains are members). The first specific aim for this project renewal is to characterize the effects of hemophilia-associated point mutations throughout the solvent-exposed surface of the factor VIII C2 domain on its stability, its membrane binding affinity and its association with von Willebrand Factor. These experiments will test the hypothesis that a specific subset of these mutations cause deficiencies in factor VIII membrane binding or vWF association. The second specific aim for this project is to determine the three-dimensional structure of full-length fVIII heterodimer. This structure will be used to study the role of domain motions involved in membrane binding by fVIII, to perform detailed analyses of the structural epidemiology of hemophilia-associated point mutations across the entire structure of the fVIII heterodimer, and to provide a high quality structural model for future crystallographic studies of protein complexes with factor VIII. The third specific aim for this project is to determine the structure of the N-terminal, D'-D3 domain from von Willebrand Factor, alone and/or in complex with factor VIII heterodimer. •
Project Title: STRUCTURE-FUNCTION CARBOXYLASE
ANALYSIS
OF
THE
GAMMA
Principal Investigator & Institution: Berkner, Kathleen L.; Assistant Professor; Molecular Medicine; Cleveland Clinic Lerner Col/Med-Cwru 9500 Euclid Avenue Cleveland, Oh 44195 Timing: Fiscal Year 2007; Project Start 01-APR-1997; Project End 31-DEC-2010 Summary: (provided by applicant): The vitamin K-dependent (VKD) carboxylase is critical to hemostasis because it converts Glus to carboxylated Glus in VKD proteins to allow their binding to cell surfaces where hemostasis occurs. VKD proteins are carboxylated in the endoplasmic reticulum during their secretion, and a single carboxylase modifies all VKD proteins, many of which are coexpressed in tissue. In the previous grant period, we developed an approach to directly analyze intracellular carboxylation in mammalian cells, which showed that the secretory process impacts carboxylation, that intracellular processing is not identical for all VKD proteins and that carboxylation is regulated by the availability of the reduced vitamin K cofactor required for Glu carboxylation. The studies also showed that the rate-limiting step in VKD turnover is different in cells than in an in vitro reaction, which may be due to posttranslational modifications in the carboxylase. Other studies revealed that Leptospira, the bacterial pathogen that causes leptospirosis, contains an ortholog of the VKD carboxylase, which appears to have been acquired by horizontal gene transfer and to have been adapted for a role other than carboxylation. Our studies also implicated novel functional carboxylase residues, including the catalytic base that initiates carboxylation and residues whose substitution cause combined VKD coagulation factor deficiency. Our long-term goal is to understand the mechanism of carboxylation, including how it interfaces with the secretory machinery and how multiple VKD proteins are modified by one carboxylase to become fully-carboxylated and active. We propose: 1. To determine how the active site facilitates carboxylation. We will identify the catalytic base that initiates carboxylation and will determine how substitutions in carboxylase residues cause combined VKD factor deficiency. 2. To determine if turnovers of VKD proteins differ and are impacted by a second site of VKD protein-carboxylase interaction. We will
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determine whether the VKD proteins factor X and prothrombin are carboxylated with equal efficiencies, and whether having two sites of VKD protein-carboxylase interaction impacts efficiency. 3. To test our hypothesis that post-translational carboxylase modifications are important to VKD protein turnover. Sites of post-translational modification in the carboxylase will be identified and mutated to determine if they impact VKD protein turnover. These studies will make important contributions to understanding carboxylation, which will be significant for developing superior anticoagulants and for producing VKD proteins for therapies in hemophilia and sepsis. Lay abstract. Vitamin K in the diet is used to activate a set of factors critical to blood clotting, and therefore it is important to understand how they become activated. The studies will impact the development of anticoagulants and the production of therapeutic proteins for treating hemophilia and septic shock. •
Project Title: THE IMMUNE RESPONSE TO FACTOR VIII Principal Investigator & Institution: Lollar, John S.; Professor; Pediatrics; Emory University 1784 North Decatur Road, Suite 510 Atlanta, Ga 30322 Timing: Fiscal Year 2005; Project Start 27-SEP-2005; Project End 31-AUG-2009 Summary: (provided by applicant): The development of inhibitory antibodies to fVIII (fVIII) is the most significant complication in management of hemophilia A. Moreover, autoantibodies to fVIII in nonhemophiliacs produce the most common autoimmune bleeding disorder involving the coagulation system. In this application, we propose an experimental approach towards developing a comprehensive understanding of the humoral response to fVIII in human and murine hemophilia A. In Aim 1, we will characterize the diversity of anti-human and anti-porcine fVIII B cell epitopes recognized by Hemophilia A mice. We will determine the relative immunodominance of human and porcine fVIII domains using a novel mapping method. This method will be extended to identify all of the non-overlapping epitopes that are targeted by antihuman or anti-porcine fVIII antibodies in the murine Hemophilia A model. In the process, we expect to find important new epitopes and/or common epitopes that are recognized by most or all individuals. In Aim 2, we will characterize the interaction of fVIII with a class of antibodies that bind to both the A1 and A3 domains of human fVIll that we have recently discovered. We hypothesize that these antibodies cross-link fVIII on the B cell surface, which initiates signaling of immunogenic pathways. In Aim 3, we will produce a low immunogenicity fVIII molecule by substituting hypoantigenic porcine sequences identified in the first 2 aims for the corresponding human sequences. Candidate low immunogenicity molecules will be tested in a Hemophilia A mouse model. Our ultimate goal is to identify a candidate low immunogenicity fVIII molecule for comparison to human fVIII in clinical trials in previously untreated patients (PUPs) with hemophilia A and in Hemophilia A gene therapy trials. In Aim 4, we will study the natural history of anti-fVIII antibody development in severe Hemophilia A PUPs using a sensitive anti-fVIII immunoassay and a novel domain specific immunoassay resulting from Aim 1. We anticipate these assays will be useful prognosticators for the development of clinically significant inhibitory antibodies. We intend to test this hypothesis by participating in the Hemophilia Inhibitor PUP Study (HIPS), a prospective natural history cohort study of inhibitor development of PUPs with severe hemophilia A. As an outcome of this project, new therapeutic and diagnostic approaches in the management of Hemophilia A will be produced.
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Project Title: THERAPY OF HEMOPHILIA BY EMBRYONIC STEM CELL TRANSPLANTS Principal Investigator & Institution: Fair, Jeffrey Haskell.; Surgery; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2005; Project Start 30-SEP-2005; Project End 31-AUG-2009 Summary: (provided by applicant): Hemophilia A and B are congenital coagulation disorders. Hemophilia A occurs in 1 in 10,000 individuals whereas hemophilia B affects 1 in 30,000. Clinically, hemophilia is characterized by spontaneous and prolonged bleeding that can result in disability and death. Current protein replacements therapies are limited by incomplete efficacy, high cost, restricted availability, and the possible development of neutralizing antibodies against F.VIII or F.IX in chronically treated individuals. The long range goal of our lab is the development of strategies for cell transplantation, particularly to the liver. Transplanted cells with wild type genes and normal hepatocyte function, may serve as "gene vectors" for restoring function and synthesis of deficient proteins. Hemophilia is ideally suited for this approach. Gene transfer approaches to correct the single gene defects of F.VIII or F.IX have been aggressively investigated but have been frequently been limited by insufficient factor synthesis or by immune response against transgenic or viral proteins. We have developed an alternative strategy using embryonic stem (ES) cells differentiated in vitro and transplanted into hepatic parenchyma to restore wild type function and the synthesis of deficient proteins responsible for hemophilia. In a murine model, we have shown 1) that ES cells can be directly differentiated in vitro into putative endodermal precursors (PEPs) and injected into liver parenchyma resulting in robust engraftment that does not require a hepatocellular deficit or liver injury; 2) that engraftment results in long-term, mature hepatocyte function as demonstrated by persistent reversal of F.IX deficiency in a F.IX knockout mouse and; 3) that engraftment occurs across an allogeneic barrier without recipient immunosuppression. Although these findings suggest therapeutic potential of transplanted PEPs in hemophilia, significant challenges remain. The proposed investigations will address these challenges with the following specific aims: Specific Aim 1: Develop definitive strategies in vitro to separate ES derived PEPs from ES cells that lack endodermal differentiation. Specific Aim 2: Determine the potential for efficacious and safe correction of hemophilia by characterizing the in vivo functional interaction of PEP-derived clotting factors with host coagulation and immune systems. Specific Aim 3: Determine the host immune response to allogeneic PEP engraftment and the immunologic mechanism for the persistence of PEP engraftment. Our overall hypothesis is that allogeneic ES derived PEPs are capable of safe engraftment into the hepatic parenchyma, providing long-term coagulation factor synthesis in vivo and the correction of hemophilia.
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Project Title: TRANSFERRING INTEGRASE TECHNOLOGY TO ANIMALS Principal Investigator & Institution: Calos, Michele P.; Associate Professor; Genetics; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2005; Project Start 01-JUL-2001; Project End 30-JUN-2007 Summary: (provided by applicant): The goal of this proposal is to continue advancing this innovative site-specific integration technology toward utility in gene therapy through studies in animals. The technology uses the phage phiC31 integrase to provide safe and efficient site-specific integration of incoming gene therapy vectors at preferred locations in the genome. PhiC31-mediated integration provides robust, long-term expression of the integrated therapeutic gene, without the risk of random integration. During the two years of the grant to date, we demonstrated that the phiC31 integrase
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technology was effective in providing long-term, high level liver expression of factor IX in mice. We also demonstrated therapeutic expression of collagen VII and laminin B3 in human skin grafted on to mouse models and expression of human alpha1 antitrypsin in mouse liver. In addition, we used the technology to create transgenic animals. We now wish to continue development of the integrase technology for long-term gene therapy by moving to larger animal models in two important tissues, liver and muscle. We have already demonstrated effective DNA delivery methods for these tissues. In both liver and muscle we observed more robust and longer-lived gene expression when phiC31 integrase technology was used, compared to unintegrated plasmid DNA. We will employ hydrodynamic delivery of the phiC31 integrase system to express therapeutic levels of factor IX from the livers of rats, rabbits, and dogs. We will also explore alternative methods to deliver the integrase system to liver. In addition, we will use the phiC31 integrase technology, delivered to muscle by DNA injection and electroporation, for integration and long-term expression of plasmids bearing VEGF and other angiogenic factors to correct ischemia in mice, rats, and rabbits. By scaling up to animals more similar to humans, these experiments will move the site-specific integrase technology closer to the clinic. •
Project Title: TRANSFUSION MEDICINE/HEMOSTASIS CLINICAL RESEARCH NETWO* Principal Investigator & Institution: Triulzi, Darrell J.; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2005; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Core Center Program Objectives: The Pittsburgh Transfusion Medicine/Hemostasis Research Network (PTN) seeks to contribute to important multicenter clinical trials in transfusion medicine and hemostasis by capitalizing on our three strengths: 1) The integrated delivery of transfusion medicine and coagulation services to all the major University of Pittsburgh Medical Center Health System (UPMCHS) hospitals by the University of Pittsburgh faculty at the Institute For Transfusion Medicine (ITxM);2) The extraordinary patient base afforded by the UPMCHS hospitals including a Pittsburgh Cancer Institute (PCI), adult and pediatric level I trauma centers, a largest organ transplant program, a children's hospital, a women's hospital and outpatient facilities including the Hemophilia Center of Western PA and PCI; and3) The extensive experience and extertice of all three core center investigators in running and/or participating in multicenter clinical trials in transfusion medicine and hemostasis. Specific Aims: We propose two protocols to accomplish these objectives:1) Prospective Randomized Trial of Activase in the Prevention of Central Venous Access Device Infection in Hemophilia" (Project 1); and2) Multi-center, Randomized, Controlled Clinical Trial of Plasma Exchange Therapy vs Standard of Care in Children with Thrombocytopenia Associated Multi-Organ Failure (Project 2)The Core Center will provide the infrastructure and oversight necessary for the successful implementation and execution of these trials including: management of the budget for each protocol, timely establishment of program network office, coordinate resources for the operation of each protocol (e.g., research nurse, data clerk), assure timely implementation and operation of new protocols (e.g., accrural, timely data reporting, patient follow up) through biweekly research meetings with protocol investigators, establish a local DSMB for each protocol, assist protocol investigators with data analysis, interpretation, and publication, establish a Community Advisory Group to educate the community and to discuss and disseminate study results, and work with other network sites to select and revise study protocols.
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Project Title: TRANSPLANTATION OF ENDOTHELIAL CELLS Principal Investigator & Institution: Gupta, Sanjeev; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2011 Summary: (provided by applicant): Liver-directed cell therapy has significant potential for many disorders. Studies of hepatocyte transplantation provided insights into cell therapy, as well as novel models for basic studies concerning liver regeneration and stem cell biology. We now wish to define the potential of additional liver cell types, especially endothelial cells, which constitute a major liver cell compartment and contribute in cell-cell signaling, coagulation factor synthesis and immunological responses. Our major hypothesis is that sinusoidal liver endothelial cells will engraft and proliferate in the liver of suitable recipients. Insights into these properties of liver endothelial cells will offer ways to treat specific disorders and to modulate the behavior of other liver cell types for various applications. Therefore, we propose to conduct studies in mice for establishing mechanisms concerning the survival, fate and function of transplanted endothelial cells. Our specific objectives are to first establish the efficiency with which transgenically marked endothelial cells will engraft in the liver of congeneic recipients, including after the introduction of reporter genes with viral vectors, and demonstrate specific mechanisms that would facilitate engraftment and/or proliferation of transplanted endothelial cells. We will then examine whether therapeutic genes can be successfully expressed in transplanted endothelial cells and whether the natural history of hepatic disease processes could be altered by such manipulations. Furthermore, we will examine whether cell-cell interactions can be reproduced in the in vivo setting, such that engraftment of transplanted mouse or human hepatocytes could be modulated in immunodeficient animals by cotransplantation of endothelial cells. Also, we will examine whether transplantation of unperturbed or genetically modified endothelial liver cells and transplantation of endothelial stem/progenitor cells could help ameliorate disease in mice. We expect that these studies will generate insights into endothelial cell biology, offer novel biological models and help define the therapeutic potential of liver endothelial cells.
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Project Title: WNT/BETA-CATENIN AND WNT/CA2+ SIGNALING IN STEM CELLS Principal Investigator & Institution: Kohn, Aimee D.; Medicine; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 01-JAN-2005; Project End 31-DEC-2005 Summary: (provided by applicant): Wnt proteins signal through either the canonical Wnt/beta-catenin or the noncanonical Wnt/Ca2+ pathway. In some vertebrates, these pathways have been shown to function antagonistically. The beta-catenin pathway has been implicated in the maintenance and renewal of a variety of stem cells, including human embryonic stem cells (HESCs). The role of the Wnt/Ca2+ pathway in HESCs is unknown. The goal of this research is to determine the role of Wnt/Ca2+ signaling in the self-renewal and differentiation of HESCs. Stem cells (H7 or WA07 and HSF-6 or UC06) will be treated with either canonical or noncanonical purified Wnts or Wnt conditioned media. HESCs will also be transduced with lentivirus that express inducible conditional alleles capable of beta-catenin or Ca2+ directed signaling. Stem cells will be identified by staining for specific markers; also, their ability to differentiate into tissue derived from all three germ layers will be assessed by quantitative RT-PCR of specific tissue markers and by the ability to form teratomas upon injection into NOD/SCID mice. This research will enhance our understanding of the requirements for stem cell
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propagation, which, in turn, may contribute to the treatment of such diseases as diabetes and hemophilia.
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.7 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with hemophilia, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type hemophilia (or synonyms) into the search box, and click Go. The following is the type of output you can expect from PubMed for hemophilia (hyperlinks lead to article summaries): •
A case of subcapsular rupture of liver in a neonate associated with hemophilia A. Author(s): Oshio T, Hino M, Nakamizo H, Yoshikawa K, Takano S. Source: Journal of Pediatric Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16863857&query_hl=23&itool=pubmed_docsum
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A Chinese family with hemophilia B Leyden due to T-->A transition at position +6 of the FIX gene. Author(s): Chan V, Ha SY, Au P, Lam C, Chan TK. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16550516&query_hl=23&itool=pubmed_docsum
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A hemophilic son of a hemophiliac: did my son inherit my hemophilia? Author(s): Williams V, Griffiths A, Tapp H, Mangos H, Casey G. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17239168&query_hl=23&itool=pubmed_docsum
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A highly informative, multiplexed assay for the indirect detection of hemophilia A using five-linked microsatellites. Author(s): Harraway JR, Smith MP, George PM. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16460441&query_hl=23&itool=pubmed_docsum
7
PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Author(s): Jacquemin M, Lavend'homme R, Benhida A, Vanzieleghem B, d'Oiron R, Lavergne JM, Brackmann HH, Schwaab R, VandenDriessche T, Chuah MK, Hoylaerts M, Gilles JG, Peerlinck K, Vermylen J, Saint-Remy JM. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10910910&query_hl=23&itool=pubmed_docsum
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A patient's perspective on hemophilia. Author(s): Sulser E. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16631822&query_hl=23&itool=pubmed_docsum
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A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia. Author(s): Allen GA, Persson E, Campbell RA, Ezban M, Hedner U, Wolberg AS. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17204663&query_hl=23&itool=pubmed_docsum
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AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Author(s): Manno CS, Chew AJ, Hutchison S, Larson PJ, Herzog RW, Arruda VR, Tai SJ, Ragni MV, Thompson A, Ozelo M, Couto LB, Leonard DG, Johnson FA, McClelland A, Scallan C, Skarsgard E, Flake AW, Kay MA, High KA, Glader B. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12515715&query_hl=23&itool=pubmed_docsum
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AAV-mediated gene transfer for hemophilia. Author(s): High K. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12544490&query_hl=23&itool=pubmed_docsum
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Abciximab for the treatment of an acute thrombotic coronary occlusion during stent implantation in a patient with severe hemophilia B. Author(s): Bovenzi F, De Luca L, Signore N, Fusco F, de Luca I. Source: Ital Heart J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14664288&query_hl=23&itool=pubmed_docsum
72
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Acquired hemophilia A. Author(s): Franchini M. Source: Hematology (Amsterdam, Netherlands). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16753853&query_hl=23&itool=pubmed_docsum
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Acquired hemophilia as a cause of primary postpartum hemorrhage. Author(s): Borna S, Hantoushzadeh S. Source: Arch Iran Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17198466&query_hl=23&itool=pubmed_docsum
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Acquired hemophilia in association with ANCA-associated vasculitis: response to rituximab. Author(s): Clatworthy MR, Jayne DR. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16564946&query_hl=23&itool=pubmed_docsum
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Adeno-associated virus-mediated gene transfer for hemophilia B. Author(s): High KA. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12463593&query_hl=23&itool=pubmed_docsum
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Allele frequencies of three factor VIII gene polymorphisms in Iranian populations and their application in hemophilia A carrier detection. Author(s): Azimifar SB, Seyedna SY, Zeinali S. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16628729&query_hl=23&itool=pubmed_docsum
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An unusual reason for obstructive sleep apnea in a boy with hemophilia B: supraglottic papilloma. Author(s): Jakubikova J, Zitnan D, Batorova A. Source: International Journal of Pediatric Otorhinolaryngology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8770685&query_hl=23&itool=pubmed_docsum
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Anaphylaxis in patients with hemophilia. Author(s): Jadhav M, Warrier I. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10919414&query_hl=23&itool=pubmed_docsum
Studies
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Angioedema and the Canadian Network of Rare Blood Disorder Organizations: extending the Canadian hemophilia care model. Author(s): Bowen T. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17060658&query_hl=23&itool=pubmed_docsum
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Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG. Author(s): Moreau A, Lacroix-Desmazes S, Stieltjes N, Saenko E, Kaveri SV, D'Oiron R, Sultan Y, Scandella D, Kazatchkine MD. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10828026&query_hl=23&itool=pubmed_docsum
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Attention in HIV-infected children: results from the Hemophilia Growth and Development Study. Author(s): Watkins JM, Cool VA, Usner D, Stehbens JA, Nichols S, Loveland KA, Bordeaux JD, Donfield S, Asarnow RF, Nuechterlein KH. Source: Journal of the International Neuropsychological Society : Jins. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10902413&query_hl=23&itool=pubmed_docsum
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Bacillus cereus central line infection in an immunocompetent child with hemophilia. Author(s): Srivaths PR, Rozans MK, Kelly E Jr, Venkateswaran L. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15125613&query_hl=23&itool=pubmed_docsum
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Bedside measurement of factor VIII:C activity in individuals with hemophilia A. Author(s): Kessler CM, Bernstein Z, Ghesani S, Shamsipour Z, Frances C, Zucker ML, LaDuca FM. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8619397&query_hl=23&itool=pubmed_docsum
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Behavioral adaptation to human immunodeficiency virus-seropositive status in children and adolescents with hemophilia. Author(s): Hooper SR, Whitt JK, Tennison M, Burchinal M, Gold S, Hall C. Source: Am J Dis Child. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8488800&query_hl=23&itool=pubmed_docsum
74
Hemophilia
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Beta-propiolactone UV inactivated clotting factor concentrate is the source of HIVinfection of 8 hemophilia B patients: confirmed. Author(s): Kupfer B, Oldenburg J, Brackmann HH, Matz B, Schneweis KE, Kaiser R. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8607133&query_hl=23&itool=pubmed_docsum
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Bilateral pneumothorax accompanied by mild deficiency type hemophilia a: report of a case. Author(s): Kitami A, Suzuki T, Suzuki S, Hirota Y. Source: Surgery Today. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14605959&query_hl=23&itool=pubmed_docsum
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Bimaxillary osteotomy in a female patient with hemophilia A. Author(s): Guzel MZ, Arslan H, Kilic A. Source: The Journal of Craniofacial Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16877919&query_hl=23&itool=pubmed_docsum
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Blood coagulation in hemophilia A and hemophilia C. Author(s): Cawthern KM, van 't Veer C, Lock JB, DiLorenzo ME, Branda RF, Mann KG. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9616154&query_hl=23&itool=pubmed_docsum
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Blood products for hemophilia: past, present and future. Author(s): Giangrande PL. Source: Biodrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15244500&query_hl=23&itool=pubmed_docsum
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Blood-induced joint damage in hemophilia. Author(s): Roosendaal G, Lafeber FP. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12640563&query_hl=23&itool=pubmed_docsum
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Bone marrow stromal cell-mediated gene therapy for hemophilia A: in vitro expression of human factor VIII with high biological activity requires the inclusion of the proteolytic site at amino acid 1648. Author(s): Chiang GG, Rubin HL, Cherington V, Wang T, Sobolewski J, McGrath CA, Gaffney A, Emami S, Sarver N, Levine PH, Greenberger JS, Hurwitz DR. Source: Human Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10022531&query_hl=23&itool=pubmed_docsum
Studies
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Bone marrow stromal cells as targets for gene therapy of hemophilia A. Author(s): Chuah MK, Brems H, Vanslembrouck V, Collen D, Vandendriessche T. Source: Human Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9508053&query_hl=23&itool=pubmed_docsum
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Brachial plexus palsy presenting as an initial manifestation of hemophilia in a middle-aged man. Author(s): Ogawa K, Yoshida A, Ui M. Source: Journal of Shoulder and Elbow Surgery / American Shoulder and Elbow Surgeons. [et Al.]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9814940&query_hl=23&itool=pubmed_docsum
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Brain abnormalities in male children and adolescents with hemophilia: detection with MR imaging. The Hemophilia Growth and Development Study Group. Author(s): Wilson DA, Nelson MD Jr, Fenstermacher MJ, Bohan TP, Hopper KD, Tilton A, Mitchell WG, Contant CF Jr, Maeder MA, Donfield SM, et al. Source: Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1410372&query_hl=23&itool=pubmed_docsum
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Breakpoint of a balanced translocation (X:14) (q27.1;q32.3) in a girl with severe hemophilia B maps proximal to the factor IX gene. Author(s): Di Paola J, Goldman T, Qian Q, Patil SR, Schutte BC. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15009460&query_hl=23&itool=pubmed_docsum
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Can evidence harm? Certainly not hemophilia treatment and community. Author(s): Iorio A, Stobart K, Bolton-Maggs P. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16460430&query_hl=23&itool=pubmed_docsum
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Cardiac tamponade in a patient with moderate hemophilia A and factor VIII Inhibitors. Author(s): Ghosh N, Teefy P, Laudenbach L, Rivard GE. Source: The Canadian Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16450022&query_hl=23&itool=pubmed_docsum
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Carrier detection and prenatal diagnosis of hemophilia in developing countries. Author(s): Peyvandi F. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16276463&query_hl=23&itool=pubmed_docsum
76
Hemophilia
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Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII. Author(s): Lacroix-Desmazes S, Wootla B, Dasgupta S, Delignat S, Bayry J, Reinbolt J, Hoebeke J, Saenko E, Kazatchkine MD, Friboulet A, Christophe O, Nagaraja V, Kaveri SV. Source: Journal of Immunology (Baltimore, Md. : 1950). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16818797&query_hl=23&itool=pubmed_docsum
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Central venous access devices in patients with hemophilia. Author(s): Valentino LA, Kapoor M. Source: Expert Rev Med Devices. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16293097&query_hl=23&itool=pubmed_docsum
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Characterization of human hybridoma clones isolated from hemophilia patients with specificity for different domains of coagulating factor VIII. Author(s): Gharagozlou S, Ghods R, Bahrami ZS, Roohi A, Jeddi-Tehrani M, Conti-Fine BM, Sharifian RA, Rabbani H, Shokri F. Source: Human Antibodies. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14646035&query_hl=23&itool=pubmed_docsum
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Children's knowledge of illness and treatment experiences in hemophilia. Author(s): Spitzer A. Source: Journal of Pediatric Nursing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1548561&query_hl=23&itool=pubmed_docsum
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Classic polyarteritis nodosa presenting rare clinical manifestations in a patient with hemophilia A. Author(s): Matsushita T, Adachi H, Watanabe H, Shimoyama Y, Adachi T, Sobue G, Ito M, Kojima T, Saito H, Naoe T. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16787873&query_hl=23&itool=pubmed_docsum
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Clearance of GB virus C during highly active antiretroviral therapy and course of HIV disease progression in HIV-infected patients with hemophilia. Author(s): Toyoda H, Honda T, Katano Y, Goto H, Takamatsu J. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16200339&query_hl=23&itool=pubmed_docsum
Studies
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Clinical correlates among 49 families with hemophilia A and factor VIII gene inversions. Author(s): Weinmann AF, Schoof JM, Thompson AR. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8619399&query_hl=23&itool=pubmed_docsum
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Clinical evaluation of recombinant factor VIII preparation (Kogenate) in previously treated patients with hemophilia A: descriptive meta-analysis of post-marketing study data. Author(s): Yoshioka A, Fukutake K, Takamatsu J, Shirahata A; Kogenate Post-Marketing Surveillance Study Group. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16926139&query_hl=23&itool=pubmed_docsum
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Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Author(s): Stobart K, Iorio A, Wu JK. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16625581&query_hl=23&itool=pubmed_docsum
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Comorbidity of constrictive pericarditis and hemophilia A. Author(s): Demiralp E, Ulusoy RE, Kirilmaz A, Cebeci BS, Kucukarslan N, Ozmen N, Aparci M. Source: Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16651841&query_hl=23&itool=pubmed_docsum
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Confirmation of the value of a modified long-distance polymerase chain reaction in the detection of inversion intron 22 in severe hemophilia a: a technical note. Author(s): Lombardi AM, Cabrio L, Zanon E, Pellati D, Vettore S, Girolami A. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16244778&query_hl=23&itool=pubmed_docsum
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Consideration in hemophilia therapy selection. Author(s): Pipe S. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16631824&query_hl=23&itool=pubmed_docsum
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Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia. Author(s): Zhang M, Rosenberg PS, Brown DL, Preiss L, Konkle BA, Eyster ME, Goedert JJ; Second Multicenter Hemophilia Cohort Study. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16204310&query_hl=23&itool=pubmed_docsum
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Correlation between factor VIII genotype and inhibitor development in hemophilia A. Author(s): Fakharzadeh SS, Kazazian HH Jr. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10919409&query_hl=23&itool=pubmed_docsum
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Current issues in prophylactic therapy for persons with hemophilia. Author(s): Dunn AL, Abshire TC. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16549891&query_hl=23&itool=pubmed_docsum
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Cutaneous wound healing is impaired in hemophilia B. Author(s): Hoffman M, Harger A, Lenkowski A, Hedner U, Roberts HR, Monroe DM. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16825491&query_hl=23&itool=pubmed_docsum
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Cytomegalovirus seropositivity and human immunodeficiency virus type 1 RNA levels in individuals with hemophilia. Author(s): Sabin CA, Devereux HL, Clewley G, Emery VC, Phillips AN, Loveday C, Lee CA, Griffiths PD. Source: The Journal of Infectious Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10823788&query_hl=23&itool=pubmed_docsum
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Declining immune function in children and adolescents with hemophilia and HIV infection: effects on neuropsychological performance. Hemophilia Growth and Development Study. Author(s): Loveland KA, Stehbens JA, Mahoney EM, Sirois PA, Nichols S, Bordeaux JD, Watkins JM, Amodei N, Hill SD, Donfield S. Source: Journal of Pediatric Psychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10880061&query_hl=23&itool=pubmed_docsum
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Demographics of hemophilia in developing countries. Author(s): Evatt BL. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16276455&query_hl=23&itool=pubmed_docsum
Studies
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Dental procedures in adult patients with hereditary bleeding disorders: 10 years experience in three Italian Hemophilia Centers. Author(s): Franchini M, Rossetti G, Tagliaferri A, Pattacini C, Pozzoli D, Lorenz C, Del Dot L, Ugolotti G, Dell'aringa C, Gandini G. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16128895&query_hl=23&itool=pubmed_docsum
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Desmopressin in mild hemophilia A: indications, limitations, efficacy, and safety. Author(s): Lethagen S. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12640572&query_hl=23&itool=pubmed_docsum
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Detailed characterization of an anti-factor IX monoclonal antibody that neutralizes the prolonged ox brain prothrombin time of hemophilia B(M) by synthetic peptides. Author(s): Takahashi I, Kojima T, Sano M, Watanabe T, Kamiya T, Saito H. Source: Peptides. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10876041&query_hl=23&itool=pubmed_docsum
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Detection of 95 novel mutations in coagulation factor VIII gene F8 responsible for hemophilia A: results from a single institution. Author(s): Guillet B, Lambert T, d'Oiron R, Proulle V, Plantier JL, Rafowicz A, Peynet J, Costa JM, Bendelac L, Laurian Y, Lavergne JM. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16786531&query_hl=23&itool=pubmed_docsum
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Detection of Pneumocystis carinii, Mycobacterium tuberculosis, and cytomegalovirus in human immunodeficiency virus (HIV)-infected patients with hemophilia by polymerase chain reaction of induced sputum samples. Author(s): Shimomoto H, Hasegawa Y, Takagi N, Ichiyama S, Takamatsu J, Saito H, Shimokata K. Source: Intern Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8563099&query_hl=23&itool=pubmed_docsum
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Development and analysis of retroviral vectors expressing human factor VIII as a potential gene therapy for hemophilia A. Author(s): Chuah MK, Vandendriessche T, Morgan RA. Source: Human Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8573610&query_hl=23&itool=pubmed_docsum
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Development of improved factor VIII molecules and new gene transfer approaches for hemophilia A. Author(s): Saenko EL, Ananyeva NM, Moayeri M, Ramezani A, Hawley RG. Source: Current Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12553533&query_hl=23&itool=pubmed_docsum
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Diagnosis of hemophilia B carriers using two novel dinucleotide polymorphisms and Hha I RFLP of the factor IX gene in Japanese subjects. Author(s): Toyozumi H, Kojima T, Matsushita T, Hamaguchi M, Tanimoto M, Saito H. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8560402&query_hl=23&itool=pubmed_docsum
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Dissociation of CD4(+) cell counts from viral load and association with immune complexes in HIV(+) hemophilia patients. Author(s): Sadeghi M, Daniel V, Naujokat C, Susal C, Weimer R, Huth-Kuhne A, Zimmermann R, Opelz G. Source: Immunology Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14757366&query_hl=23&itool=pubmed_docsum
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DNA microarray analysis for the detection of mutations in hemophilia A. Author(s): Berber E, Leggo J, Brown C, Berber E, Gallo N, Feilotter H, Lillicrap D. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16879218&query_hl=23&itool=pubmed_docsum
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DNA variation in a 13-Mb region including the F9 gene: inferring the genealogical history and causal role of a hemophilia B mutation (IVS 5+13 A-->G). Author(s): Anagnostopoulos T, Morris AP, Ayres KL, Giannelli F, Green PM. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14675097&query_hl=23&itool=pubmed_docsum
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Does an enzyme other than thrombin contribute to unexpected changes in the levels of the different forms of thrombin activatable fibrinolysis inhibitor in patients with hemophilia A, hemophilia B and von Willebrand disease? Author(s): Antovic JP, Schulman S, An SS, Greenfield RS, Blomback M. Source: Scandinavian Journal of Clinical and Laboratory Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15719893&query_hl=23&itool=pubmed_docsum
Studies
81
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Does hemophilia protect against atherosclerosis? A case-control study. Author(s): Bilora F, Zanon E, Petrobelli F, Cavraro M, Prandoni P, Pagnan A, Girolami A. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16708121&query_hl=23&itool=pubmed_docsum
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Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry. Author(s): Parameswaran R, Shapiro AD, Gill JC, Kessler CM; HTRS Registry Investigators. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15810910&query_hl=23&itool=pubmed_docsum
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Dose titration of recombinant factor VIIa using thromboelastograph monitoring in a child with hemophilia and high titer inhibitors to factor VIII: a case report and brief review. Author(s): Trowbridge CC, Stammers AH, Ciccarelli N, Klayman M. Source: J Extra Corpor Technol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17089513&query_hl=23&itool=pubmed_docsum
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Dr Leandro Tocantins's inhibitor theory of hemophilia and factor X: reply. Author(s): Hougie C. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14717984&query_hl=23&itool=pubmed_docsum
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Dual vectors expressing murine factor VIII result in sustained correction of hemophilia A mice. Author(s): Mah C, Sarkar R, Zolotukhin I, Schleissing M, Xiao X, Kazazian HH, Byrne BJ. Source: Human Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12614565&query_hl=23&itool=pubmed_docsum
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Duplication of exon 13 causes one third of the cases of mild hemophilia A in northern Italy. Author(s): Acquila M, Pasino M, Lanza T, Bottini F, Molinari AC, Bicocchi MP. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15194549&query_hl=23&itool=pubmed_docsum
82
Hemophilia
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Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia. Multicenter Hemophilia Cohort Study. Author(s): Yeo AE, Matsumoto A, Hisada M, Shih JW, Alter HJ, Goedert JJ. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10858179&query_hl=23&itool=pubmed_docsum
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Effect of intracranial bleeds on the health and quality of life of boys with hemophilia. Author(s): Revel-Vilk S, Golomb MR, Achonu C, Stain AM, Armstrong D, Barnes MA, Anderson P, Logan WJ, Sung L, McNeely M, Blanchette V, Feldman BM. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15069398&query_hl=23&itool=pubmed_docsum
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Effects of radiosynovectomy with p-32 colloid therapy in hemophilia and rheumatoid arthritis. Author(s): Soroa VE, del Huerto Velazquez Espeche M, Giannone C, Caviglia H, Galatros G, Fernandez D, Mendez M, Naswetter GG, Nicolini JO. Source: Cancer Biotherapy & Radiopharmaceuticals. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15989482&query_hl=23&itool=pubmed_docsum
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Efficacy of induction therapy with high-dose interferon for patients with hemophilia and human immunodeficiency virus-hepatitis C virus coinfection. Author(s): Hanabusa H. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12471573&query_hl=23&itool=pubmed_docsum
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Efficient AAV1-AAV2 hybrid vector for gene therapy of hemophilia. Author(s): Hauck B, Xu RR, Xie J, Wu W, Ding Q, Sipler M, Wang H, Chen L, Wright JF, Xiao W. Source: Human Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16409124&query_hl=23&itool=pubmed_docsum
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Elective orthopedic surgery for hemophilia patients with inhibitors: New opportunities. Author(s): Rodriguez-Merchan EC, Wiedel Jd J, Wallny T, Caviglia H, Hvid I, Berntorp E, Rivard GE, Goddard Nj N, Querol F. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14872431&query_hl=23&itool=pubmed_docsum
Studies
83
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Eleven novel mutations in the factor VIII gene from Brazilian hemophilia A patients. Author(s): Arruda VR, Pieneman WC, Reitsma PH, Deutz-Terlouw PP, AnnichinoBizzacchi JM, Briet E, Costa FF. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7579394&query_hl=23&itool=pubmed_docsum
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Endovascular management of a mandibular arteriovenous malformation in a patient with severe hemophilia a. Author(s): Benndorf G, Kim DM, Menneking H, Klein M. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15090353&query_hl=23&itool=pubmed_docsum
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Endpoints in clinical trials involving hemostasis and bleeding in patients with hemophilia. Author(s): Escobar MA. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15989684&query_hl=23&itool=pubmed_docsum
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Enhanced communication between care professionals and patients with hemophilia by using a web enabled electronic logbook. Author(s): Roosendaal G, Drenth ER, Poerschke M, Verkerk EC, Van den Berg HM, Metselaar M. Source: Stud Health Technol Inform. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15747920&query_hl=23&itool=pubmed_docsum
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Evaluation of denaturing high-performance liquid chromatography (DHPLC) in the screening of mutations in hemophilia B patients. Author(s): Herbert O, Trossaert M, Boisseau P, Fressinaud E, Gerson F. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15613048&query_hl=23&itool=pubmed_docsum
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Evidence for a shift from a type I lymphocyte pattern with HIV disease progression. Hemophilia Growth and Development Study. Author(s): Jason J, Sleeper LA, Donfield SM, Murphy J, Warrier I, Arkin S, Evatt B. Source: Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology : Official Publication of the International Retrovirology Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7583444&query_hl=23&itool=pubmed_docsum
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Evidence for the benefits of prophylaxis in the management of hemophilia A. Author(s): Hoots WK, Nugent DJ. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17003919&query_hl=23&itool=pubmed_docsum
84
Hemophilia
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Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Author(s): Jiang H, Pierce GF, Ozelo MC, de Paula EV, Vargas JA, Smith P, Sommer J, Luk A, Manno CS, High KA, Arruda VR. 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=16822719&query_hl=23&itool=pubmed_docsum
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Evolution of the imaging tests in hemophilia with emphasis on radiography and magnetic resonance imaging. Author(s): Kilcoyne RF, Lundin B, Pettersson H. Source: Acta Radiologica (Stockholm, Sweden : 1987). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16613310&query_hl=23&itool=pubmed_docsum
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Exon skipping partially restores factor VIII coagulant activity in patients with mild hemophilia A with exon 13 duplication. Author(s): Acquila M, Pasino M, Lanza T, Molinari AC, Rosano C, Bicocchi MP. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15996947&query_hl=23&itool=pubmed_docsum
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Expanding hemophilia care in developing countries. Author(s): O'Mahony B, Black C. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16276465&query_hl=23&itool=pubmed_docsum
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Expression of human coagulation factor VIII in adipocytes transduced with the simian immunodeficiency virus agmTYO1-based vector for hemophilia A gene therapy. Author(s): Ogata K, Mimuro J, Kikuchi J, Tabata T, Ueda Y, Naito M, Madoiwa S, Takano K, Hasegawa M, Ozawa K, Sakata Y. Source: Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14737084&query_hl=23&itool=pubmed_docsum
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Expression of therapeutic levels of factor VIII in hemophilia A mice using a novel adeno/adeno-associated hybrid virus. Author(s): Gnatenko DV, Wu Y, Jesty J, Damon AL, Hearing P, Bahou WF. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15269828&query_hl=23&itool=pubmed_docsum
Studies
85
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Extracorporeal membrane oxygenation as a bridge to cardiac transplantation in a patient with cardiomyopathy and hemophilia A. Author(s): Thiagarajan RR, Roth SJ, Margossian S, Mackie AS, Neufeld EJ, Laussen PC, Forbess JM, Blume ED. Source: Intensive Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12719805&query_hl=23&itool=pubmed_docsum
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Factor concentrate usage in persons with hemophilia in New York State. Author(s): Linden JV, Kolakoski MH, Lima JE, Du P, Lipton RA. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12662279&query_hl=23&itool=pubmed_docsum
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Factor IX mutations: rapid, direct screening methods for 20 new families with hemophilia B. Author(s): Thompson AR, Schoof JM, Weinmann AF, Chen SH. Source: Thrombosis Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1579901&query_hl=23&itool=pubmed_docsum
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Factor IX variants improve gene therapy efficacy for hemophilia B. Author(s): Schuettrumpf J, Herzog RW, Schlachterman A, Kaufhold A, Stafford DW, Arruda VR. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15550487&query_hl=23&itool=pubmed_docsum
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Factor products in the treatment of hemophilia. Author(s): Miller KL. 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=15129219&query_hl=23&itool=pubmed_docsum
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Factor VIII alloantibodies in hemophilia. Author(s): Jacquemin MG, Saint-Remy JM. Source: Current Opinion in Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15257012&query_hl=23&itool=pubmed_docsum
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Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment. Author(s): Yarovoi HV, Kufrin D, Eslin DE, Thornton MA, Haberichter SL, Shi Q, Zhu H, Camire R, Fakharzadeh SS, Kowalska MA, Wilcox DA, Sachais BS, Montgomery RR, Poncz M. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12881300&query_hl=23&itool=pubmed_docsum
86
Hemophilia
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Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with hightiter inhibitory antibodies. Author(s): Shi Q, Wilcox DA, Fahs SA, Weiler H, Wells CW, Cooley BC, Desai D, Morateck PA, Gorski J, Montgomery RR. Source: The Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16823491&query_hl=23&itool=pubmed_docsum
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Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Author(s): Antonarakis SE, Rossiter JP, Young M, Horst J, de Moerloose P, Sommer SS, Ketterling RP, Kazazian HH Jr, Negrier C, Vinciguerra C, Gitschier J, Goossens M, Girodon E, Ghanem N, Plassa F, Lavergne JM, Vidaud M, Costa JM, Laurian Y, Lin SW, Lin SR, Shen MC, Lillicrap D, Taylor SA, Windsor S, Valleix SV, Nafa K, Sultan Y, Delpech M, Vnencak-Jones CL, Phillips JA 3rd, Ljung RC, Koumbarelis E, Gialeraki A, Mandalaki T, Jenkins PV, Collins PW, Pasi KJ, Goodeve A, Peake I, Preston FE, Schwartz M, Scheibel E, Ingerslev J, Cooper DN, Millar DS, Kakkar VV, Giannelli F, Naylor JA, Tizzano EF, Baiget M, Domenech M, Altisent C, Tusell J, Beneyto M, Lorenzo JI, Gaucher C, Mazurier C, Peerlinck K, Matthijs G, Cassiman JJ, Vermylen J, Mori PG, Acquila M, Caprino D, Inaba H. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7662970&query_hl=23&itool=pubmed_docsum
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Factor VIII half-life and clinical phenotype of severe hemophilia A. Author(s): van Dijk K, van der Bom JG, Lenting PJ, de Groot PG, Mauser-Bunschoten EP, Roosendaal G, Grobbee DE, van den Berg HM. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15820945&query_hl=23&itool=pubmed_docsum
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Factor VIII inhibitor developed in a 60-year-old patient with mild hemophilia A after surgery for colon cancer. Author(s): Suzuki T, Arai M, Miyasaka S, Watanabe J, Sugimura D, Amano K, Yamagishi T, Kagawa K, Fukue H, Fukutake K. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8590774&query_hl=23&itool=pubmed_docsum
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Factor VIII inhibitors development following introduction of B-domain-deleted recombinant factor VIII in four hemophilia A previously treated patients. Author(s): Roussel-Robert V, Torchet MF, Legrand F, Rothschild C, Stieltjes N. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14629482&query_hl=23&itool=pubmed_docsum
Studies
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Factors affecting choice of hemostatic agent for the hemophilia patient with an inhibitor antibody. Author(s): Monahan PE, Aledort LM; Hemophilia Inhibitor Study Group. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15558804&query_hl=23&itool=pubmed_docsum
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Failure of a sibling umbilical cord blood transplantation to correct hemophilia A. Author(s): Andolina M, Maximova N, Rabusin M, Bruno G, Cerneca F. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15257959&query_hl=23&itool=pubmed_docsum
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Female hemophilia A heterozygous for a de novo frameshift and a novel missense mutation of factor VIII. Author(s): Cai XH, Wang XF, Dai J, Fang Y, Ding QL, Xie F, Wang HL. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16805874&query_hl=23&itool=pubmed_docsum
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Free flaps: the hemophilia factor. Author(s): Ostric SA, Martin WJ, Bajnrauh R, Bittar S. Source: Plastic and Reconstructive Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16772993&query_hl=23&itool=pubmed_docsum
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Frequency of factor VIII intron 1 inversion in a cohort of severe hemophilia A Italian patients. Author(s): Acquila M, Pasino M, Lanza T, Bottini F, Boeri E, Bicocchi MP. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12745291&query_hl=23&itool=pubmed_docsum
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Functional analysis of the EGF-like domain mutations Pro55Ser and Pro55Leu, which cause mild hemophilia B. Author(s): Knobe KE, Persson KE, Sjorin E, Villoutreix BO, Stenflo J, Ljung RC. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12871416&query_hl=23&itool=pubmed_docsum
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Further characterization of the new marker at DXS115 with regard to carrier detection in hemophilia A. Author(s): Kling S, Ljung R, Sjorin E, Nilsson IM. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1740327&query_hl=23&itool=pubmed_docsum
88
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Future aspects of hemophilia research and care. Author(s): Valentino LA, Scheiflinger F. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16804834&query_hl=23&itool=pubmed_docsum
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Future perspective for the treatment of hemophilia A. Author(s): Laurian Y. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946228&query_hl=23&itool=pubmed_docsum
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Gene conversion and evolution of Xq28 duplicons involved in recurring inversions causing severe hemophilia A. Author(s): Bagnall RD, Ayres KL, Green PM, Giannelli F. Source: Genome Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15687285&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia. Author(s): Ponder KP. Source: Current Opinion in Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16888433&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia: an imperative to succeed. Author(s): Hough C, Lillicrap D. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946210&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia: are viral vectors really feasible? Author(s): Walsh C. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12871491&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia? Author(s): Brettler DB. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946227&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia? Author(s): Hoots WK. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946226&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia? Author(s): Srivastava A. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946223&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia? Author(s): White GC 2nd, Roberts HR. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946222&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia? Gene therapy for hemophilia is both desirable and achievable in the near future. Author(s): Tuddenham EG. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946224&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia? No. Author(s): Giangrande PL. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15304021&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia? The debate reframed. Author(s): DiMichele D. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15946225&query_hl=23&itool=pubmed_docsum
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Gene therapy for hemophilia? Yes. Author(s): Negrier C. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15304020&query_hl=23&itool=pubmed_docsum
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Gene therapy. Side effects sideline hemophilia trial. Author(s): Kaiser J. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15178771&query_hl=23&itool=pubmed_docsum
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Gene transfer as an approach to treating hemophilia. Author(s): High KA. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12640573&query_hl=23&itool=pubmed_docsum
90
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Gene transfer for hemophilia: can therapeutic efficacy in large animals be safely translated to patients? Author(s): High K. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16102034&query_hl=23&itool=pubmed_docsum
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Genetic counseling of hemophilia carriers. Author(s): Ljung R, Tedgard U. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12640562&query_hl=23&itool=pubmed_docsum
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Genotyping the hemophilia inversion hotspot by use of inverse PCR. Author(s): Rossetti LC, Radic CP, Larripa IB, De Brasi CD. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15860568&query_hl=23&itool=pubmed_docsum
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Germline mosaicism resulting in the transmission of severe hemophilia B from a grandfather with a mild deficiency. Author(s): Cutler JA, Mitchell MJ, Smith MP, Savidge GF. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15266608&query_hl=23&itool=pubmed_docsum
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Good things come in small packages for hemophilia. Author(s): Kaufman RJ. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14675080&query_hl=23&itool=pubmed_docsum
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Guam's quest for improved hemophilia care. Author(s): Zabala RV, Baker JR. Source: Pac Health Dialog. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14736122&query_hl=23&itool=pubmed_docsum
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HCV kinetics, quasispecies, and clearance in treated HCV-infected and HCV/HIV-1coinfected patients with hemophilia. Author(s): Shire NJ, Horn PS, Rouster SD, Stanford S, Eyster ME, Sherman KE; Multicenter Hemophilia Cohort HCV Study Group. Source: Hepatology (Baltimore, Md.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17058240&query_hl=23&itool=pubmed_docsum
Studies
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Heart surgery in infants with hemophilia. Author(s): Murugan SJ, Viswanathan S, Thomson J, Parsons JM, Richards M. Source: The Annals of Thoracic Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16368397&query_hl=23&itool=pubmed_docsum
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Hemophilia and immunology at the crossroads. Author(s): Lollar P. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16869935&query_hl=23&itool=pubmed_docsum
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Hemophilia and related bleeding disorders: a story of dismay and success. Author(s): Mannucci PM. Source: Hematology Am Soc Hematol Educ Program. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12446416&query_hl=23&itool=pubmed_docsum
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Hemophilia B caused by five different nondeletion mutations in the protease domain of factor IX. Author(s): Ludwig M, Sabharwal AK, Brackmann HH, Olek K, Smith KJ, Birktoft JJ, Bajaj SP. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1346975&query_hl=23&itool=pubmed_docsum
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Hemophilia B diagnosed by hematoma at the columella base. Author(s): Kuwahara M, Yurugi S, Takeda M, Fukuda K, Yoshioka A. Source: Plastic and Reconstructive Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16641746&query_hl=23&itool=pubmed_docsum
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Hemophilia emergencies. Author(s): Bush MT, Roy N. Source: Journal of Emergency Nursing: Jen : Official Publication of the Emergency Department Nurses Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8709468&query_hl=23&itool=pubmed_docsum
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Hemophilia gene therapy: novel rAAV vectors and RNA repair strategy. Author(s): Chao H, Walsh CE. Source: Curr Opin Mol Ther. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12435052&query_hl=23&itool=pubmed_docsum
92
Hemophilia
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Hemophilia replacement therapy in developing countries: complementary approaches to the question of indigenous product manufacture versus importation. Author(s): Gellert GA. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8815594&query_hl=23&itool=pubmed_docsum
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Hemophilia therapy and blood-borne pathogen risk. Author(s): Knight R, Stanley S, Wong M, Dolan G. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16804829&query_hl=23&itool=pubmed_docsum
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Hemophilia--an ancient disease with new problems and new solutions. Author(s): Rogers JS 2nd, Ritchey AK. Source: W V Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1557907&query_hl=23&itool=pubmed_docsum
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Hepatitis A among persons with hemophilia who received clotting factor concentrate-United States, September-December 1995. Author(s): Centers for Disease Control and Prevention (CDC). Source: Mmwr. Morbidity and Mortality Weekly Report. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8531917&query_hl=23&itool=pubmed_docsum
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Hepatitis C at the israeli national hemophilia center. Author(s): Maor Y, Bashari D, Kenet G, Lalezari S, Lubetsky A, Luboshitz J, Schapiro JM, Avidan B, Bar-Meir S, Martinowitz U. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16409178&query_hl=23&itool=pubmed_docsum
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Herpes simplex virus type 1 and human immunodeficiency virus type 1 antigens in platelets from a hemophilia B patient with human immunodeficiency virus type 1related thrombocytopenia. Author(s): Koike K, Matsumoto K, Arai M, Yorifuji H, Fukutake K, Fujimaki M. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1324748&query_hl=23&itool=pubmed_docsum
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Heterozygous factor VII deficiency and severe hemophilia A in the same kindred. Author(s): Girolami A, Sartori MT, Rossi C, Cogo A, Zerbinati P. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8562840&query_hl=23&itool=pubmed_docsum
Studies
93
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High efficacy of combined therapy with pegylated interferon plus ribavirin in patients with hemophilia and chronic hepatitis C. Author(s): Mancuso ME, Rumi MG, Santagostino E, Linari S, Coppola A, Mannucci PM, Colombo M; Hepatitis Study Group of the Association of Italian Hemophilia Centers. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17018386&query_hl=23&itool=pubmed_docsum
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High efficient transfer and expression of human clotting factor IX cDNA in cultured human primary skin fibroblasts from hemophilia B patient by retroviral vectors. Author(s): Dai YF, Qiu XF, Xue JL, Liu ZD. Source: Science in China. Series B, Chemistry, Life Sciences & Earth Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1581003&query_hl=23&itool=pubmed_docsum
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High-dose recombinant factor VIIa therapy in hemophilia patients with inhibitors. Author(s): Kenet G. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16427376&query_hl=23&itool=pubmed_docsum
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Highlights from the XXV International Congress of the World Federation of Hemophilia. May 19-24, 2002, Seville, Spain. Author(s): Lusher JM; World Federation of Hemophilia. Source: Medgenmed [electronic Resource] : Medscape General Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12466757&query_hl=23&itool=pubmed_docsum
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HIV-infected adolescents with hemophilia: adaptation and coping. The Hemophilia Behavioral Intervention Evaluation Project. Author(s): Brown LK, Schultz JR, Gragg RA. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7651778&query_hl=23&itool=pubmed_docsum
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Identification of 32 novel mutations in the factor VIII gene in Indian patients with hemophilia A. Author(s): Ahmed RP, Ivaskevicius V, Kannan M, Seifried E, Oldenburg J, Saxena R. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15710596&query_hl=23&itool=pubmed_docsum
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Identification of a novel immunodominant cytotoxic T lymphocyte epitope derived from human factor VIII in a murine model of hemophilia A. Author(s): Wang W, Merchlinsky M, Inman J, Golding B. Source: Thrombosis Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16038719&query_hl=23&itool=pubmed_docsum
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Hemophilia
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Identification of plasma antibody epitopes and gene abnormalities in Japanese hemophilia A patients with factor VIII inhibitor. Author(s): Sugihara T, Takahashi I, Kojima T, Okamoto Y, Yamamoto K, Kamiya T, Matsushita T, Saito H. Source: Nagoya J Med Sci. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10911718&query_hl=23&itool=pubmed_docsum
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Immune tolerance in two high responder, severe hemophilia A patients with inhibitors: the importance of high doses and the duration of the treatment. Author(s): Ciavarella N, Schiavoni M, Fasano A, Giliberti MG, Ettorre C, Stefanile C. Source: Vox Sanguinis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8869475&query_hl=23&itool=pubmed_docsum
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Immune tolerance induction with highly purified plasma-derived factor VIII containing von Willebrand factor in hemophilia A patients with high-responding inhibitors. Author(s): Orsini F, Rotschild C, Beurrier P, Faradji A, Goudemand J, Polack B. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16154861&query_hl=23&itool=pubmed_docsum
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Immune tolerance induction with recombinant factor VIII in hemophilia A patients with high responding inhibitors. Author(s): Rocino A, Santagostino E, Mancuso ME, Mannucci PM. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16585022&query_hl=23&itool=pubmed_docsum
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Impact of choice of treatment for bleeding episodes on inhibitor outcome in patients with mild/moderate hemophilia a and inhibitors. Author(s): d'Oiron R, Volot F, Reynaud J, Peerlinck K, Goudemand J, Guerois C, Rothschild C, Chambost H, Borel-Derlon A, Roussel-Robert V, Marques-Verdier A, Lienhart A, Berthier AM, Moreau P, Lambert T; MHAI Study Group. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16427382&query_hl=23&itool=pubmed_docsum
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Incidence of inhibitors in a cohort of 838 males with hemophilia A previously treated with factor VIII concentrates. Author(s): Kempton CL, Soucie JM, Abshire TC. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17002659&query_hl=23&itool=pubmed_docsum
Studies
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Incidence of lymphomas and other cancers in HIV-infected and HIV-uninfected patients with hemophilia. Author(s): Rabkin CS, Hilgartner MW, Hedberg KW, Aledort LM, Hatzakis A, Eichinger S, Eyster ME, White GC 2nd, Kessler CM, Lederman MM, et al. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1735926&query_hl=23&itool=pubmed_docsum
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Influence of aggregation on immunogenicity of recombinant human Factor VIII in hemophilia A mice. Author(s): Purohit VS, Middaugh CR, Balasubramanian SV. Source: Journal of Pharmaceutical Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16372314&query_hl=23&itool=pubmed_docsum
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Influence of factor VIIa and phospholipids on coagulation in "acquired" hemophilia. Author(s): Butenas S, Brummel KE, Paradis SG, Mann KG. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12524235&query_hl=23&itool=pubmed_docsum
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Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Author(s): Goudemand J, Rothschild C, Demiguel V, Vinciguerrat C, Lambert T, Chambost H, Borel-Derlon A, Claeyssens S, Laurian Y, Calvez T; FVIII-LFB and Recombinant FVIII study groups. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16166584&query_hl=23&itool=pubmed_docsum
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Inhibitor development in patients with hemophilia A after continuous infusion of FVIII concentrates. Author(s): von Auer Ch, Oldenburg J, von Depka M, Escuriola-Ettinghausen C, Kurnik K, Lenk H, Scharrer I. Source: Annals of the New York Academy of Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16126990&query_hl=23&itool=pubmed_docsum
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Inhibitor development in patients with hemophilia: an overview. Author(s): Leissinger CA. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16690370&query_hl=23&itool=pubmed_docsum
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Inhibitors to factor VIII in a family with mild hemophilia: molecular characterization and response to factor VIII and desmopressin. Author(s): Santagostino E, Gringeri A, Tagliavacca L, Mannucci PM. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8584995&query_hl=23&itool=pubmed_docsum
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Int22h-related inversions causing hemophilia A: a novel insight into their origin and a new more discriminant PCR test for their detection. Author(s): Bagnall RD, Giannelli F, Green PM. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16460442&query_hl=23&itool=pubmed_docsum
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Intracranial haemorrhage as initial presentation of severe haemophilia B: case report and review of Mayo Clinic Comprehensive Hemophilia Center experience. Author(s): Rodriguez V, Schmidt KA, Slaby JA, Pruthi RK. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15660992&query_hl=23&itool=pubmed_docsum
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Intramural hematoma of the cecum as the lead point of intussusception in an elderly patient with hemophilia A: report of a case. Author(s): Nakayama Y, Fukushima M, Sakai M, Hisano T, Nagata N, Shirahata A, Itoh H. Source: Surgery Today. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16715431&query_hl=23&itool=pubmed_docsum
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Inversion in Japanese patients with hemophilia A. Author(s): Inaba H, Shibata H, Yoshida S, Hagiwara T, Hanabusa H, Nagao T, Fukutake K. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8585037&query_hl=23&itool=pubmed_docsum
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Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate. Author(s): Soucie JM, Erdman DD, Evatt BL, Anderson LJ, Torok TJ, El-Jamil M, Barnhart E, Tepper M, Burrill HN, Pickett AM, Mengeling WL. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10864993&query_hl=23&itool=pubmed_docsum
Studies
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Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors. Author(s): Soucie JM, Cianfrini C, Janco RL, Kulkarni R, Hambleton J, Evatt B, Forsyth A, Geraghty S, Hoots K, Abshire T, Curtis R, Forsberg A, Huszti H, Wagner M, White GC 2nd. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14615381&query_hl=23&itool=pubmed_docsum
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Kaposiform hemangioendothelioma with associated Kasabach-Merritt phenomenon. The Hemophilia Growth and Development Study. Author(s): Arnaout MK, Pappo AS. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9842045&query_hl=23&itool=pubmed_docsum
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Knee arthroplasty in hemophilia. 5-12 year follow-up of 15 patients. Author(s): Teigland JC, Tjonnfjord GE, Evensen SA, Charania B. Source: Acta Orthopaedica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8498174&query_hl=23&itool=pubmed_docsum
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Knowledge, attitudes, and behaviors of youths in the US hemophilia population: results of a national survey. Author(s): Nazzaro AM, Owens S, Hoots WK, Larson KL. Source: American Journal of Public Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16873741&query_hl=23&itool=pubmed_docsum
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Lack of desmopressin (DDAVP) response in men with hemophilia A following liver transplantation. Author(s): Lamont PA, Ragni MV. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16194203&query_hl=23&itool=pubmed_docsum
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Lack of F8 mRNA: a novel mechanism leading to hemophilia A. Author(s): El-Maarri O, Singer H, Klein C, Watzka M, Herbiniaux U, Brackmann HH, Schroder J, Graw J, Muller CR, Schramm W, Schwaab R, Haaf T, Hanfland P, Oldenburg J. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16339403&query_hl=23&itool=pubmed_docsum
98
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Lack of prophylactic anticoagulant therapy is not associated with clinical thrombotic complications in patients with hemophilia who undergo orthopedic surgical procedures. Author(s): Djulbegovic B. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7485094&query_hl=23&itool=pubmed_docsum
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Lack of protection from HIV infection by the mutant HIV coreceptor CCR5 in intravenously HIV infected hemophilia patients. Author(s): Malo A, Rommel F, Bogner J, Gruber R, Schramm W, Goebel FD, Riethmuller G, Wank R. Source: Immunobiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9562872&query_hl=23&itool=pubmed_docsum
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Life expectancy in hemophilia outcome. Author(s): Mejia-Carvajal C, Czapek EE, Valentino LA. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16460431&query_hl=23&itool=pubmed_docsum
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Life-threatening bleeding after dental extraction in a hemophilia A patient with inhibitors to factor VIII: a case report. Author(s): Heiland M, Weber M, Schmelzle R. Source: Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14613094&query_hl=23&itool=pubmed_docsum
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Life-threatening mediastinal-retroperitoneal hemorrhage in a child with moderate hemophilia A and high inhibitor titer: successful management with recombinant activated factor VII. Author(s): Ylmaz S, Oren H, Irken G, Atabay B, Duman M, Ylmaz E, Cakmakc H. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16012333&query_hl=23&itool=pubmed_docsum
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Life-threatening thrombosis complicating the management of hepatic hemorrhage: anticoagulant treatment in a newborn with hemophilia B. Author(s): Douvas MG, Monahan PE. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15087956&query_hl=23&itool=pubmed_docsum
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Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus. Author(s): Iversen AK, Christiansen CB, Attermann J, Eugen-Olsen J, Schulman S, Berntorp E, Ingerslev J, Fugger L, Scheibel E, Tengborn L, Gerstoft J, Dickmeiss E, Svejgaard A, Skinhoj P. Source: The Journal of Infectious Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12552446&query_hl=23&itool=pubmed_docsum
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Living-donor liver transplantation in an HIV-positive patient with hemophilia. Author(s): Sugawara Y, Ohkubo T, Makuuchi M, Kimura S, Morisawa Y, Tachikawa N, Oka S. Source: Transplantation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12490807&query_hl=23&itool=pubmed_docsum
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Long distance PCR in detection of inversion mutations of F8C gene in hemophilia A patients. Author(s): Polakova H, Zmetakova I, Kadasi L. Source: Gen Physiol Biophys. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14699993&query_hl=23&itool=pubmed_docsum
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Long-term aspects of hemophilia B treatment: part II. Author(s): Gringeri A. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15322453&query_hl=23&itool=pubmed_docsum
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Long-term aspects of hemophilia B treatment: part I-role for prophylaxis. Author(s): Ettingshausen CE, Kreuz W. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15322452&query_hl=23&itool=pubmed_docsum
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Long-term efficacy of adeno-associated virus serotypes 8 and 9 in hemophilia a dogs and mice. Author(s): Sarkar R, Mucci M, Addya S, Tetreault R, Bellinger DA, Nichols TC, Kazazian HH Jr. Source: Human Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16610930&query_hl=23&itool=pubmed_docsum
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Long-term nonprogressive infection with human immunodeficiency virus type 1 in a hemophilia cohort. Author(s): Greenough TC, Brettler DB, Kirchhoff F, Alexander L, Desrosiers RC, O'Brien SJ, Somasundaran M, Luzuriaga K, Sullivan JL. Source: The Journal of Infectious Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10558933&query_hl=23&itool=pubmed_docsum
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Long-term results of primary total knee replacement in patients with hemophilia. Author(s): Silva M, Luck JV Jr. Source: The Journal of Bone and Joint Surgery. American Volume. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15634817&query_hl=23&itool=pubmed_docsum
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Low cost locally prepared fibrin glue for clinical applications: reported of 145 cases. Committee of Bangkok International Hemophilia Training Center. Author(s): Isarangkura P, Chiewsilp P, Chuansumrit A, Suwannuraks M, Keorochana S, Attanawanich S, Tardtong P, Martinowitz U, Horoszowski H. Source: J Med Assoc Thai. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10730518&query_hl=23&itool=pubmed_docsum
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Low detection rate of antibodies to non-functional epitopes on factor VIII in patients with hemophilia A and negative for inhibitors by Bethesda assay. Author(s): Ling M, Duncan EM, Rodgers SE, Street AM, Lloyd JV. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14675091&query_hl=23&itool=pubmed_docsum
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Lower inhibitor development in hemophilia A mice following administration of recombinant factor VIII-O-phospho-L-serine complex. Author(s): Purohit VS, Ramani K, Sarkar R, Kazazian HH Jr, Balasubramanian SV. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15728582&query_hl=23&itool=pubmed_docsum
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Lyophilized cryoprecipitate for children with hemophilia A. Author(s): Nuchprayoon I, Sahasittiwat S, Kittikalayawong A, Chantanakajornfung A. Source: J Med Assoc Thai. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12188426&query_hl=23&itool=pubmed_docsum
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Management and prevention of recurrent hemarthrosis in patients with hemophilia. Author(s): Dunn AL. Source: Current Opinion in Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16093785&query_hl=23&itool=pubmed_docsum
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Management of hemophilia with minimal factor replacement in developing countries: role of ancillary therapy. Author(s): Chandy M. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16276457&query_hl=23&itool=pubmed_docsum
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Managing hemophilia: safer, more effective but expensive. Author(s): Golden WE, Wells C. Source: J Ark Med Soc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15318445&query_hl=23&itool=pubmed_docsum
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Measuring health state preferences for hemophilia: development of a disease-specific utility instrument. Author(s): Wasserman J, Aday LA, Begley CE, Ahn C, Lairson DR. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15660989&query_hl=23&itool=pubmed_docsum
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Milestones in hemophilia and concepts in future clinical trial design. Author(s): Lusher JM. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16427391&query_hl=23&itool=pubmed_docsum
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Molecular characterization of hemophilia B in North Indian families: identification of novel and recurrent molecular events in the factor IX gene. Author(s): Mahajan A, Chavali S, Kabra M, Chowdhury MR, Bharadwaj D. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15590401&query_hl=23&itool=pubmed_docsum
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Molecular diagnosis of hemophilia A in Chinese patients by an analysis of inversions in the factor VIII gene. Author(s): Chen YD, Zhang YZ, Wu JS, Wang HL, Shao HZ, Ren ZR, Chen Z, Wang ZY, Zeng YT. Source: Hematopathol Mol Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8792148&query_hl=23&itool=pubmed_docsum
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More on: polymorphism and hemophilia A causing inversions in distal Xq28: a complex picture. Author(s): Ross MT, Bentley DR. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16241968&query_hl=23&itool=pubmed_docsum
102
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More on: uncertain times for research on hemophilia and allied disorders. Author(s): Vermylen J. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15978120&query_hl=23&itool=pubmed_docsum
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Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Author(s): Soucie JM, Nuss R, Evatt B, Abdelhak A, Cowan L, Hill H, Kolakoski M, Wilber N. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10887103&query_hl=23&itool=pubmed_docsum
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Mortality and causes of death in patients with hemophilia, 1992-2001: a prospective cohort study. Author(s): Plug I, Van Der Bom JG, Peters M, Mauser-Bunschoten EP, De Goede-Bolder A, Heijnen L, Smit C, Willemse J, Rosendaal FR. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16460432&query_hl=23&itool=pubmed_docsum
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Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Author(s): Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briet E. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7486463&query_hl=23&itool=pubmed_docsum
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Mortality rates and causes of death among all HIV-positive individuals with hemophilia in Canada over 21 years of follow-up. Author(s): Arnold DM, Julian JA, Walker IR; Association of Hemophilia Clinic Directors of Canada. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16551974&query_hl=23&itool=pubmed_docsum
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Myocardial infarction and other arterial occlusions in hemophilia a patients. A cardiological evaluation of all 42 cases reported in the literature. Author(s): Girolami A, Ruzzon E, Fabris F, Varvarikis C, Sartori R, Girolami B. Source: Acta Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16914907&query_hl=23&itool=pubmed_docsum
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Naked DNA transfer of Factor VIII induced transgene-specific, species-independent immune response in hemophilia A mice. Author(s): Ye P, Thompson AR, Sarkar R, Shen Z, Lillicrap DP, Kaufman RJ, Ochs HD, Rawlings DJ, Miao CH. 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=15233948&query_hl=23&itool=pubmed_docsum
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National survey of patients with hemophilia and other congenital bleeding disorders in Thailand. Author(s): Chuansumrit A, Mahasandana C, Chinthammitr Y, Pongtanakul B, Laossombat V, Nawarawong W, Lektakul Y, Wangruangsatid S, Sriboriboonsin L, Rojnakarin P, Angchaisuksiri P; Hemophilia Study Group. Source: Southeast Asian J Trop Med Public Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15691153&query_hl=23&itool=pubmed_docsum
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Need for randomized trials in hemophilia. Author(s): Mannucci PM. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16460428&query_hl=23&itool=pubmed_docsum
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New coagulant bypasses clotting dysfunction in hemophilia. Author(s): Morrow T. Source: Manag Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17285814&query_hl=23&itool=pubmed_docsum
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New insight into the molecular basis of hemophilia A. Author(s): Oldenburg J, El-Maarri O. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16513526&query_hl=23&itool=pubmed_docsum
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No protective effect of breastfeeding on inhibitor formation in severe hemophilia. Author(s): Jansen IM, Fischer K, Van Der Bom JG, Van Den Berg HM. Source: Pediatric Hematology and Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16166050&query_hl=23&itool=pubmed_docsum
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Non-catheter associated venous thrombosis in hemophilia A and B. A critical review of all reported cases. Author(s): Girolami A, Scandellari R, Zanon E, Sartori R, Girolami B. Source: Journal of Thrombosis and Thrombolysis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16683222&query_hl=23&itool=pubmed_docsum
104
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Nonoperative management of a splenic tear in a Jehovah's Witness with hemophilia. Author(s): Zieg PM, Cohn SM, Beardsley DS. Source: The Journal of Trauma. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8637084&query_hl=23&itool=pubmed_docsum
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Nonoperative management of delayed splenic rupture in a patient with hemophilia B. Author(s): Terry NE, Boswell WC. Source: Journal of Pediatric Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16952601&query_hl=23&itool=pubmed_docsum
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Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene. Author(s): Sabatino DE, Armstrong E, Edmonson S, Liu YL, Pleimes M, Schuettrumpf J, Fitzgerald J, Herzog RW, Arruda VR, High KA. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15217833&query_hl=23&itool=pubmed_docsum
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Obstructive Ileus caused by blood clot after emergency total gastrectomy in a patient with hemophilia A: report of a case. Author(s): Onda M, Urazumi K, Abe R, Matsuo K. Source: Surgery Today. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9872546&query_hl=23&itool=pubmed_docsum
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Occurrence of hemophilia in the United States. The Hemophilia Surveillance System Project Investigators. Author(s): Soucie JM, Evatt B, Jackson D. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9840909&query_hl=23&itool=pubmed_docsum
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Off-pump myocardial revascularization in a diabetic patient with severe hemophilia B and impaired left ventricular function: hematological and operative strategies. Author(s): Grandmougin D, Delolme MC, Reynaud J, Barral X. Source: Journal of Cardiac Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15985141&query_hl=23&itool=pubmed_docsum
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On the treatment of hemorrhage in patients with hemophilia and associated inhibitors. Author(s): Tarantino M, Aledort L. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11778084&query_hl=23&itool=pubmed_docsum
Studies
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Onco-retroviral and lentiviral vector-based gene therapy for hemophilia: preclinical studies. Author(s): Van Damme A, Chuah MK, Collen D, VandenDriessche T. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15118930&query_hl=23&itool=pubmed_docsum
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Optimization of the human factor VIII complementary DNA expression plasmid for gene therapy of hemophilia A. Author(s): Ill CR, Yang CQ, Bidlingmaier SM, Gonzales JN, Burns DS, Bartholomew RM, Scuderi P. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9607110&query_hl=23&itool=pubmed_docsum
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Optimizing clotting factor replacement therapy in hemophilia: a global need. Author(s): Srivastava A. Source: Hematology (Amsterdam, Netherlands). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16188679&query_hl=23&itool=pubmed_docsum
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Oral immunosuppressive therapy for acquired hemophilia. Author(s): Green D. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9471947&query_hl=23&itool=pubmed_docsum
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Orthopedic management of hemophilia. Author(s): Heyworth BE, Su EP, Figgie MP, Acharya SS, Sculco TP. Source: Am J Orthop. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16304795&query_hl=23&itool=pubmed_docsum
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Orthotic management of the knee in patients with hemophilia. Author(s): Heim M, Martinowitz U, Horoszowski H. Source: Clin Orthop Relat Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9345206&query_hl=23&itool=pubmed_docsum
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Parvovirus B19 infection in patients with hemophilia. Author(s): Ragni MV, Koch WC, Jordan JA. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8604509&query_hl=23&itool=pubmed_docsum
106
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Pattern of factor VIII inhibitors in patients with hemophilia A in the north east of Iran. Author(s): Modaresi AR, Torghabeh HM, Pourfathollah AA, Shooshtari MM, Yazdi ZR. Source: Hematology (Amsterdam, Netherlands). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17325965&query_hl=23&itool=pubmed_docsum
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Peptidomimetic inhibitors for activated protein C: implications for hemophilia management. Author(s): Butenas S, Orfeo T, Kalafatis M, Mann KG. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17059471&query_hl=23&itool=pubmed_docsum
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Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Author(s): Astermark J, Oldenburg J, Carlson J, Pavlova A, Kavakli K, Berntorp E, Lefvert AK. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16926287&query_hl=23&itool=pubmed_docsum
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Postoperative management of hemophilia A and low titer inhibitor at home using factor VIII continuous infusion. Author(s): Travis SF, Burns N, Greenbaum BH, Stark E. Source: Clinical Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8825851&query_hl=23&itool=pubmed_docsum
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Potential role of recombinant factor FVIIa in prophylaxis in severe hemophilia patients with inhibitors. Author(s): Hedner U. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16907841&query_hl=23&itool=pubmed_docsum
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Preventing joint damage from hemophilia. Author(s): Feldman BM. Source: The Journal of Rheumatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10914833&query_hl=23&itool=pubmed_docsum
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Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients. Author(s): Scandella DH. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10919405&query_hl=23&itool=pubmed_docsum
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Proposal to establish a European Association for Hemophilia and Allied Disorders. Author(s): Ludlam CA, Mannucci PM; Interdisciplinary Working Group. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16863537&query_hl=23&itool=pubmed_docsum
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Psychological response to HIV positivity in hemophilia. Author(s): Drotar DD, Agle DP, Eckl CL, Thompson PA. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7491222&query_hl=23&itool=pubmed_docsum
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Quantifying practice effects in longitudinal research with the WISC-R and WAIS-R: a study of children and adolescents with hemophilia and male siblings without hemophilia. Author(s): Sirois PA, Posner M, Stehbens JA, Loveland KA, Nichols S, Donfield SM, Bell TS, Hill SD, Amodei N; Hemophilia Growth and Development Study. Source: Journal of Pediatric Psychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11821496&query_hl=23&itool=pubmed_docsum
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Quantitative real-time PCR assay for rapid identification of deletion carriers in hemophilia. Author(s): Catherine C, Jean-Marie J, Nathalie S, Jean-Marc C, Emmanuelle G, Michel G. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15229165&query_hl=23&itool=pubmed_docsum
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Rapid detection of intron 22 inversions of the factor VIII gene in Chinese patients with severe hemophilia A. Author(s): Gau JP, Hsu HC, Ho CH, Chau WK, Chen CC, You JY. Source: J Chin Med Assoc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14649674&query_hl=23&itool=pubmed_docsum
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Rapid single-step detection of the inversion hotspot of mutation in hemophilia A by real-time PCR. Author(s): Vidal F, Sanchez-Garcia JF, Farssac E, Ramirez L, Gallardo D. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16359527&query_hl=23&itool=pubmed_docsum
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Recombinant factor VIII concentrate. The MSAC, Canadian Hemophilia Society. Canadian Hemophilia Clinic Directors Group. Author(s): Walker I, Poon MC. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1345984&query_hl=23&itool=pubmed_docsum
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Recurrent intramural hematoma of the small intestine in a severe hemophilia A patient with a high titer of factor VIII inhibitor: a case report and review of the literature. Author(s): Katsumi A, Matsushita T, Hirashima K, Iwasaki T, Adachi T, Yamamoto K, Kojima T, Takamatsu J, Saito H, Naoe T. Source: International Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16926140&query_hl=23&itool=pubmed_docsum
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Resection of arteriovenous malformation in a patient with hemophilia type A. Author(s): Saito N, Yamazaki M, Kobayashi S, Teramoto A. Source: Neurol Med Chir (Tokyo). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16636510&query_hl=23&itool=pubmed_docsum
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Rheumatological management of patients with hemophilia. Part 1: joint manifestations. Author(s): Alcalay M, Deplas A. Source: Joint, Bone, Spine : Revue Du Rhumatisme. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12477227&query_hl=23&itool=pubmed_docsum
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Rheumatological management of patients with hemophilia. Part II: Muscle hematomas and pseudotumors. Author(s): Alcalay M, Deplas A. Source: Joint, Bone, Spine : Revue Du Rhumatisme. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12537262&query_hl=23&itool=pubmed_docsum
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Rituximab in postpartum-related acquired hemophilia. Author(s): Maillard H, Launay D, Hachulla E, Goudemand J, Lambert M, Morell-Dubois S, Queyrel V, Hatron PY. Source: The American Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16431202&query_hl=23&itool=pubmed_docsum
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Rituximab in the treatment of acquired hemophilia. Author(s): Stachnik JM. Source: The Annals of Pharmacotherapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16735671&query_hl=23&itool=pubmed_docsum
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Rituximab-induced long-term remission in patients with refractory acquired hemophilia. Author(s): Abdallah A, Coghlan DW, Duncan EM, Chunilal SD, Lloyd JV. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16241963&query_hl=23&itool=pubmed_docsum
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School absenteeism in boys with hemophilia. Author(s): Eksioglu E, Gurcay E, Ezer U, Tuncay R, Cakci A. Source: Saudi Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16758068&query_hl=23&itool=pubmed_docsum
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Sequencing of the factor 8(F8) coding regions in 10 Turkish hemophilia A patients reveals three novel pathological mutations, and one rediagnosis of von Willebrand's disease type 2N. Author(s): Berber E, Fidanci ID, Un C, El-Maarri O, Aktuglu G, Gurgey A, Celkan T, Meral A, Oldenburg J, Graw J, Akar N, Caglayan H. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16834740&query_hl=23&itool=pubmed_docsum
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Sexual behavior change among human immunodeficiency virus-infected adolescents with hemophilia. Adolescent Hemophilia Behavioral Intervention Evaluation Project Study Group. Author(s): Brown LK, Schultz JR, Parsons JT, Butler RB, Forsberg AD, Kocik SM, King G, Manco-Johnson M, Aledort L. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10920178&query_hl=23&itool=pubmed_docsum
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Should hemophilia treaters switch to albumin-free recombinant factor VIII concentrates. Author(s): Meeks SL, Josephson CD. Source: Current Opinion in Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17053459&query_hl=23&itool=pubmed_docsum
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Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Author(s): Bogdanova N, Markoff A, Eisert R, Wermes C, Pollmann H, Todorova A, Chlystun M, Nowak-Gottl U, Horst J. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16972227&query_hl=23&itool=pubmed_docsum
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Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Author(s): Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi PK, Nakai H, Chew A, Leonard D, Wright JF, Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, High KA, Kay MA. Source: Nature Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16474400&query_hl=23&itool=pubmed_docsum
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Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy--International KogenateFS Study Group. Author(s): Abshire TC, Brackmann HH, Scharrer I, Hoots K, Gazengel C, Powell JS, Gorina E, Kellermann E, Vosburgh E. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10896230&query_hl=23&itool=pubmed_docsum
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Surgery in patients with hemophilia and inhibitors: a review of the Norwegian experience with FEIBA. Author(s): Tjonnfjord GE. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16690372&query_hl=23&itool=pubmed_docsum
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Surgical management of intractable epilepsy in children with hemophilia. Author(s): Yeh DJ, Lee M, Park YD, Smith JR, Lightsey AL Jr. Source: Stereotactic and Functional Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10853108&query_hl=23&itool=pubmed_docsum
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Sustained FVIII expression and phenotypic correction of hemophilia A in neonatal mice using an endothelial-targeted sleeping beauty transposon. Author(s): Liu L, Mah C, Fletcher BS. 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=16464640&query_hl=23&itool=pubmed_docsum
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Ten-year experience with living related donated splenic transplantation for the treatment of hemophilia A. Author(s): Jiang HC, Gao Y, Dai WJ, Sun B, Xu J, Qiao HQ, Meng QH, Wu CJ. Source: Transplantation Proceedings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16797339&query_hl=23&itool=pubmed_docsum
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The limitation of factor IX coagulant activity determination in the diagnosis of hemophilia B carriers. Author(s): Rurgkhum S, Sasanakul W, Chotsuppakarn S, Pintadit P, Chuansumrit A. Source: J Med Assoc Thai. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12549778&query_hl=23&itool=pubmed_docsum
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The National Hemophilia Foundation provides a model of a national blood monitoring system. Author(s): Lusher J, Kessler CM, Bajardi SE, Dickinson J, Augustyniak L. Source: Transfusion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8607165&query_hl=23&itool=pubmed_docsum
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The next generation of hemophilia treatment specialists. Author(s): Berntorp E, Gomperts E, Hoots K, Wong WY. Source: Seminars in Thrombosis and Hemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16804835&query_hl=23&itool=pubmed_docsum
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The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients. Author(s): David D, Ventura C, Moreira I, Diniz MJ, Antunes M, Tavares A, Araujo F, Morais S, Campos M, Lavinha J, Kemball-Cook G. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16769589&query_hl=23&itool=pubmed_docsum
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The tragic history of AIDS in the hemophilia population, 1982-1984. Author(s): Evatt BL. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16972935&query_hl=23&itool=pubmed_docsum
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Thrombelastgram as a hemostatic monitor during recombinant factor VIIa treatment in hemophilia A patients with inhibitor to factor VIII. Author(s): Yoshioka A, Nishio K, Shima M. Source: Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8904189&query_hl=23&itool=pubmed_docsum
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Treatment of bleeding episodes in patients with hemophilia and an inhibitor: comparison of two treatment protocols with recombinant activated factor VII. Author(s): Kenet G, Lubetsky A, Gitel S, Luboshitz J, Varon D, Martinowitz U. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10850562&query_hl=23&itool=pubmed_docsum
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Treatment of patients with hemophilia A and inhibitors to factor FVIII with cimetidine. Author(s): Ambriz Fernandez R, Quintana Gonzalez S, Martinez Murillo C, Dominguez Garcia V, Rodriguez Moyado H, Collazo Jaloma J. Source: Archives of Medical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8867361&query_hl=23&itool=pubmed_docsum
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Trends in AIDS and mortality in HIV-infected subjects with hemophilia from 1985 to 2003: the competing risks for death between AIDS and liver disease. Author(s): del Amo J, Perez-Hoyos S, Moreno A, Quintana M, Ruiz I, Cisneros JM, Ferreros I, Gonzalez C, Garcia de Olalla P, Perez R, Hernandez I. Source: Journal of Acquired Immune Deficiency Syndromes (1999). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16652037&query_hl=23&itool=pubmed_docsum
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Uncertain times for research on hemophilia and allied disorders. Author(s): Srivastava A. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16460452&query_hl=23&itool=pubmed_docsum
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Uncertain times for research on hemophilia and allied disorders. Author(s): Mannucci PM, Roberts HR. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15748225&query_hl=23&itool=pubmed_docsum
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Unresolved issues in diagnosis and management of inherited bleeding disorders in the perinatal period: a White Paper of the Perinatal Task Force of the Medical and Scientific Advisory Council of the National Hemophilia Foundation, USA. Author(s): Kulkarni R, Ponder KP, James AH, Soucie JM, Koerper M, Hoots WK, Lusher JM. Source: Haemophilia : the Official Journal of the World Federation of Hemophilia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16643202&query_hl=23&itool=pubmed_docsum
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Unusual case of coronary artery disease in a patient with severe hemophilia B. Author(s): Au WY, Jim MH, Lam CC. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11835358&query_hl=23&itool=pubmed_docsum
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Unusual expression of the F9 gene in peripheral lymphocytes hinders investigation of F9 mRNA in hemophilia B patients. Author(s): Green PM, Rowley G, Giannelli F. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14675105&query_hl=23&itool=pubmed_docsum
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Update on liver disease in hemophilia patients. Author(s): Kessler CM. Source: Semin Hematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16427378&query_hl=23&itool=pubmed_docsum
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Use of factor IX concentrates in active teenagers with hemophilia B. Author(s): Tagariello G. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15322451&query_hl=23&itool=pubmed_docsum
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Use of implantable venous access devices in children with severe hemophilia: benefits and burden. Author(s): Van Dijk K, Van Der Bom JG, Bax KN, Van Der Zee DC, Van Den Berg MH. Source: Haematologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15003894&query_hl=23&itool=pubmed_docsum
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Use of Intron 1 and 22 inversions and linkage analysis in carrier detection of hemophilia A in Indians. Author(s): Ahmed R, Kannan M, Biswas A, Ranjan R, Choudhry VP, Saxena R. 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=16129422&query_hl=23&itool=pubmed_docsum
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Use of recombinant factor vila to control bleeding in an adolescent male with severe hemophilia A, HIV thrombocytopenia, hepatitis C, and end-stage liver disease. Author(s): Puetz JJ, Bouhasin JD. Source: Am J Hosp Palliat Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12141793&query_hl=23&itool=pubmed_docsum
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Value of DNA analysis with multiple DNA probes for the detection of hemophilia A carriers. Author(s): Kemahli S, Goldman E, McCraw A, Jenkins V, Kernoff PB. Source: Pediatric Hematology and Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8155501&query_hl=23&itool=pubmed_docsum
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Van Creveld, pioneer of hemophilia care and coagulation research in the Netherlands: a personal account. Author(s): Van Mourik JA. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15219180&query_hl=23&itool=pubmed_docsum
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Variability of in vivo recovery of factor IX after infusion of monoclonal antibody purified factor IX concentrates in patients with hemophilia B. The Mononine Study Group. Author(s): White GC 2nd, Shapiro AD, Kurczynski EM, Kim HC, Bergman GE. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7482403&query_hl=23&itool=pubmed_docsum
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Variant of intron 22 inversions in the factor VIII gene in severe hemophilia A. Author(s): Yamazaki E, Mohri H, Inaba H, Harano H, Kanamori H, Okubo T. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9391727&query_hl=23&itool=pubmed_docsum
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Viral infections among patients with hemophilia in the state of Georgia. Author(s): Hill HA, Stein SF. Source: American Journal of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9723574&query_hl=23&itool=pubmed_docsum
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Viral vector-mediated gene therapy for hemophilia B. Author(s): Eisensmith RC, Woo SL. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9198122&query_hl=23&itool=pubmed_docsum
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Viral vector-mediated gene therapy for hemophilia. Author(s): VandenDriessche T, Collen D, Chuah MK. Source: Current Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12109144&query_hl=23&itool=pubmed_docsum
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Virus load and risk of heterosexual transmission of human immunodeficiency virus and hepatitis C virus by men with hemophilia. The Multicenter Hemophilia Cohort Study. Author(s): Hisada M, O'Brien TR, Rosenberg PS, Goedert JJ. Source: The Journal of Infectious Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10753732&query_hl=23&itool=pubmed_docsum
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Von Willebrand disease, hemophilia A and B, and other factor deficiencies. Author(s): Lee JW. Source: International Anesthesiology Clinics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15205640&query_hl=23&itool=pubmed_docsum
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von Willebrand's disease and hemophilia are associated with diminished thromboxane A2 (TXA2) formation in clotting whole blood. Author(s): Beitz A, Muller G, Beitz J, Giessler C. 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=8146208&query_hl=23&itool=pubmed_docsum
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What can we learn from the immune response to human factor VIII in a mouse model of hemophilia A? Author(s): Reipert BM, Schwarz HP. Source: Thrombosis and Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12195723&query_hl=23&itool=pubmed_docsum
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What factors influence the age at diagnosis of hemophilia? Results of the French hemophilia cohort. Author(s): Chambost H, Gaboulaud V, Coatmelec B, Rafowicz A, Schneider P, Calvez T; Suivi therapeutique National des Hemophiles (SNH) Group. Source: The Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12378196&query_hl=23&itool=pubmed_docsum
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When the bleeding won't stop: a case report on a patient with hemophilia. Author(s): Shapiro N. Source: The Journal of the American Dental Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8277060&query_hl=23&itool=pubmed_docsum
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Whole blood clot formation phenotypes in hemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa. Author(s): Sorensen B, Ingerslev J. Source: Journal of Thrombosis and Haemostasis : Jth. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14717973&query_hl=23&itool=pubmed_docsum
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X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B. Author(s): Brandstetter H, Bauer M, Huber R, Lollar P, Bode W. 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=7568220&query_hl=23&itool=pubmed_docsum
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Zidovudine overdose in an asymptomatic HIV seropositive patient with hemophilia. Author(s): Stern RA, van der Horst CM, Hooper SR, Bloodgood KM, High KA. Source: Psychosomatics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1461972&query_hl=23&itool=pubmed_docsum
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CHAPTER 2. ALTERNATIVE MEDICINE AND HEMOPHILIA Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to hemophilia. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to hemophilia and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select CAM on PubMed. Enter hemophilia (or synonyms) into the search box. Click Go. The following references provide information on particular aspects of complementary and alternative medicine that are related to hemophilia: •
“Yakugai” AIDS and the Yokohama Xth international AIDS conference. Author(s): Haas GJ. Source: Common Factor. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11362335&query_hl=1&itool=pubmed_docsum
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32P Radiosynoviorthesis in children with hemophilia. Author(s): Manco-Johnson MJ, Nuss R, Lear J, Wiedel J, Geraghty SJ, Hacker MR, Funk S, Kilcoyne RF, Murphy J. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12368689&query_hl=1&itool=pubmed_docsum
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Activated recombinant human coagulation factor VII therapy for intracranial hemorrhage in patients with hemophilia A or B with inhibitors. Results of the
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novoseven emergency-use program. Author(s): Arkin S, Cooper HA, Hutter JJ, Miller S, Schmidt ML, Seibel NL, Shapiro A, Warrier I. Source: Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10087434&query_hl=1&itool=pubmed_docsum •
Ancient descriptions of hemophilia and preconception gender selection. Author(s): Rosner F. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6379212&query_hl=1&itool=pubmed_docsum
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Behavioral medicine in hemophilia arthritic pain management: two case studies. Author(s): Varni JW. Source: Archives of Physical Medicine and Rehabilitation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7016064&query_hl=1&itool=pubmed_docsum
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Case report: the effect of a Chinese herbal medicine, BG-104 in two HIV positive hemophiliacs. Author(s): Arimori S, Nozaki H, Morita K, Arimori K. Source: Biotherapy (Dordrecht, Netherlands). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7915126&query_hl=1&itool=pubmed_docsum
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Dental extractions in the hemophiliac: control of the emotional factors by hypnosis. Author(s): LUCAS ON. Source: Am J Clin Hypn. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14280120&query_hl=1&itool=pubmed_docsum
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Factor IX and prothrombin in amniotic fluid and fetal plasma: constraints on prenatal diagnosis of hemophilia B and evidence of proteolysis. Author(s): Thompson AR. Source: Blood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6478059&query_hl=1&itool=pubmed_docsum
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Failure in oral treatment of hemophilia by Huang-lien-chieh-tu-tang (plant extract), one of the kanpo medicines. Author(s): Brochier G, Bosser C, Noel L. Source: Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6534822&query_hl=1&itool=pubmed_docsum
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Flavonoids in hemophilia. Author(s): QUICK AJ.
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Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14489472&query_hl=1&itool=pubmed_docsum •
Hemophilia and AIDS: dealing with nurse burnout. Author(s): Bolivar E. Source: Caring. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10183513&query_hl=1&itool=pubmed_docsum
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Hemophilia in classic rabbinic texts. Author(s): Rosner F. Source: Journal of the History of Medicine and Allied Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8034967&query_hl=1&itool=pubmed_docsum
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Hemophilia in context: adjunctive hypnosis for families with a hemophiliac member. Author(s): Ritterman MK. Source: Family Process. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7160463&query_hl=1&itool=pubmed_docsum
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Hemophilia in the Talmud and rabbinic writings. Author(s): Rosner F. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4890512&query_hl=1&itool=pubmed_docsum
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Hemophilia: a story of success--disaster and the perseverance of the human spirit, Part 2. Author(s): Dubin CS. Source: The Journal of the Association of Nurses in Aids Care : Janac. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10394564&query_hl=1&itool=pubmed_docsum
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High prevalence of GB virus C strains genetically related to strains with Asian origin in Nicaraguan hemophiliacs. Author(s): Gonzalez-Perez MA, Norder H, Bergstrom A, Lopez E, Visona KA, Magnius LO. Source: Journal of Medical Virology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9179760&query_hl=1&itool=pubmed_docsum
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Holistic care for children with hemophilia. Author(s): Cogliano J.
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Source: Nurs Spectr (Wash D C). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10542647&query_hl=1&itool=pubmed_docsum •
Hypnosis and stress in hemophilia. Author(s): Lucas ON. Source: Bibl Haematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=5309421&query_hl=1&itool=pubmed_docsum
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Hypnosis for hemophiliacs: methodologic problems and risks. Author(s): LeBaron S, Zeltzer L. Source: Am J Pediatr Hematol Oncol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2416232&query_hl=1&itool=pubmed_docsum
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Hypnosis for patients with hemophilia. Author(s): Newman M. Source: The Journal of the American Dental Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=277567&query_hl=1&itool=pubmed_docsum
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Hypnosis may reduce hemophiliacs' blood needs. Author(s): Martin J. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6620471&query_hl=1&itool=pubmed_docsum
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Management and surveillance of the hemophiliacs at the National Institute of Hematology and Blood Transfusion of Vietnam. Author(s): Bach QT, Colab. Source: Southeast Asian J Trop Med Public Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7886550&query_hl=1&itool=pubmed_docsum
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Management of tooth extractions in hemophiliacs by the combined use of hypnotic suggestion, protective splints and packing of sockets. Author(s): LUCAS ON, FINKELMAN A, TOCANTINS LM. Source: J Oral Surg Anesth Hosp Dent Serv. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13931407&query_hl=1&itool=pubmed_docsum
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Oral treatment of hemophilia A using traditional kanpo medicine, Huang-lien-chiehtu-tang (plant extract). Author(s): Adachihara A.
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Source: Haemostasis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6409712&query_hl=1&itool=pubmed_docsum •
Orthopaedic and other surgical aspects of hemophilia. Introduction of topic. Author(s): Jordan HH. Source: Bibl Haematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=5436342&query_hl=1&itool=pubmed_docsum
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Peripheral nerve complications in hemophilia. Author(s): Saraf SK, Singh OP, Singh VP. Source: J Assoc Physicians India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12725260&query_hl=1&itool=pubmed_docsum
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Progressive versus self-control relaxation to reduce spontaneous bleeding in hemophiliacs. Author(s): Lichstein KL, Eakin TL. Source: Journal of Behavioral Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3897550&query_hl=1&itool=pubmed_docsum
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Psychological factors in hemophilia--the concept of self care. Author(s): Agle D. Source: Annals of the New York Academy of Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1053867&query_hl=1&itool=pubmed_docsum
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Research on hypnosis in hemophilia--preliminary success and problems: a brief communication. Author(s): LeBaron S, Zeltzer LK. Source: Int J Clin Exp Hypn. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6490216&query_hl=1&itool=pubmed_docsum
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Surveillance and care of four Chinese hemophiliacs with human immunodeficiency virus (HIV) infection. Author(s): Tang D, Qu G, Pang X, Lang Y, Liang Y, Yu Y, Zeng Y, Shao Y. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8274721&query_hl=1&itool=pubmed_docsum
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Telephone support group intervention for persons with hemophilia and HIV/AIDS and family caregivers. Author(s): Stewart MJ, Hart G, Mann K, Jackson S, Langille L, Reidy M.
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Source: International Journal of Nursing Studies. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11223062&query_hl=1&itool=pubmed_docsum •
The effects of a comprehensive self-hypnosis training program on the use of factor VIII in severe hemophilia. Author(s): Swirsky-Sacchetti T, Margolis CG. Source: Int J Clin Exp Hypn. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3084393&query_hl=1&itool=pubmed_docsum
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The lack of antiplatelet effect of crude extracts from ganoderma lucidum on HIVpositive hemophiliacs. Author(s): Gau JP, Lin CK, Lee SS, Wang SR. Source: The American Journal of Chinese Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2270852&query_hl=1&itool=pubmed_docsum
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The Missouri Hemophilia Program. Utilizing consumer involvement in the delivery of comprehensive public health services. Author(s): Wilson RB. Source: Mo Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6708925&query_hl=1&itool=pubmed_docsum
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The use of analgetics by hemophiliacs. Author(s): Ikkala E, Nevanlinna HR. Source: Bibl Haematol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=5297242&query_hl=1&itool=pubmed_docsum
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The use of hypnosis in hemophilia dental care. Author(s): Lucas ON. Source: Annals of the New York Academy of Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1078618&query_hl=1&itool=pubmed_docsum
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The use of hypnosis with hemophilia. Author(s): LaBaw W. Source: Psychiatr Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1289965&query_hl=1&itool=pubmed_docsum
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Update on the use of orthotics in hemophilia. Author(s): Heim M, Steinbach T.
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Source: Orthop Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3054732&query_hl=1&itool=pubmed_docsum
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 hemophilia; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Bruising Source: Healthnotes, Inc.; www.healthnotes.com Capillary Fragility Source: Healthnotes, Inc.; www.healthnotes.com Cyclic Mastalgia Alternative names: Cyclic Mastitis, Fibrocystic Breast Disease Source: Prima Communications, Inc.www.personalhealthzone.com Hemophilia Source: Integrative Medicine Communications; www.drkoop.com
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Herbs and Supplements Glycyrrhiza glabra Source: Integrative Medicine Communications; www.drkoop.com
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Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Licorice Alternative names: Glycyrrhiza glabra, Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com Origanum Alternative names: Oregano; Origanum vulgare Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com Willow Bark Alternative names: There are several species of willow includingSalix alba, Salix nigra, Salix fragilis, Salix purpurea, Salix babylonica, White Willow, European Willow, Black Willow, Pussy Willow, Crack Willow, Purple Willow, Weeping Willow, Liu-zhi Source: Integrative Medicine Communications; www.drkoop.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 3. PATENTS ON HEMOPHILIA Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “hemophilia“ (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hemophilia, we have not necessarily excluded nonmedical patents in this bibliography.
Patent Applications on Hemophilia As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to hemophilia:
8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm. 9 This has been a common practice outside the United States prior to December 2000.
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Drug for treating hemophilia and method of treating hemophilia using the same Inventor(s): Chuah; Maurinee; (Bierbcek, BE), Kondo; Akihiko; (Hyogo, JP), Kuroda; Shunichi; (Osaka, JP), Senoo; Masaharu; (Okayama, JP), Tanizawa; Katsuyuki; (Osaka, JP), Ueda; Masakazu; (Tokyo, JP), Vandendriessche; Thierry; (Bierbcek, BE) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20060240114 Date filed: March 17, 2004 Abstract: A therapeutic product or drug for therapy of hemophilia may be produced by a simplified method including embedding genes of the blood clotting factors VIII (IX) for therapy of hemophilia in hollow nano particles obtained on expressing the protein having a particle forming function, such as hepatitis B virus surface antigen protein, in eucaryotic cells. The drug so produced is able to introduce the genes of the blood clotting factors efficaciously into liver cells with the least risk of side effects. Excerpt(s): This invention relates to a therapeutic product (drug) for treating hemophilia using hollow nano particles, and a method of treating hemophilia using this drug. More particularly, it relates to a therapeutic product (drug) comprising a substance enclosed in particles for transfer into cells, which substance may be specifically introduced into the cells for hemophilia treatment, and to a method of treating hemophilia using the product. This application claims priority of Japanese Patent Application 2003-071788, filed in Japan on Mar. 17, 2003, which is incorporated by reference herein. In the field of medicine in recent years, development of a drug, directly acting on the affected site to display a high therapeutic efficacy with lesser side effects, is proceeding briskly. In particular, a method termed the drug delivery system (DDS) is attracting notice as being a method for specifically transporting effective components, such as those of a drug, to a target cell or tissue for causing the components to act on the target site. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Ex-vivo and in vivo factor XII gene therapy for hemophilia A and B Inventor(s): Pollard, Bette; (Potomac, MD), Pollard, Harvey; (Potomac, MD) Correspondence: Arent Fox Kintner Plotkin & Kahn; 1050 Connecticut Avenue, N.W.; Suite 400; Washington; DC; 20036; US Patent Application Number: 20030073652 Date filed: May 17, 2001 Abstract: Bypass activity for hemophilia A and B can be generated by natural or recombinant Factor VIIa. Factor XIIa when implanted into a guinea pig or monkey also facilitates the conversion of endogenous factor VII to VIIa, thereby providing bypass activity. Additionally, certain modified versions of Factor XII are known to be intrinsically active, with properties like Factor XIIa. Administration of unencapsulated Factor XIIa to a guinea pig causes a transient increase in plasma bypass activity. A continuous source of Factor XIIa, as provided by a gene therapy, is therapeutic for both Hemophilia A and B. There are three ways to provide for gene therapy. In each case, the gene for Factor XII (or Factor XIIa) can be introduced into the cell by the usual means, including, but not limited to, as naked DNA, as a DNA/lipid mixture, or as part of a
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viral vector system. In one manifestation, cells can be transfected with full length or modified versions of Factor XII, ex-vivo, and allowed to continuously express versions of recombinant Factor XII from unencapsulated recombinant cells implanted in the body of the patient. A second mechanism would require encapsulating the cells within the body. As a third mechanism of introducing Factor XIIa into the patient, full length or modified versions of the gene for human Factor XII can be directly administered in vivo. The advantage is provision of a universal gene therapy for hemophilia A and B, rather than separate gene therapies involving either Factor VIII (Hemophilia A) or Factor IX (Hemophilia B). Excerpt(s): This application claims priority under 35 U.S.C.sctn.1.119(e) to provisional application serial No. 60/205,014, filed May 17, 2000. The invention relates to the use of recombinant Factor XII and truncated or mutated forms thereof, in gene therapy for conversion of inactive Factor VII to its active form in the treatment of Hemophelia A and B. Hemophilia A is a coagulation disorder caused by a deficiency in Factor VIII:C (Factor 8) (Bloom, 1991; Rosendaal et al, 1991; Thompson, 1991; Handin et al, 1994). Hemophilia B is a coagulation disorder caused by a deficiency of Factor IX. Most U.S. and European hemophiliacs are undertreated due to the extraordinary cost of recombinant Factor VIII:C, and the high incidence of "inhibitors" or auto-antibodies to Factor VIII:C in patients (Aledort, 1998). Not only do these antibodies inhibit Factor VIII activity, but they also have a catalytic destructive effect (Lacroix-Desmazes, et al, 1999). Between 10% (Yee, et al, 1999) and 25% (Prescott et al, 1997) of hemophiliacs have such inhibitors, and they cost 10-fold more than the average to treat due to more frequent hospitalizations (Goudemand, 1998). Attempts to induce immune tolerance to Factor VIII:C are not often successful. Initially, such antibody development was not as frequently reported for recombinant Factor VIII:C as for plasma-derived Factor VIII:C (see Seremetis et al, 1999). However, Prescott et al (1997) from the American Red Cross report that there is no significant difference between the two classes of patients. Given financial limitations, priorities have been established for access to therapy, in which HIV-positive and/or hepatitis C-positive hemophiliacs are less likely to be treated optimally (Giangrande, 1997). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Oral treatment of hemophilia Inventor(s): Alpan, Oral; (Rockville, MD), Kamala, Tirumalaj; (Rockville, MD), Matzinger, Polly; (Bethesda, MD), Velander, William Hugold; (Blacksburg, VA) Correspondence: Klarquist Sparkman, Llp; 121 SW Salmon Street; Suite 1600; Portland; OR; 97204; US Patent Application Number: 20040209829 Date filed: February 2, 2004 Abstract: Disclosed herein is a simple method for the treatment of antigen-deficiency diseases, by orally administering to a subject a therapeutically effective amount of the deficient antigen, wherein the antigen is not present in a liposome. In one embodiment, the method increases hemostasis in a subject having hemophilia A or B, by orally administering to the hemophiliac a therapeutically effective amount of the appropriate clotting factor other than in a liposome, sufficient to induce oral tolerance and supply exogenous clotting factor to the subject.
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Excerpt(s): This application claims priority to U.S. Provisional application No. 60/310,150, filed Aug. 3, 2001, which is hereby incorporated by reference in its entirety. This disclosure relates to methods for treating a subject suffering from an antigendeficiency which causes a disease, by orally administering a therapeutically effective amount of the deficient antigen to the subject, sufficient to induce oral tolerance and relieve symptoms of the disease. In one example, the disclosure relates to oral administration of clotting factor VIII or IX for treating hemophilia A and B, respectively. Hemophilia A and B, caused respectively by decreased levels of clotting factor VIII (F.VIII) and IX (F.IX) levels in peripheral blood, are the most common severe inherited bleeding disorders. Although purified clotting factors from human plasma can be infused into these patients to prevent or treat bleeding episodes, this poses the risk of spreading of diseases such as Creutzfled-Jakob disease, HIV, and hepatitis C. Although recombinant clotting factor preparations are available, the supply is insufficient to cover the world-wide demand. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Use of blood coagulation factor XIII for treating hemophilia A Inventor(s): Bishop; Paul D.; (Fall City, WA), Ohrstrom; Jan; (Mercer Island, WA), Rose; Lynn Massman; (Seattle, WA) Correspondence: Novo Nordisk, INC.;PATENT Department; 100 College Road West; Princeton; NJ; 08540; US Patent Application Number: 20070021340 Date filed: September 20, 2006 Abstract: A patient having hemophilia A is treated by administering factor XIII generally in conjunction with factor VIII or desmopressin. Excerpt(s): This patent application is a continuation of copending and commonly owned U.S. patent application Ser. No. 10/415,424, filed Apr. 29, 2003, which is the US national phase of International Patent Application PCT/US01/47073, filed Nov. 5, 2001, and claims the benefit of U.S. Provisional Patent Application 60/245,751, filed Nov. 3, 2000, each of which being hereby incorporated by reference. Hemophilia A is an inherited disorder of blood coagulation characterized by a permanent tendency to hemorrhage due to a defect in the blood coagulation mechanism. Hemophilia A is caused by a deficiency in factor VIII. Factor VIII coagulant protein is a single-chain protein that regulates the activation of factor X by proteases in the intrinsic coagulation pathway. It is synthesized in liver parenchymal cells and circulates complexed to the von Willebrand protein. One in 10,000 males is born with deficiency or dysfunction of the factor VIII molecule. The resulting disorder, hemophilia A is characterized by bleeding into soft tissues, muscles, and weight-bearing joints. Although normal hemostasis requires 25 percent factor VIII activity, symptomatic patients usually have factor VIII levels below 5 percent. Hemophilic bleeding occurs hours or days after injury, can involve any organ and, if untreated, may continue for days or weeks. This can result in large collections of partially clotted blood putting pressure on adjacent normal tissues and can cause necrosis of muscle, venous congestion, or ischemic damage to nerves. Hemophilia A is generally treated by administering to the patient either recombinant or plasma-derived factor VIII, or mild cases can be treated with desmopressin. However, there are times when treating such patients with factor VIII or desmopressin produces less than satisfactory results, and hemorrhaging continues.
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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with hemophilia, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under Issued Patents, click Quick Search. Then, type hemophilia (or 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 hemophilia. You can also use this procedure to view pending patent applications concerning hemophilia. Simply go back to http://www.uspto.gov/patft/index.html. Select Quick Search under Published Applications. Then proceed with the steps listed above.
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CHAPTER 4. BOOKS ON HEMOPHILIA Overview This chapter provides bibliographic book references relating to hemophilia. In addition to online booksellers such as www.amazon.com and www.bn.com, the National Library of Medicine is an excellent source for book titles on hemophilia. 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 hemophilia at online booksellers’ Web sites, you may discover non-medical books that use the generic term “hemophilia” (or a synonym) in their titles. The following is indicative of the results you might find when searching for hemophilia (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
"My blood doesn't have muscles!": How children understand hemophilia from preschool to adolescence Laureen A Kelley (1993); ISBN: B0006P5VUS; http://www.amazon.com/exec/obidos/ASIN/B0006P5VUS/icongroupinterna
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21st Century Complete Medical Guide to Hemophilia and Related Bleeding Disorders, Authoritative Government Documents, Clinical References, and Practical Information for Patients and Physicians PM Medical Health News (2004); ISBN: 1592487904; http://www.amazon.com/exec/obidos/ASIN/1592487904/icongroupinterna
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30th Hemophilia Symposium Hamburg 1999: HIV Infection and Epidemiology in Hemophilia; Gene Therapy in Hemophilia A and B; Therapy of Hepatitis C; Inhibitors. Pediatric Hemostasiology; Case Reports I. Scharrer and W. Schramm (2000); ISBN: 3540676775; http://www.amazon.com/exec/obidos/ASIN/3540676775/icongroupinterna
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31st Hemophilia Symposium Hamburg 2000 I. Scharrer and W. Schramm (2001); ISBN: 3540421319; http://www.amazon.com/exec/obidos/ASIN/3540421319/icongroupinterna
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32nd Hemophilia Symposium Hamburg 2001: Epidemiology; Genetic Diagnosis of Clotting Disorders; Hemophilia; Hemotherapy in Sepsis; Pediatric Hemostaseology Free Lectures Inge Scharrer and Wolfgang Schramm (2003); ISBN: 354043884X; http://www.amazon.com/exec/obidos/ASIN/354043884X/icongroupinterna
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33rd Hemophilia Symposium Hamburg 2002: Epidemiology; New Findings and Possibilities in the Therapy of Antibodies; Hemophilia: Therapeutic Exercise and. Pediatric Hemostasiology; Free Lectures I. Scharrer and W. Schramm (2004); ISBN: 3540009027; http://www.amazon.com/exec/obidos/ASIN/3540009027/icongroupinterna
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34th Hemophilia Symposium Hamburg 2003: HIV Infection and Epidemiology; Management of Bleedings in Hemophiliacs with Inhibitors;Orthopedic Problems and. C;Pediatric Hemostaseology;Free Lectures I. Scharrer and W. Schramm (2005); ISBN: 3540228861; http://www.amazon.com/exec/obidos/ASIN/3540228861/icongroupinterna
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35th Hemophilia Symposium Hamburg 2004: Epidemiology; Risk of Infections and Inhibitors in Hemophilia; Chronic lic Synovitis and Long-term Results of Orthopedic. Hemostaseology; Free Lectures Inge Scharrer and Wolfgang Schramm (2005); ISBN: 3540285431; http://www.amazon.com/exec/obidos/ASIN/3540285431/icongroupinterna
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36th Hemophilia Symposium Hamburg 2005: Epidemiology; Hemophilia Therapy; Orthopedic Treatment in Hemophiliacs; Hemostaseologic Diagnosis; Pediatric Hemostaseology; Free Lectures Inge Scharrer and Wolfgang Schramm (2006); ISBN: 3540367144; http://www.amazon.com/exec/obidos/ASIN/3540367144/icongroupinterna
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A financial and compliance review of Great Lakes Hemophilia Foundation Maternal and Child Health Block Grant, January 1, 1986 through December 31, 1986 Jacob Klam (1988); ISBN: B00071BWYK; http://www.amazon.com/exec/obidos/ASIN/B00071BWYK/icongroupinterna
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A review of Maternal and Child Health Services Block Grant, January 1, 1989December 31, 1991, Acquired Immune Deficiency Syndrome (AIDS) Grant, July 1,. 30, 1990, Great Lakes Hemophilia Foundation Jacob Klam (1992); ISBN: B0006OVTG4; http://www.amazon.com/exec/obidos/ASIN/B0006OVTG4/icongroupinterna
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A Study of the Coagulation Defect in Hemophilia Armand James QUICK (1935); ISBN: B000MWZMVI; http://www.amazon.com/exec/obidos/ASIN/B000MWZMVI/icongroupinterna
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Acquired Hemophilia Craig M. Kessler (1996); ISBN: 9995485206; http://www.amazon.com/exec/obidos/ASIN/9995485206/icongroupinterna
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Activated Prothrombin Complex Concentrates: Managing Hemophilia with Factor VIII Inhibitor G. Mariani, Matteo A. Russo, and F. Mandelli (1982); ISBN: 0275913732; http://www.amazon.com/exec/obidos/ASIN/0275913732/icongroupinterna
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Alexis: The Prince Who Had Hemophilia Laureen A Kelley (1992); ISBN: B000BWFW1O; http://www.amazon.com/exec/obidos/ASIN/B000BWFW1O/icongroupinterna
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American Home and Targeted Genetics establish partnership for B-domain deleted factor VIII hemophilia gene Therapy.(Genetics Institute Inc.)(Brief Article): An article from: BIOTECH Patent News (2005); ISBN: B0008J74SY; http://www.amazon.com/exec/obidos/ASIN/B0008J74SY/icongroupinterna
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Avigen granted broad hemophilia A gene therapy patent.: An article from: BIOTECH Patent News (2005); ISBN: B0008HYHDQ; http://www.amazon.com/exec/obidos/ASIN/B0008HYHDQ/icongroupinterna
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Basic Concepts of Hemophilia: A Self-Study and Planning Workbook Regina Butler, Sally O. Crudder, Brenda Riske, and Susan Toal (2001); ISBN: B000EKBZMI; http://www.amazon.com/exec/obidos/ASIN/B000EKBZMI/icongroupinterna
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BAYER UNVEILS KOGENATE FS WITH BIO-SET FOR HEMOPHILIA A. : An article from: Biotech Business (2006); ISBN: B000EMI8GM; http://www.amazon.com/exec/obidos/ASIN/B000EMI8GM/icongroupinterna
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Beloved warrior: Hemophilia and other battles Virginia Nyman Arver (1997); ISBN: B0006QSR5S; http://www.amazon.com/exec/obidos/ASIN/B0006QSR5S/icongroupinterna
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Blood Brothers: Ryan, Chris, and Hemophilia Nancy Shaw (1990); ISBN: 0915541602; http://www.amazon.com/exec/obidos/ASIN/0915541602/icongroupinterna
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Blood Saga: Hemophilia, AIDS, and the Survival of a Community, Updated Edition With a New Preface Susan Resnik (1999); ISBN: 0520211952; http://www.amazon.com/exec/obidos/ASIN/0520211952/icongroupinterna
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Cell Genesys obtains results from preclinical hemophilia gene therapy studies.(Brief Article): An article from: BIOTECH Patent News (2005); ISBN: B0008I3N2Q; http://www.amazon.com/exec/obidos/ASIN/B0008I3N2Q/icongroupinterna
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Challenges for social work in hemophilia care.(Practice Forum): An article from: Health and Social Work Gregory Taylor (2005); ISBN: B00082I6PG; http://www.amazon.com/exec/obidos/ASIN/B00082I6PG/icongroupinterna
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Codeine Diary: True Confessions of a Reckless Hemophiliac Tom Andrews (1999); ISBN: 015600657X; http://www.amazon.com/exec/obidos/ASIN/015600657X/icongroupinterna
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Comprehensive care in hemophilia Vytas Mickevicius (1979); ISBN: B0006YIXI6; http://www.amazon.com/exec/obidos/ASIN/B0006YIXI6/icongroupinterna
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Comprehensive care of hemophilia (DHEW publication; no) Margaret W Hilgartner (1979); ISBN: B0006XCSHE; http://www.amazon.com/exec/obidos/ASIN/B0006XCSHE/icongroupinterna
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Comprehensive Management of Hemophilia Donna C. Boone (1976); ISBN: 0803610009; http://www.amazon.com/exec/obidos/ASIN/0803610009/icongroupinterna
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Comprehensive management of musculoskeletal disorders in hemophilia;: A symposium held in Miami Beach, Florida, October 12-14, 1972 (1973); ISBN: 0309021391; http://www.amazon.com/exec/obidos/ASIN/0309021391/icongroupinterna
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Connections 1999: The Resource Guide for People with Hemophilia and Other Bleeding Disorders President, National Organization for Rare Disorders Abbey Meyers, M.D. Gilbert C. White II, M.D. Jeanne M. Lusher, and M.D. Susan J. Geraghty (1999);
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ISBN: B000BNC4KA; http://www.amazon.com/exec/obidos/ASIN/B000BNC4KA/icongroupinterna •
Coumarine poisoning as phenocopy to hemophilia P Koch (1980); ISBN: B0007ARJIE; http://www.amazon.com/exec/obidos/ASIN/B0007ARJIE/icongroupinterna
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Diagnosis and treatment of hemophilia;: A practical guide Herbert S Strauss (1972); ISBN: B0006C50GG; http://www.amazon.com/exec/obidos/ASIN/B0006C50GG/icongroupinterna
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Diagnostic Imaging in Hemophilia: Musculoskeletal and Other Hemorrhagic Complications H. Pettersson and M. S. Gilbert (1985); ISBN: 0387139915; http://www.amazon.com/exec/obidos/ASIN/0387139915/icongroupinterna
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Diseases and Disorders - Hemophilia (Diseases and Disorders) Barbara Sheen and Beverly Britton (2003); ISBN: 1560069066; http://www.amazon.com/exec/obidos/ASIN/1560069066/icongroupinterna
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Encyclopedia of Family Health; Vol 5: Flotation Therapy - Hemophilia JacoDavid B (1998); ISBN: 0761406301; http://www.amazon.com/exec/obidos/ASIN/0761406301/icongroupinterna
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Ethical Dilemmas in the Pediatric Hemophilia Community.: An article from: Pediatric Nursing Judy Schaefer (2005); ISBN: B000996V50; http://www.amazon.com/exec/obidos/ASIN/B000996V50/icongroupinterna
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Evaluation of dental procedures on hemophilic patients in a comprehensive program for the care of hemophilia Osamu Chiono (1967); ISBN: B0007H4Q2Y; http://www.amazon.com/exec/obidos/ASIN/B0007H4Q2Y/icongroupinterna
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Gale Encyclopedia of Medicine: Hemophilia Jennifer F. Wilson MS (2004); ISBN: B00075UYQ8; http://www.amazon.com/exec/obidos/ASIN/B00075UYQ8/icongroupinterna
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Gale Encyclopedia of Nursing and Allied Health: Hemophilia Jr., MD, DrPH L. Fleming Fallon (2004); ISBN: B00075V9KI; http://www.amazon.com/exec/obidos/ASIN/B00075V9KI/icongroupinterna
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Gene Therapy Promising for Hemophilia B.(Brief Article): An article from: Family Practice News Bruce Jancin (2005); ISBN: B0008HF9PQ; http://www.amazon.com/exec/obidos/ASIN/B0008HF9PQ/icongroupinterna
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Gene therapy safe, feasible for patients with severe hemophilia A, Phase I study finds.(Brief Article): An article from: Transplant News (2005); ISBN: B0008I0B1M; http://www.amazon.com/exec/obidos/ASIN/B0008I0B1M/icongroupinterna
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Genetic Disorders Sourcebook: Basic Consumer Health Information About Hereditary Diseases and Disorders, Including Cystic Fibrosis, Down Syndrome, Hemophilia,. Disease (Health Reference Series) Kathy Massimini (2000); ISBN: 0780802411; http://www.amazon.com/exec/obidos/ASIN/0780802411/icongroupinterna
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Genetic Disorders Sourcebook: Basic Information About Heritable Diseases and Disorders Such As Down Synd Rome, Pku, Hemophilia, Von Willebrand Disease,. Tay-Sachs d (Health Reference Series) Karen Bellenir (1996); ISBN: 0780800346; http://www.amazon.com/exec/obidos/ASIN/0780800346/icongroupinterna
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Handbook of hemophilia (1975); ISBN: 0444167072; http://www.amazon.com/exec/obidos/ASIN/0444167072/icongroupinterna
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Hemophilia - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References Health Publica Icon Health Publications (2004); ISBN: 0597839786; http://www.amazon.com/exec/obidos/ASIN/0597839786/icongroupinterna
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Hemophilia & surgery: What to expect before and after surgery Craig Epson-Nelms (1995); ISBN: B0006RUAW0; http://www.amazon.com/exec/obidos/ASIN/B0006RUAW0/icongroupinterna
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Hemophilia (Diseases and People) Edward Willett (2001); ISBN: 0766016846; http://www.amazon.com/exec/obidos/ASIN/0766016846/icongroupinterna
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Hemophilia (Genetic Diseases) Jeri Freedman (2006); ISBN: 1404206981; http://www.amazon.com/exec/obidos/ASIN/1404206981/icongroupinterna
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Hemophilia and Hemophiliod Diseases Kenneth M. Brinkhous (1957); ISBN: B000K0BIOM; http://www.amazon.com/exec/obidos/ASIN/B000K0BIOM/icongroupinterna
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Hemophilia and new hemorrhagic states;: International symposium, New York (1970); ISBN: 0807811335; http://www.amazon.com/exec/obidos/ASIN/0807811335/icongroupinterna
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Hemophilia Care in the New Millennium (Advances in Experimental Medicine and Biology) Dougald M. Monroe, Ulla Hedner, Maureane R. Hoffman, and Claude Negrier (2001); ISBN: 0306465213; http://www.amazon.com/exec/obidos/ASIN/0306465213/icongroupinterna
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Hemophilia Foundation Gives Bayer A Headache.(Brief Article): An article from: The Non-profit Times Matthew Sinclair (2005); ISBN: B0008IBDDW; http://www.amazon.com/exec/obidos/ASIN/B0008IBDDW/icongroupinterna
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Hemophilia in children (Progress in pediatric hematology/oncology) (1976); ISBN: 0884161382; http://www.amazon.com/exec/obidos/ASIN/0884161382/icongroupinterna
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Hemophilia in Classic Rabbinic Texts Fred Rosner (1994); ISBN: B0006RBND0; http://www.amazon.com/exec/obidos/ASIN/B0006RBND0/icongroupinterna
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Hemophilia in the Child and Adult Margaret W. Hilgartner and Carl Pochedly (1989); ISBN: 0881674923; http://www.amazon.com/exec/obidos/ASIN/0881674923/icongroupinterna
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Hemophilia Likely to Be First Gene Therapy Cure.: An article from: Internal Medicine News Timothy F. Kirn (2005); ISBN: B0008I8GJQ; http://www.amazon.com/exec/obidos/ASIN/B0008I8GJQ/icongroupinterna
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Hemophilia, hemophiliacs and the health care delivery system (DHEW publication; no) Caroline Roth Petit (1976); ISBN: B0006W8RN4; http://www.amazon.com/exec/obidos/ASIN/B0006W8RN4/icongroupinterna
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HIV disease in people with hemophilia: Your questions answered Glenn F Pierce (1991); ISBN: B0006OWDAK; http://www.amazon.com/exec/obidos/ASIN/B0006OWDAK/icongroupinterna
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How to live with hemophilia James M Vogel (1974); ISBN: B0006VZZO4; http://www.amazon.com/exec/obidos/ASIN/B0006VZZO4/icongroupinterna
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Inheritance of hemophilia Connie Miller (1998); ISBN: B0006R97XS; http://www.amazon.com/exec/obidos/ASIN/B0006R97XS/icongroupinterna
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Inhibitors in Patients with Hemophilia E. C. Rodriguez-Merchan and Christine A. Lee (2002); ISBN: 0632064773; http://www.amazon.com/exec/obidos/ASIN/0632064773/icongroupinterna
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Joshua The Knight of the Red Snake (What is Hemophilia?) Laureen A. Kelley (2001); ISBN: B000EK8LNY; http://www.amazon.com/exec/obidos/ASIN/B000EK8LNY/icongroupinterna
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Let Harold (A Boy with hemophilia) Do it Nan Frelander and Ann Thompson (0001); ISBN: B000KGEPI2; http://www.amazon.com/exec/obidos/ASIN/B000KGEPI2/icongroupinterna
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Living With Hemophilia Peter Jones (1974); ISBN: 0803650604; http://www.amazon.com/exec/obidos/ASIN/0803650604/icongroupinterna
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Living with hemophilia.(Neighborhood Heart Watch)(Brief Article): An article from: Medical Update Douglas Zipes (2005); ISBN: B0008263IS; http://www.amazon.com/exec/obidos/ASIN/B0008263IS/icongroupinterna
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Molecular genetics of hemophilia A Wouterina Cynthia Pieneman (1998); ISBN: B0006FCPBQ; http://www.amazon.com/exec/obidos/ASIN/B0006FCPBQ/icongroupinterna
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News potpourri (*). (SPECIAL FEATURE).(smoking and cancer, hemophilia, pediatric cardiology, air pollution and heart attacks, headache, thrombosis): An article from: Southern Medical Journal (2005); ISBN: B0008IGFUI; http://www.amazon.com/exec/obidos/ASIN/B0008IGFUI/icongroupinterna
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PED1 Complications of central venous access devices in pediatric hemophilia patients. (Pediatrics & Adolescent Medicine).(Brief Article): An article from: Southern Medical Journal (2005); ISBN: B0008IMWEG; http://www.amazon.com/exec/obidos/ASIN/B0008IMWEG/icongroupinterna
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Proceedings of the XIth Congress of World Federation of Hemophilia (Kyoto Japan, 1976) Editorial Board (1976); ISBN: B000FAB7CA; http://www.amazon.com/exec/obidos/ASIN/B000FAB7CA/icongroupinterna
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Prothrombin in enzymology, thrombosis, and hemophilia, (American lecture series, publication no. 681. A monograph in the Bannerstone divi-sion of American lectures in hematology) Walter H Seegers (1967); ISBN: B0006BQC3W; http://www.amazon.com/exec/obidos/ASIN/B0006BQC3W/icongroupinterna
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Raising a Child With Hemophilia: A Practical Guide for Parents (3rd Edition) Laureen A Kelley (1999); ISBN: B000NROMYU; http://www.amazon.com/exec/obidos/ASIN/B000NROMYU/icongroupinterna
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RECENT ADVANCES IN HEMOPHILIA Louis M. (Ed.) Aledort (1975); ISBN: B000AS4U6W; http://www.amazon.com/exec/obidos/ASIN/B000AS4U6W/icongroupinterna
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Resource book for hemophilia nurse coordinators Catharine Cranford Mintzer (1981); ISBN: B0006Y2I7I; http://www.amazon.com/exec/obidos/ASIN/B0006Y2I7I/icongroupinterna
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Ricky Ray Hemophilia Relief Fund Act of 1995: Hearing before the Subcommittee on Immigration and Claims of the Committee on the Judiciary, House of Representatives,. session, on H.R. 1023. September 19, 1996 United States (1997); ISBN: 0160552338; http://www.amazon.com/exec/obidos/ASIN/0160552338/icongroupinterna
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Social Work and Chronic Health Conditions: An Orientation Manual With Special Reference to Hemophilia John R. McDonald (1984); ISBN: 0889530610; http://www.amazon.com/exec/obidos/ASIN/0889530610/icongroupinterna
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Tell Them the Facts! About Hemophilia (What is Hemophilia?) Laureen A. Kelley and Laureen A Kelley (2001); ISBN: B000EK8NLY; http://www.amazon.com/exec/obidos/ASIN/B000EK8NLY/icongroupinterna
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TEXTBOOK OF HEMOPHILIA Lee Berntorp HOOTS (2005); ISBN: B000N5AGFQ; http://www.amazon.com/exec/obidos/ASIN/B000N5AGFQ/icongroupinterna
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Textbook of Hemophilia Erik Berntorp, Natalya Ananyeva, Jan Astermark, and Keith Hoots (2005); ISBN: 1405127694; http://www.amazon.com/exec/obidos/ASIN/1405127694/icongroupinterna
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The 2002 Official Patient's Sourcebook on Hemophilia James N. Parker and Philip M. Parker (2002); ISBN: 0597831815; http://www.amazon.com/exec/obidos/ASIN/0597831815/icongroupinterna
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The Child With a Chronic Medical Problem-Cardiac Disorders, Diabetes, Hemophilia (National Children's Bureau Bibliographies, 3) Rosemary Dinnage (1986); ISBN: 0700510133; http://www.amazon.com/exec/obidos/ASIN/0700510133/icongroupinterna
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The experience of children with hemophilia and HIV infection. (human immunodeficiency virus): An article from: Journal of School Health Christopher S. Hall (2005); ISBN: B0009211ZW; http://www.amazon.com/exec/obidos/ASIN/B0009211ZW/icongroupinterna
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The hemophilia educational resources list Rhonda Bisker (1981); ISBN: B0006E63WO; http://www.amazon.com/exec/obidos/ASIN/B0006E63WO/icongroupinterna
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The Hemophilia Handbook. Ruth, And Cornett, Jeff. Brown (1998); ISBN: B000GKO3ZM; http://www.amazon.com/exec/obidos/ASIN/B000GKO3ZM/icongroupinterna
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The Hemophilias (Methods in hematology) (1982); ISBN: 0443024391; http://www.amazon.com/exec/obidos/ASIN/0443024391/icongroupinterna
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The hemophilias (Monograph by Dade education) Andrew E Weiss (1978); ISBN: B0006XJC46; http://www.amazon.com/exec/obidos/ASIN/B0006XJC46/icongroupinterna
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The Hemophilias. International Symposium Washington Kenneth M. Brinkhous (1964); ISBN: B000MU2T02; http://www.amazon.com/exec/obidos/ASIN/B000MU2T02/icongroupinterna
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The Official Patient's Sourcebook On Hemophilia: Directory For The Internet Age Icon Health Publications (2005); ISBN: 0497009781; http://www.amazon.com/exec/obidos/ASIN/0497009781/icongroupinterna
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The politics of blood: Hemophilia activism in the AIDS crisis (Working paper) David L Kirp (1997); ISBN: B0006QPK58; http://www.amazon.com/exec/obidos/ASIN/B0006QPK58/icongroupinterna
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The relationship between athletic involvement, self-esteem, and symptoms of adolescent boys with hemophilia (Masters' theses. Education) Wendy K Connell (1994); ISBN: B0006PCHTG; http://www.amazon.com/exec/obidos/ASIN/B0006PCHTG/icongroupinterna
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They will probably ask you-- "What is hemophilia?" (What is hemophilia?) Laureen A Kelley (2001); ISBN: B0006RP4IU; http://www.amazon.com/exec/obidos/ASIN/B0006RP4IU/icongroupinterna
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Treatment of Hemophilia and Von Willebrand's Disease: New Developments Robert G. Westphal and Dennis M. Smith (1990); ISBN: 0915355728; http://www.amazon.com/exec/obidos/ASIN/0915355728/icongroupinterna
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Treatment of hemophilia B with a new clotting-factor concentrate M. Silvija Hoag (1969); ISBN: B0007K16X8; http://www.amazon.com/exec/obidos/ASIN/B0007K16X8/icongroupinterna
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Understanding Hemophilia Marie Berger (1989); ISBN: 1853980102; http://www.amazon.com/exec/obidos/ASIN/1853980102/icongroupinterna
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Vox Sanguinis (Viral Safety of Plasma-Derived Replacement Factors for Hemophilia , Vol 67, Suppl 4) P. M. Mannucci and Stanley M. Lemon (1994); ISBN: 3805560664; http://www.amazon.com/exec/obidos/ASIN/3805560664/icongroupinterna
The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select LocatorPlus. Once you are in the search area, simply type hemophilia (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 Medicine10: •
Abstracts, VIth International Congress on Thrombosis and Haemostasis, XIIth congress of the World Federation of Hemophilia.; Year: 1977; Stuttgart; New York: Schattauer, 1977
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Activated prothrombin complex concentrates: managing hemophilia with factor VIII inhibitor Author: Mariani, G. (Guglielmo); Year: 1982; New York, N.Y.: Praeger, 1982; ISBN: 9780030603 http://www.amazon.com/exec/obidos/ASIN/9780030603/icongroupinterna
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Blood money: a gaming-simulation of the problems of hemophilia and health care delivery systems Author: Greenblat, Cathy Stien.; Year: 1976; Bethesda, Md.]: U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health; Washington: for sale by the Supt. of Docs., U. S. Govt. Print. Off., [1976]
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Comprehensive management of hemophilia Author: Boone, Donna C.; Year: 1976; Philadelphia: Davis, c1976; ISBN: 9780303610 http://www.amazon.com/exec/obidos/ASIN/9780303610/icongroupinterna
10
In addition to LocatorPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a Books button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
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Comprehensive management of musculoskeletal disorders in hemophilia; a symposium held in Miami Beach, Florida, October 12-14, 1972. Edited by Newton C. McCollough. Author: McCollough, Newton C.; Year: 1973; Washington, National Academy of Sciences, 1973; ISBN: 9780309021 http://www.amazon.com/exec/obidos/ASIN/9780309021/icongroupinterna
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Diagnosis and treatment of hemophilia; a practical guide. Author: Strauss, Herbert S.,; Year: 1972; Albany ? c1972]
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Diagnostic imaging in hemophilia: musculoskeletal and other hemorrhagic complications Author: Pettersson, Holger,; Year: 1985; Berlin; New York: SpringerVerlag, c1985; ISBN: 9780387139 http://www.amazon.com/exec/obidos/ASIN/9780387139/icongroupinterna
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Haemophilia: based on symposia held during the XIIIth Congress of the World Federation of Hemophilia, Tel-Aviv, Israel, 1979 Author: Seligsohn, Uri.; Year: 1981; Tunbridge Wells, Kent: Castle House Publications, 1981; ISBN: 9780719400 http://www.amazon.com/exec/obidos/ASIN/9780719400/icongroupinterna
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Handbook of hemophilia. Edited by K. M. Brinkhous and H. C. Hemker. Author: Brinkhous, K. M. (Kenneth Merle),; Year: 1975; Amsterdam, Excerpta medica; New York, American Elsevier Pub. Co., 1975; ISBN: 9789021920 http://www.amazon.com/exec/obidos/ASIN/9789021920/icongroupinterna
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Hemophilia act of 1973: hearing before the Subcommittee on Health of the Committee on Labor and Public Welfare, United States Senate, Ninety-third Congress, first session, on S. 1326: to amend the Public Health Service act. November 15, 1973. Author: United States. Congress. Senate. Committee on Labor and Public Welfare. Subcommittee on Health.; Year: 1974; Washington: U. S. Govt. Print. Off., 1974
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Hemophilia and hemophilioid diseases; international symposium [held in New York City, August 24-25, 1956]. Author: Brinkhous, K. M. (Kenneth Merle),; Year: 1957; Chapel Hill, Univ. of North Carolina Press [c1957]
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Hemophilia and hemostasis Author: MeÌ nacheÌ , Doris.; Year: 1981; New York: Liss, c1981; ISBN: 9780845100 http://www.amazon.com/exec/obidos/ASIN/9780845100/icongroupinterna
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Hemophilia in children Author: Hilgartner, Margaret W.,; Year: 1976; Littleton, Mass.: Publishing Sciences Group, c1976; ISBN: 9780884161 http://www.amazon.com/exec/obidos/ASIN/9780884161/icongroupinterna
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Hemophilia in Sweden: studies on demography of hemophilia and surgery in hemophilia and von Willebrand’s disease Author: Larsson, S. Anders.; Year: 1984; Malmö: Distributed by Almqvist & Wiksell Periodical Co., 1984
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Hemophilia in the child and adult Author: Hilgartner, Margaret W.,; Year: 1989; New York: Raven Press, c1989; ISBN: 9780881674 http://www.amazon.com/exec/obidos/ASIN/9780881674/icongroupinterna
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Hemophilia today; a handbook of information. Author: Junior League of Montreal.; Year: 1962; Montreal] 1962
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Hemophilia, hemophiliacs, and the health care delivery system: National Heart and Lung Institute, Division of Blood Diseases and Resources, Office of Prevention, Control, and Education Author: Petit, Caroline Roth.; Year: 1975; Bethesda, Md.: U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Heart and Lung Institute, 1975
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Orthopedic problems in hemophilia: symposium, Düsseldorf, 1985 Author: Döhring, S. (Stephan); Year: 1986; München: W. Zuckschwerdt, c1986; ISBN: 9783886031 http://www.amazon.com/exec/obidos/ASIN/9783886031/icongroupinterna
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Prothrombin in enzymology, thrombosis and hemophilia. Author: Seegers, Walter H. (Walter Henry),; Year: 1967; Springfield, Ill., Thomas [c1967]
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th Hemophilia Symposium: Hamburg 2005 Author: Scharrer, I.; Year: 2007; Berlin; New York: Springer, c2007; ISBN: 9783540367 http://www.amazon.com/exec/obidos/ASIN/9783540367/icongroupinterna
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The hemophilia games: an experiment in health education planning. Author: Hemophilia Health Education Planning Project.; Year: 1975; Bethesda, Md.]: U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Office of Prevention, Control, and Education, National Heart and Lung Institute; Washington: for sale by the Supt. of Docs., U. S. Govt. Print. Office, [1976]
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The hemophiliac and his world. L’univers de l’heÌ mophile. Proceedings of the 5th congress of the World Federation of Hemophilia, Montreal, August 26-28, 1968. Edited by R. Gourdeau. Author: World Federation of Hemophilia.; Year: 1969; Basel, New York, Karger, 1969
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Transfusion and immunology: plenary session lectures of the XIV congress of the International Society of Blood Transfusion and the X congress of the World Federation of Hemophilia, Helsinki, July 27-August 2, 1975 Author: International Society of Blood Transfusion.; Year: 1975; Vammala: Vammalan Kirjapaino Oy, 1975
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CHAPTER 5. MULTIMEDIA ON HEMOPHILIA Overview In this chapter, we show you how to find bibliographic information related to multimedia sources of information on hemophilia.
Bibliography: Multimedia on Hemophilia The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select LocatorPlus. Once you are in the search area, simply type hemophilia (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 hemophilia: •
Haemophilia: the official journal of the World Federation of Hemophilia. Source: 1995-9999; Osney Mead, Oxford, UK: Blackwell Science, [1994-
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Hemophilia [slide] Source: American Society of Hematology; Year: 1974; Format: Slide; Seattle: The Society: for sale by American Society of Hematology National Slide Bank, 1974]
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Hemophilia [slide]: orthopaedic manifestations and treatment Source: American Academy of Orthop[a]edic Surgeons; Year: 1985; Format: Slide; Park Ridge, Ill.]: AAOS, [1985]
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Hemophilia [videorecording] Source: [Stanley P.] Balcerzak; produced by Ohio State University, Medical Audiovisual and Television Center; Year: 1971; Format: Videorecording; Columbus, Ohio]: The Center, c1971
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Hemophilia [videorecording] Source: Children's Hospital, Boston; Year: 1994; Format: Videorecording; Boynton Beach, FL: Universal Health Communications, [1994]
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Hemophilia and von Willebrand’s disease [videorecording] Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1982; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1982
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Hemophilia in infants and children [videorecording] Source: [presented by] the Medical University of South Carolina, Departments of Pathology and Laboratory Medicine and Pediatrics; produced by the Health Communications Network, Division of Television Services; Year: 1993; Format: Videorecording; Charleston, S.C.: The University, c1993
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Hemophilia in the 1990’s [videorecording] Source: produced by UT-TV Houston; Year: 1991; Format: Videorecording; Houston, Tex.]: UT-TV Houston, c1991
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Hemophilia update [videorecording] Source: College of Medicine, Division of Hemophilia, the Pennsylvania State University; produced by Penn-State Television; Year: 1975; Format: Videorecording; University Park, Pa.: The University: [for loan or sale by its Audio-Visual Services], c1975
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Orthopaedic surgery [sound recording]: AIDS--trauma and hemophilia Source: American College of Surgeons; Year: 1989; Format: Sound recording; Chicago, IL: The College, [1989]
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APPENDICES
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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.11
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.
•
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.
11 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.12 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 12
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.
•
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.
•
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.
•
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).
•
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.
•
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)
•
One or more major signs or symptoms of the disorder (for example, sickle cell anemia)
•
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.
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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 Institute13: •
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.14 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic
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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 Medicine15: •
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
15
See http://www.nlm.nih.gov/databases/index.html.
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The NLM Gateway16 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.17 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type hemophilia (or synonyms) into the search box and click Search. The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 16759 374 11 681 0 17825
HSTAT18 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.19 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.20 Simply search by hemophilia (or synonyms) at the following Web site: http://text.nlm.nih.gov.
Coffee Break: Tutorials for Biologists21 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are 16
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
17
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). 18 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 19 20
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. 21 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
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used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.22 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.23 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
MD Consult: Access to electronic clinical resources, see http://www.mdconsult.com/.
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Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Hemophilia In the following section, we will discuss databases and references which relate to the Genome Project and hemophilia. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).24 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type hemophilia (or synonyms) into the search box, and click 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 hemophilia: 22
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 23 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 24 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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HEMOPHILIA A Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=306700
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HEMOPHILIA a with VASCULAR ABNORMALITY Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=306800
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HEMOPHILIA B; HEMB Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=306900 Genes and Disease (NCBI - Map)
The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •
Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html
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Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
•
Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
•
Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html
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Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner
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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
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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
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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
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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/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 hemophilia (or synonyms) into the search box and click Go. Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database25 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database26 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the 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 hemophilia (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word and or or (using or might be useful when using synonyms).
25
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 26 Adapted from the Genome Database: http://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 hemophilia can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources This section directs you to sources which either publish fact sheets or can help you find additional guidelines on topics related to hemophilia. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are health topic pages which list links to available materials relevant to hemophilia. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for hemophilia:
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Bleeding Disorders http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html Blood and Blood Disorders http://www.nlm.nih.gov/medlineplus/bloodandblooddisorders.html Genetic Disorders http://www.nlm.nih.gov/medlineplus/geneticdisorders.html Genetic Testing http://www.nlm.nih.gov/medlineplus/genetictesting.html Hemochromatosis http://www.nlm.nih.gov/medlineplus/hemochromatosis.html Hemophilia http://www.nlm.nih.gov/medlineplus/hemophilia.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. 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: •
geneticalliance.org Source: www.geneticalliance.org http://www.geneticalliance.org/ws_display.asp?filter=resources_family_history& char=H&s_Diseases=
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Hemophilia, Hereditary Blood Disorders, DD, NCBDDD, CDC Source: www.cdc.gov http://www.cdc.gov/ncbddd/hbd/hemophilia.htm
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HHT.org - What is HHT Source: www.hht.org http://www.hht.org/web/what_is_hht/overview.asp
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MedlinePlus: Bleeding Disorders Source: www.nlm.nih.gov http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html
•
NORD - National Organization for Rare Disorders, Inc. Source: www.rarediseases.org http://www.rarediseases.org/search/rdblist.html?query_start=501
•
Women, Hereditary Blood Disorders, DD, NCBDDD, CDC Source: www.cdc.gov http://www.cdc.gov/ncbddd/hbd/women.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 hemophilia. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://health.nih.gov/index.asp. Under Search Health Topics, type hemophilia (or synonyms) into the search box, and click Search. NORD (The National Organization of Rare Disorders, Inc.) NORD provides an invaluable service to the public by publishing short yet comprehensive guidelines on over 1,000 diseases. NORD primarily focuses on rare diseases that might not be covered by the previously listed sources. NORD’s Web address is http://www.rarediseases.org/. A complete guide on hemophilia can be purchased from NORD for a nominal fee. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
Family Village: http://www.familyvillage.wisc.edu/specific.htm
•
Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
•
Med Help International: http://www.medhelp.org/HealthTopics/A.html
•
Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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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 hemophilia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with hemophilia. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about hemophilia. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://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 hemophilia (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://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. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type hemophilia (or a synonym) into the search box, and click Submit Query.
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Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families27: •
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
27
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 hemophilia: •
Basic Guidelines for Hemophilia Christmas disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000539.htm Hemophilia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000537.htm Hemophilia - resources Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002204.htm Hemophilia A Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000538.htm Hemophilia B Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000539.htm
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•
Signs & Symptoms for Hemophilia Bleeding disorder Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001304.htm Bleeding disorders Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001304.htm Blood in the urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003138.htm Bruising Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Hematomas Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Hematuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003138.htm Nosebleed - symptom Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003106.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm
•
Diagnostics and Tests for Hemophilia Bleeding time Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003656.htm Factor I Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003650.htm Fibrinogen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003650.htm Partial thromboplastin time Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003653.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm Prothrombin time Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm PT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm
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PTT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003653.htm Serum factor IX Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003679.htm Serum factor VIII antigen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003678.htm •
Nutrition for Hemophilia Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm Vitamin K Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002407.htm
•
Surgery and Procedures for Hemophilia Synovectomy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002972.htm
•
Background Topics for Hemophilia Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Hemophilia - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002204.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Intrauterine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002389.htm Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.htm X-linked recessive Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002051.htm
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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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HEMOPHILIA 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] Ablate: In surgery, is to remove. [NIH] Absenteeism: Chronic absence from work or other duty. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [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 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] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When
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transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] 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] 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] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] 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] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allo: A female hormone. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH]
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Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] 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] 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] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anergy: Absence of immune response to particular substances. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] 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] Animal Husbandry: The science of breeding, feeding, and care of domestic animals; includes housing and nutrition. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
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Anterograde: Moving or extending forward; called also antegrade. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidiuretic: Suppressing the rate of urine formation. [EU] Antifibrinolytic: Inhibiting fibrinolysis. [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] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] 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] Apheresis: Components plateletpheresis. [NIH]
being
separated
out,
as
leukapheresis,
plasmapheresis,
Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]
Apnea: A transient absence of spontaneous respiration. [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] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Argipressin: Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2, cyclic 1-6 disulfide. The usual
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mammalian antidiuretic hormone, it is a cyclic nonapeptide with arginine in position 8 of the chain. Argipressin is used to treat diabetes insipidus and as hemostatic because of its vasoconstrictor action. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthropathy: Any joint disease. [EU] Arthroplasty: Surgical reconstruction of a joint to relieve pain or restore motion. [NIH] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH]
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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 Physiology: Physiological processes and activities of bacteria. [NIH] Bacteriophage lambda: A temperate inducible phage and type species of the genus lambdalike Phages, in the family Siphoviridae. Its natural host is E. coli K12. Its virion contains linear double-stranded DNA, except for 12 complementary bases at the 5'-termini of the polynucleotide chains. The DNA circularizes on infection. [NIH] Bacteriophages: Viruses whose host is a bacterial cell. [NIH] Balloon Occlusion: Use of a balloon catheter to block the flow of blood through an artery or vein. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Bewilderment: Impairment or loss of will power. [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] 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] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Bioengineering: The application of engineering principles to the solution of biological problems, for example, remote-handling devices, life-support systems, controls, and displays. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to
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infection and disease. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bleeding Time: Duration of blood flow after skin puncture. This test is used as a measure of capillary and platelet function. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [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]
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Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Chloride: A salt used to replenish calcium levels, as an acid-producing diuretic, and as an antidote for magnesium poisoning. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are compared. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]
Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiological: Relating to the study of the heart. [EU] Cardiology: The study of the heart, its physiology, and its functions. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often
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of obscure or unknown etiology. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cecum: The beginning of the large intestine. The cecum is connected to the lower part of the small intestine, called the ileum. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell motility: The ability of a cell to move. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH]
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Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] 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] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Chest wall: The ribs and muscles, bones, and joints that make up the area of the body between the neck and the abdomen. [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] Chloroplasts: Plant cell inclusion bodies that contain the photosynthetic pigment chlorophyll, which is associated with the membrane of thylakoids. Chloroplasts occur in cells of leaves and young stems of higher plants. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] 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
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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 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] Cimetidine: A histamine congener, it competitively inhibits histamine binding to H2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrin output. It also blocks the activity of cytochrome P450. [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] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clonal Deletion: Removal, via cell death, of immature lymphocytes that interact with antigens during maturation. For T-lymphocytes this occurs in the thymus and ensures that mature T-lymphocytes are self tolerant. B-lymphocytes may also undergo clonal deletion. [NIH]
Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in
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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] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] 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] Complete remission: The disappearance of all signs of cancer. Also called a complete
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response. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] 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] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [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] Consumer Organizations: Organized groups of users of goods and services. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or
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clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Coumarins: Synthetic or naturally occurring substances related to coumarin, the deltalactone of coumarinic acid. Coumarin itself occurs in the tonka bean. The various coumarins have a wide range of proposed actions and uses including as anticoagulants, pharmaceutical aids, indicators and reagents, photoreactive substances, and antineoplastic agents. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] 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] Cytotoxic: Cell-killing. [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] 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] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide,
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from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demography: Statistical interpretation and description of a population with reference to distribution, composition, or structure. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] 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] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Desmopressin: A synthetic analog of the natural hormone 8-arginine vasopressin (argipressin). Its action is mediated by the vasopressin receptor V2. It has prolonged antidiuretic activity, but little pressor effects. It also modulates levels of circulating factor VIII and von Willebrand factor. [NIH] 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] Diathesis: A constitution or condition of the body which makes the tissues react in special
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ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Didanosine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. Didanosine is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA by binding to reverse transcriptase; ddI is then metabolized to dideoxyadenosine triphosphate, its putative active metabolite. [NIH] Dideoxyadenosine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is an inhibitor of HIV replication, acting as a chain-terminator of viral DNA by binding to reverse transcriptase. Its principal side effect is nephrotoxicity. In vivo, dideoxyadenosine is rapidly metabolized to didanosine (ddI) by enzymatic deamination; ddI is then converted to dideoxyinosine monophosphate and ultimately to dideoxyadenosine triphosphate, the putative active metabolite. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [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] 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] 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] 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] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject
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nor the person administering treatment knows which treatment any particular subject is receiving. [EU] 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] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectopic: Pertaining to or characterized by ectopia. [EU] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ejaculation: The release of semen through the penis during orgasm. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolytes: Substances that break up into ions (electrically charged particles) when they are dissolved in body fluids or water. Some examples are sodium, potassium, chloride, and calcium. Electrolytes are primarily responsible for the movement of nutrients into cells, and the movement of wastes out of cells. [NIH] 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] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Ellagic Acid: A fused four ring compound occurring free or combined in galls. Isolated from the kino of Eucalyptus maculata Hook and E. Hemipholia F. Muell. Activates Factor XII of the blood clotting system which also causes kinin release; used in research and as a dye. [NIH]
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] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [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]
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Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [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] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemics: A period of increased prevalence of a particular disease in a population. [NIH] 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
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lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroleukemia: Cancer of the blood-forming tissues in which large numbers of immature, abnormal red blood cells are found in the blood and bone marrow. [NIH] Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [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] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excrete: To get rid of waste from the body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] 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] Extraction: The process or act of pulling or drawing out. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] 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] Factor V: Heat- and storage-labile plasma glycoprotein which accelerates the conversion of prothrombin to thrombin in blood coagulation. Factor V accomplishes this by forming a complex with factor Xa, phospholipid, and calcium (prothrombinase complex). Deficiency of
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factor V leads to Owren's disease. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [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] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [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] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] 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] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH]
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Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [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] Gametogenesis: The first phase of sexual reproduction which involves the transforming of certain cells in the parent into specialized reproductive cells. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastrectomy: An operation to remove all or part of the stomach. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Acid: Hydrochloric acid present in gastric juice. [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 tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Duplication: It encodes the major envelope protein and includes all the specifications for HBsAg. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene 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]
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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] Gene-modified: Cells that have been altered to contain different genetic material than they originally contained. [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, 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] 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] Germ Layers: The three layers of cells comprising the early embryo. [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] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] 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] 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
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through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Guanine: One of the four DNA bases. [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] Haematoma: A localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel. [EU] Haematuria: Blood in the urine. [EU] Haemophilia: A haemorrhagic diathesis occurring in two main forms: 1. Haemophilia A (classic haemophilia, factor VIII deficiency), an X-linked disorder due to deficiency of coagulation factor VIII; 2. Haemophilia B (factor IX deficiency, Christmas disease), also Xlinked, due to deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but a different loci, and are characterized by subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] 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] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH]
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Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Behavior: Behaviors expressed by individuals to protect, maintain or promote their health status. For example, proper diet, and appropriate exercise are activities perceived to influence health status. Life style is closely associated with health behavior and factors influencing life style are socioeconomic, educational, and cultural. [NIH] Health Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [NIH] Health Promotion: Encouraging consumer behaviors most likely to optimize health potentials (physical and psychosocial) through health information, preventive programs, and access to medical care. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hemarthrosis: Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia. [NIH] Hematologist: A doctor who specializes in treating diseases of the blood. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [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] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells,
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cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhaging: A copious discharge of blood from the blood vessels. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparan Sulfate Proteoglycan: A substance released by astrocytes, which is critical in stopping nervous fibers in their tracks. [NIH] Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] 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] Heterodimer: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histology: The study of tissues and cells under a microscope. [NIH]
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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] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridoma: A hybrid cell resulting from the fusion of a specific antibody-producing spleen cell with a myeloma cell. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] 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] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] 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] Ileum: The lower end of the small intestine. [NIH] Iliac Artery: Either of two large arteries originating from the abdominal aorta; they supply blood to the pelvis, abdominal wall and legs. [NIH] Immune response: The activity of the immune system against foreign substances (antigens).
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[NIH]
Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH]
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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 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] 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] Induction therapy: Treatment designed to be used as a first step toward shrinking the cancer and in evaluating response to drugs and other agents. Induction therapy is followed by additional therapy to eliminate whatever cancer remains. [NIH] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
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] 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] Infuse: To pour (a liquid) into something. [EU] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer
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expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Integrase: An enzyme that inserts DNA into the host genome. It is encoded by the pol gene of retroviruses and also by temperate bacteriophages, the best known being bacteriophage lambda. EC 2.7.7.-. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-10: Factor that is a coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intramuscular injection: IM. Injection into a muscle. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravascular: Within a vessel or vessels. [EU]
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Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] Intussusception: A rare disorder. A part of the intestines folds into another part of the intestines, causing blockage. Most common in infants. Can be treated with an operation. [NIH]
Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isolated limb perfusion: A technique that may be used to deliver anticancer drugs directly to an arm or leg. The flow of blood to and from the limb is temporarily stopped with a tourniquet, and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the cancer occurred. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] 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
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regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] 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] Leptospirosis: Infections with bacteria of the genus Leptospira. [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]
Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [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] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Limb perfusion: A technique that may be used to deliver anticancer drugs directly to an arm or leg. The flow of blood to and from the limb is temporarily stopped with a tourniquet, and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the cancer occurred. [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] Lipid: Fat. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU]
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Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Regeneration: Repair or renewal of hepatic tissue. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Localized: Cancer which has not metastasized yet. [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] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] 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] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU]
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Malformation: A morphologic developmental process. [EU]
defect
resulting
from
an
intrinsically
abnormal
Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] 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] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [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] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane 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] 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] Menorrhagia: Excessive menstrual flow. [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 Processes: Conceptual functions or thinking in all its forms. [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] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the
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atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from 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] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] 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] Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [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 the learner is to imitate and make part of his repertoire. [NIH]
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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 Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [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] Monotherapy: A therapy which uses only one drug. [EU] 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] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Musculoskeletal System: Themuscles, bones, and cartilage of the body. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH]
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Mutagenic: Inducing genetic mutation. [EU] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplastic Syndromes: Conditions in which the bone marrow shows qualitative and quantitative changes suggestive of a preleukemic process, but having a chronic course that does not necessarily terminate as acute leukemia. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Needs Assessment: Systematic identification of a population's needs or the assessment of individuals to determine the proper level of services needed. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephropathy: Disease of the kidneys. [EU] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord.
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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] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [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] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear 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] 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] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncology: The study of cancer. [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as
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codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] 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] Orthopaedic: Pertaining to the correction of deformities of the musculoskeletal system; pertaining to orthopaedics. [EU] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteotomy: The surgical cutting of a bone. [EU] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] P-32: A radioactive form of phosphorus used in the treatment of cancer. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH]
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Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paradoxical: Occurring at variance with the normal rule. [EU] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Partial Thromboplastin Time: Test of the intrinsic (factors VIII, IX, XI, and XII) and common (fibrinogen, prothrombin, factors V and X) pathways of coagulation in which a mixture of plasma and phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides) is recalcified and the time required for the appearance of fibrin strands measured. Activation may be provided by contact with the glass tube or exposure to activators (e.g., ellagic acid, particulate silicates such as diatomaceous earth or kaolin) before addition of the calcium chloride. It is used as a screening test and to monitor heparin therapy. [NIH] Particle: A tiny mass of material. [EU] Parvovirus: A genus of the family Parvoviridae, subfamily Parvovirinae, infecting a variety of vertebrates including humans. Parvoviruses are responsible for a number of important diseases but also can be non-pathogenic in certain hosts. The type species is mice minute virus. [NIH] 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] Patient Advocacy: Promotion and protection of the rights of patients, frequently through a legal process. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Patient Satisfaction: The degree to which the individual regards the health care service or product or the manner in which it is delivered by the provider as useful, effective, or beneficial. [NIH] 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
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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] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Pepsin A: Formed from pig pepsinogen by cleavage of one peptide bond. The enzyme is a single polypeptide chain and is inhibited by methyl 2-diaazoacetamidohexanoate. It cleaves peptides preferentially at the carbonyl linkages of phenylalanine or leucine and acts as the principal digestive enzyme of 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] 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] Pericarditis: Inflammation of the pericardium. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously 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] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that
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of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU]
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Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] 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 Count: A count of the number of platelets per unit volume in a sample of venous blood. [NIH] Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Pneumonia: Inflammation of the lungs. [NIH] Pneumothorax: Accumulation of air or gas in the space between the lung and chest wall, resulting in partial or complete collapse of the lung. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyarteritis Nodosa: A form of necrotizing vasculitis involving small- and medium-sized arteries. The signs and symptoms result from infarction and scarring of the affected organ system. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides,
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proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] 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] Postpartum Hemorrhage: The presence of abnormal uterine bleeding immediately after labor or childbirth. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Diagnosis: Determination of the nature of a pathological condition or disease in the postimplantation embryo, fetus, or pregnant female before birth. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Progeny: The offspring produced in any generation. [NIH] Program Evaluation: Studies designed to assess the efficacy of programs. They may include the evaluation of cost-effectiveness, the extent to which objectives are met, or impact. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] 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]
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Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propiolactone: Disinfectant used in vapor form to sterilize vaccines, grafts, etc. The vapor is very irritating and the liquid form is carcinogenic. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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 Folding: A rapid biochemical reaction involved in the formation of proteins. It begins even before a protein has been completely synthesized and proceeds through discrete intermediates (primary, secondary, and tertiary structures) before the final structure (quaternary structure) is developed. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
Prothrombin Time: Measurement of clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen, prothrombin, and factors V, VII, and X. It is used for monitoring anticoagulant therapy with coumarins. [NIH] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] 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] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pseudogenes: Genes bearing close resemblance to known genes at different loci, but
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rendered non-functional by additions or deletions in structure that prevent normal transcription or translation. When lacking introns and containing a poly-A segment near the downstream end (as a result of reverse copying from processed nuclear RNA into doublestranded DNA), they are called processed genes. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
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 Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] 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
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radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] 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] 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] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [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] 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
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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] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Ribavirin: 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [NIH] 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] Rituximab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [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] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the
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elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] 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] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
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]
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Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin graft: Skin that is moved from one part of the body to another. [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]
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 promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of 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] 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]
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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] Splenectomy: An operation to remove the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Stabilization: The creation of a stable state. [EU] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [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] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
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] Strained: A stretched condition of a ligament. [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] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU]
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Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subcapsular: Situated below a capsule. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] 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] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Tamponade: The inserting of a tampon; a dressing is inserted firmly into a wound or body cavity, as the nose, uterus or vagina, principally for stopping hemorrhage. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH]
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Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] 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] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [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]
Thrombophilia: A disorder of hemostasis in which there is a tendency for the occurrence of thrombosis. [NIH] Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Thrombopoietin: A humoral factor that controls blood platelet production through stimulation of megakaryocyte populations. Bone marrow megakaryocytes increase in both size and number in response to exposure to thrombopoietin. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] 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] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired
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drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Tourniquet: A device, band or elastic tube applied temporarily to press upon an artery to stop bleeding; a device to compress a blood vessel in order to stop bleeding. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]
Translating: Conversion from one language to another language. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual,
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between individuals of the same species, or between individuals of different species. [NIH] Transposase: An enzyme that binds to single-stranded DNA. It is thought to recognize the repetitive ends of a transposon and to participate in the cleavage of the recipient site into which the new transposon copy inserts. EC 2.7.7.-. [NIH] Transposons: Discrete genetic elements capable of inserting, in a non-permuted fashion, into the chromosomes of many bacteria. [NIH] Trans-Splicing: The joining of RNA from two different genes. One type of trans-splicing is the "spliced leader" type (primarily found in protozoans such as trypanosomes and in lower invertebrates such as nematodes) which results in the addition of a capped, noncoding, spliced leader sequence to the 5' end of mRNAs. Another type of trans-splicing is the "discontinuous group II introns" type (found in plant/algal chloroplasts and plant mitochondria) which results in the joining of two independently transcribed coding sequences. Both are mechanistically similar to conventional nuclear pre-mRNA cis-splicing. Mammalian cells are also capable of trans-splicing. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trauma Centers: Specialized hospital facilities which provide diagnostic and therapeutic services for trauma patients. [NIH] 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]
Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] 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
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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 specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Umbilical cord blood: Blood from the placenta (afterbirth) that contains high concentrations of stem cells needed to produce new blood cells. [NIH] Umbilical cord blood transplantation: The injection of umbilical cord blood to restore an individual's own blood production system suppressed by anticancer drugs, radiation therapy, or both. It is being studied in the treatment of cancer and severe blood disorders such as aplastic anemia. Cord blood contains high concentrations of stem cells needed to produce new blood cells. [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]
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] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] 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] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [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] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives
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oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Function: The hemodynamic and electrophysiological action of the ventricles. [NIH]
Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] 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 Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viral Proteins: Proteins found in any species of virus. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] 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] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Walkers: Walking aids generally having two handgrips and four legs. [NIH] Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [NIH] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [NIH] Weight-Bearing: The physical state of supporting an applied load. This often refers to the
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weight-bearing bones or joints that support the body's weight, especially those in the spine, hip, knee, and foot. [NIH] Wheelchairs: Chairs mounted on wheels and designed to be propelled by the occupant. [NIH]
White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] 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] Zalcitabine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chainterminator of viral DNA by binding to reverse transcriptase. Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy. [NIH] Zidovudine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIVinduced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [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]
255
INDEX 3 3-dimensional, 149, 180, 198 A Abdomen, 198, 204, 207, 216, 226, 229, 236, 237, 244, 247, 253 Abdominal, 198, 223, 226, 231, 235, 237, 244 Ablate, 33, 214 Absenteeism, 109 Acetylcholine, 234 Acid, 200, 214, 218 Acute leukemia, 233 Acute renal, 222 Adaptability, 206 Adaptation, 73, 93 Adenine, 143, 198, 242 Adenosine, 144, 198, 238 Adenosine Triphosphate, 144, 198, 238 Adenovirus, 176 Adipocytes, 84 Adjustment, 198 Administration, iv, 12, 50, 125, 176, 177, 184 Adolescence, 129, 198 Adoptive Transfer, 31 Adrenal Cortex, 211 Adverse Effect, 25, 245 Aerobic, 231 Affinity, 43, 65, 199, 202 Airway, 28, 246 Albumin, 109, 199, 235, 238 Algorithms, 204 Alimentary, 236 Alkaline, 205 Alleles, 69, 162 Allergen, 212 Allo, 13, 85 Allogeneic, 67 Allylamine, 200 Alpha Particles, 199, 242 Alpha-1, 29, 158, 162 Alpha-fetoprotein, 217 Alternative medicine, 209 Amine, 222 Amino Acid Sequence, 201, 216, 219 Amino Acid Substitution, 221 Amino acids, 145, 149, 155, 200, 208, 219, 235, 237, 240, 241, 244, 245, 250
Amino Acids, 145, 149, 155, 200, 208, 219, 235, 237, 240, 241, 244, 245, 250 Ammonia, 200 Amnion, 200 Amniotic Fluid, 117, 171, 173, 200 Amygdala, 203, 248 Anaesthesia, 225 Analog, 212 Analogous, 250 Anaphylatoxins, 209 Anatomical, 207, 225, 236, 244 Anemia, 40, 157, 158, 161, 162, 167, 187, 201, 248, 254 Anergy, 33 Anesthesia, 199 Aneuploidy, 156 Animal Husbandry, 43 Animal model, 19, 23, 26, 28, 30, 32, 33, 35, 40, 42, 45, 47, 61, 62, 63, 68 Anions, 199, 227 Annealing, 239 Anode, 200 Anterior chamber, 227 Anterograde, 37 Antibacterial, 246 Antibiotic, 246 Antibodies, 13, 14, 16, 19, 23, 24, 26, 32, 33, 35, 37, 40, 41, 43, 44, 47, 62, 66, 67, 86, 100, 106, 126, 201, 220, 224, 238, 244 Antibody, 13, 14, 16, 23, 31, 33, 35, 42, 43, 65, 66, 79, 87, 94, 113, 126, 199, 201, 209, 216, 220, 223, 224, 225, 232, 243, 244, 246 Anticoagulant, 98, 241, 253 Anticoagulants, 66, 211 Antidiuretic, 202, 212 Antidote, 205 Antifibrinolytic, 71 Antigen, 23, 31, 32, 33, 35, 125, 126, 127, 196, 199, 201, 209, 223, 224, 225 Antigen-Antibody Complex, 209 Antigens, 31, 35, 92, 201, 202, 208, 223, 224, 226, 246, 253 Antilymphocyte Serum, 229 Antimetabolite, 244 Antineoplastic, 211 Antineoplastic Agents, 211 Antiviral, 226, 244 Anuria, 227 Anus, 204, 209
256
Hemophilia
Aorta, 14, 223, 253 Apheresis, 15 Aplastic anemia, 18, 252 Apnea, 246 Apolipoproteins, 228 Apoptosis, 15, 144, 153 Aqueous, 38, 203, 211, 228 Archaea, 231 Arginine, 202, 212, 223, 251 Argipressin, 212 Arterial, 64, 102, 202, 223, 241 Arteries, 201, 202, 204, 210, 223, 229, 233, 239, 252 Arteriolar, 205 Arterioles, 204, 205 Arteriosus, 242 Arteriovenous, 83, 108 Artery, 13, 112, 202, 203, 214, 215, 217, 242, 250 Arthropathy, 22, 51, 55 Arthroplasty, 97 Ascorbic Acid, 223 Aseptic, 235 Aspiration, 217 Assay, 24, 43, 70, 100, 107, 224 Astigmatism, 243 Astringents, 231 Astrocytes, 202, 222 Asymptomatic, 115 Ataxia, 186, 202, 248 Atrial, 202, 253 Atrial Fibrillation, 253 Atrium, 202, 253 Atrophy, 186 Atypical, 166 Autoantibodies, 13, 66, 202 Autoantigens, 202 Autoimmune disease, 232 Autologous, 15, 62 Autonomic Nervous System, 237 Autosuggestion, 223 Axons, 235 B Bacteria, 142, 150, 154, 201, 203, 214, 215, 216, 217, 228, 231, 239, 245, 246, 250, 251, 252 Bacterial Infections, 207 Bacterial Physiology, 198 Bacteriophage lambda, 226 Bacteriophages, 226 Bacterium, 222 Balloon Occlusion, 30
Barbiturates, 242 Basal Ganglia, 202, 203 Basal Ganglia Diseases, 202 Base, 60, 65, 68, 91, 143, 144, 147, 149, 153, 154, 155, 178, 198, 205, 211, 212, 218, 219, 227, 228, 239, 248 Base Sequence, 154, 218, 219 Basement Membrane, 216, 228 Basophils, 220 Benign, 220, 233, 236 Beta Rays, 214 Bewilderment, 210 Bile, 203, 223, 229 Bile Acids, 203 Bile Acids and Salts, 203 Bilirubin, 199 Binding Sites, 57 Biochemical, 23, 29, 34, 39, 49, 56, 57, 64, 158, 199, 201, 217, 227, 241 Bioengineering, 14, 17 Biological response modifier, 226 Biopsy, 34, 37 Biosynthesis, 22, 43, 245 Biotechnology, 178 Bladder, 210, 232, 233, 241, 252 Blastocyst, 210, 238 Bleeding Time, 15 Blood Coagulation, 14, 24, 38, 43, 57, 64, 127, 204, 205, 216, 249 Blood Coagulation Factors, 204 Blood Glucose, 221 Blood Platelets, 230, 249 Blood pressure, 161, 206, 223, 232 Blood urea, 227 Blood vessel, 165, 204, 206, 207, 210, 214, 215, 220, 221, 222, 227, 229, 231, 237, 238, 246, 247, 248, 249, 250, 252 Blood Vessels, 165, 206, 207, 215, 221, 222, 229, 231, 238, 246, 248, 252 Body Fluids, 205, 214 Body Mass Index, 235 Bone Marrow, 18, 20, 177, 198, 201, 204, 216, 219, 220, 224, 229, 230, 232, 233, 247, 254 Bone Marrow Cells, 230 Bone Marrow Transplantation, 20 Bowel, 204, 226, 233, 237, 247 Bowel Movement, 247 Brachytherapy, 243 Bradykinin, 238 Brain Hypoxia, 248 Brain Neoplasms, 248
Index 257
Breeding, 43, 200 Bronchi, 205, 250 Bronchial, 222 Buccal, 171, 173, 205 Bypass, 16, 125 C Caffeine, 242 Calcium, 205, 209, 214, 216, 236, 241 Calcium Chloride, 236 Callus, 215 Canonical, 69 Capillary, 27, 45, 204, 205, 253 Capillary Permeability, 205 Capsid, 27, 31, 33, 42, 48 Carbohydrate, 219, 240, 245 Carbohydrates, 205, 206 Carbon Dioxide, 211, 238, 243, 252 Carcinogenic, 225, 234, 240, 241 Carcinogens, 234 Carcinoma, 205, 208 Cardiac, 85, 202 Cardiological, 102 Cardiology, 134 Cardiomyopathy, 85 Cardiovascular, 24, 180 Cardiovascular disease, 24, 180 Carrier Proteins, 238 Case report, 81, 96, 98, 108, 115 Catabolism, 57 Catalytic Domain, 19 Catheter, 13, 30, 103, 203 Catheters, 30 Cathode, 206, 214 Cations, 227 Caudal, 240 Caudate Nucleus, 203 Causal, 80, 245 Cause of Death, 211 Cecum, 96, 206, 228 Cell Count, 80 Cell Cycle, 152, 153 Cell Death, 153, 201, 208, 233 Cell Differentiation, 247 Cell Division, 145, 152, 153, 165, 166, 186, 203, 206, 207, 230, 231, 238, 245 Cell membrane, 206, 214, 238 Cell motility, 222 Cell proliferation, 226 Cell Respiration, 231, 243 Cell Size, 217 Cell Transplantation, 34, 67 Cellular Structures, 232
Central Nervous System, 207, 218, 220, 232, 235 Central Nervous System Infections, 220 Centromere, 145, 148 Cerebellar, 202, 243 Cerebellar Diseases, 202 Cerebellum, 207, 243 Cerebral, 202, 203, 207, 216 Cerebral Cortex, 202, 216 Cerebral hemispheres, 203, 207 Cerebrovascular, 203, 206, 248 Cerebrovascular Disorders, 248 Cerebrum, 207, 251 Character, 212 Chemotactic Factors, 209 Chest wall, 239 Chiasma, 211 Chin, 230 Chlorophyll, 207 Chloroplasts, 251 Cholera, 245 Cholesterol, 144, 203, 211, 228, 229, 230 Cholesterol Esters, 228 Choroid, 244, 252 Chromatin, 201, 215, 229, 247 Chromosomal, 44, 153, 155, 166, 167, 168, 170, 200, 207, 223, 232, 239, 248 Chromosomal Proteins, Non-Histone, 207 Chromosome, 3, 29, 60, 145, 146, 147, 148, 149, 152, 153, 155, 156, 162, 163, 166, 167, 172, 175, 200, 207, 220, 227, 228, 232, 245, 248, 251 Chromosome Fragility, 251 Chronic, 17, 30, 43, 47, 50, 51, 55, 56, 58, 93, 186, 208, 213, 215, 225, 227, 233, 239, 247 Chronic Disease, 50, 56, 58 Chronic renal, 239 Chylomicrons, 228 Ciliary, 252 Ciliary Body, 252 Cimetidine, 111 Cirrhosis, 34, 221 CIS, 21, 39, 208, 218, 219, 251 C-kit receptor, 247 Clear cell carcinoma, 212 Clinical Medicine, 179, 240 Clinical trial, 12, 17, 18, 22, 24, 26, 28, 30, 31, 32, 33, 43, 44, 46, 47, 48, 49, 52, 58, 61, 63, 66, 68, 83, 101, 176, 177, 180, 183, 210, 213, 237, 241, 243
258
Hemophilia
Clinical Trials, 12, 17, 18, 22, 26, 28, 30, 31, 43, 46, 47, 49, 52, 66, 68, 83, 176, 177, 180, 183, 237 Clonal Deletion, 23, 33, 208 Cloning, 42, 204, 225 Coagulation, 14, 17, 24, 26, 27, 31, 33, 38, 44, 45, 48, 49, 52, 53, 56, 61, 62, 63, 64, 65, 66, 67, 68, 69, 74, 79, 84, 95, 113, 115, 116, 126, 127, 220, 222, 236, 238, 253 Codon, 150, 208, 219 Codon, Terminator, 208 Codons, 208, 219, 235 Cofactor, 64, 65, 241, 249 Collagen, 68, 203, 209, 217, 240 Collapse, 239, 246 Colloidal, 199 Colon, 21, 29, 86, 159, 186, 209, 228 Colonoscopy, 161 Complement, 209, 219, 227, 238 Complementary medicine, 116 Complete remission, 243 Complete response, 210 Compliance, 55, 59, 130, 210 Compress, 250 Computational Biology, 183, 185 Concentric, 234 Conception, 152, 210, 217, 246 Confounding, 24 Confusion, 159, 213, 252 Congestion, 127 Conjugated, 211 Connective tissue, 204, 209, 210, 217, 218, 229, 231, 247 Connective Tissue, 204, 209, 210, 217, 218, 229, 231, 247 Connective Tissue Cells, 210 Consciousness, 212, 213 Constriction, 145, 148, 227 Consultation, 49, 51, 53, 59, 167, 168, 171, 172 Consumer Organizations, 37 Contamination, 222 Continuous infusion, 23, 95, 106 Contraceptive, 63 Contraindications, ii Contralateral, 243 Control group, 240 Conus, 242 Coordination, 50, 56, 232 Cornea, 244, 247, 252 Corneum, 216 Coronary, 13, 71, 112, 206, 210, 233
Coronary heart disease, 206 Coronary Thrombosis, 233 Corpus, 253 Cortical, 245, 248 Cortisol, 199 Coumarin, 211 Coumarins, 211, 241 Cranial, 211, 220, 235, 237 Cranial Nerves, 211 Craniocerebral Trauma, 203, 220, 248 Creatinine, 227 Cricoid Cartilage, 254 Crossing-over, 243 Curative, 40, 44, 63, 249 Cyanosis, 221 Cyclic, 201 Cytochrome, 208, 235 Cytokine, 34 Cytokines, 47, 224 Cytomegalovirus, 79 Cytoplasm, 142, 143, 144, 150, 201, 203, 206, 215, 229, 232, 234, 244 Cytosine, 143, 242 Cytotoxic, 93, 224 D Data Collection, 37, 49, 51, 53, 54, 55, 56, 58 De novo, 25, 87, 153 Deamination, 213 Death Certificates, 161 Decarboxylation, 222 Decidua, 212, 238 Degenerative, 222 Dehydration, 207 Deletion, 29, 31, 107, 155, 201, 218 Dementia, 156 Demography, 137 Denaturation, 239 Dendrites, 233 Dendritic, 230 Dental Care, 121 Deoxyribonucleic, 143, 244 Deoxyribonucleic acid, 143, 244 Deoxyribonucleotides, 212 DES, 115 Desensitization, 224 Desmopressin, 96, 97, 127 Deuterium, 223 Developing Countries, 75, 78, 84, 92, 101 Diabetes Insipidus, 202 Diabetes Mellitus, 221 Diabetic Retinopathy, 238
Index 259
Diagnostic procedure, 124 Dialyzer, 221 Diastolic, 223 Diastolic pressure, 223 Diathesis, 14, 20, 24, 26, 47, 62, 220 Didanosine, 213 Dideoxyadenosine, 213 Digestion, 199, 203, 204, 226, 229, 247, 252 Digestive tract, 246 Dilation, 205 Diploid, 200, 232, 238, 251 Direct, iii, 12, 14, 23, 24, 37, 50, 51, 60, 85, 171, 172, 173, 208, 229, 243 Discrete, 241 Discrimination, 173, 174, 179 Disease Progression, 34, 47, 51, 55, 76, 83, 253 Diseases, 22, 72, 76, 78, 82, 99, 100, 114, 132, 133, 137, 182, 190, 191, 192, 193, 194, 203, 248 Disorientation, 210 Dissociation, 60, 199 Dissociative Disorders, 213 Distal, 37, 101, 237, 241 Diuretic, 205 Dopamine, 234 Dorsal, 240 Dose-dependent, 30, 254 Drug Resistance, 214 Drug Tolerance, 250 Duct, 216, 229, 244 Duodenum, 203, 247 Dyes, 203, 217 Dysplasia, 187 Dystrophy, 29, 38, 186 E Ectopic, 29, 61 Effector, 209 Efficacy, 18, 20, 21, 22, 25, 26, 27, 28, 30, 31, 35, 36, 37, 40, 41, 44, 46, 48, 50, 52, 55, 56, 63, 67, 79, 81, 85, 90, 93, 99, 125, 214, 240 Ejaculation, 245 Elastic, 250 Elastin, 25, 209 Elective, 56 Electrocoagulation, 208 Electrolysis, 200, 206 Electrolyte, 228 Electrolytes, 203, 227 Electrons, 203, 214, 227, 242 Electroporation, 68, 214
Elementary Particles, 214, 234, 241 Ellagic Acid, 236 Emboli, 253 Embolism, 253 Embolization, 253 Embolus, 225 Embryo, 152, 153, 154, 162, 200, 204, 206, 215, 219, 225, 240, 252 Embryogenesis, 29, 215, 247 Emollient, 219 Emphysema, 25 Encephalocele, 233 Endemic, 207, 247 Endogenous, 21, 60, 61, 125 Endometrium, 212 Endorphins, 234 Endothelial cell, 12, 15, 16, 62, 69, 249 Endothelial cells, 12, 15, 16, 62, 69, 249 Endothelium, 16, 215 Endothelium, Lymphatic, 215 Endothelium, Vascular, 215 Endotoxin, 251 Endotoxins, 209 End-stage renal, 208, 239 Enhancer, 44 Enkephalins, 234 Enteropeptidase, 251 Environmental Exposure, 234 Environmental Health, 182, 183 Enzymatic, 38, 205, 206, 209, 213, 217, 222, 230, 239 Enzyme, 27, 38, 45, 80, 144, 206, 215, 219, 226, 237, 238, 239, 241, 248, 249, 250, 251, 253, 254 Enzyme Inhibitors, 238 Enzymes, 144, 154, 199, 217, 233, 235, 241 Eosinophils, 220 Epidemic, 247 Epidemics, 17 Epidermal, 253 Epidermis, 242 Epigastric, 235 Epinephrine, 234 Epithelial, 212, 216, 222, 228, 236 Epithelial Cells, 216, 222, 228 Epithelium, 203, 215, 227, 236 Epitope, 13, 93 Erythrocytes, 200, 204, 216, 243 Erythroleukemia, 40 Esophagus, 213, 247 Essential Tremor, 186 Ethnic Groups, 167, 170
260
Hemophilia
Eukaryotic Cells, 235 Evoke, 247 Excitation, 216, 217, 234 Excrete, 201, 227 Exocrine, 235 Exogenous, 126, 215, 216 Exon, 29, 81, 84 Exons, 61, 216 Expiration, 243 External-beam radiation, 242 Extracellular, 202, 210, 216, 217 Extracellular Matrix, 210, 217 Extracellular Space, 216 Extraction, 98 Extravasation, 221 Eye Color, 154 Eye Infections, 198 F Family Planning, 183 Fast Neutrons, 234 Fat, 204, 211, 214, 215, 232, 235, 246 Fathers, 162 Fats, 203, 207, 217 Fatty acids, 199, 219 Feces, 247 Femoral, 37 Femoral Artery, 37 Femur, 217 Fetoprotein, 30, 199 Fetus, 42, 170, 171, 173, 177, 199, 217, 224, 238, 240, 247, 252 Fibrin, 48, 64, 100, 204, 217, 236, 249 Fibrinogen, 217, 236, 238, 241, 249 Fibrinolysis, 80, 201 Fibroblasts, 93, 226 Fibrosis, 34, 154, 157, 161, 162, 187, 244 Filtration, 227 Flatus, 218 Flow Cytometry, 17, 43 Fluorescence, 217 Fluorescent Dyes, 217 Fold, 43, 57, 65, 126, 231 Foramen, 207, 237 Forearm, 204 Frameshift, 87, 155 Frameshift Mutation, 155 Free Radicals, 213 G Gallbladder, 198 Gametogenesis, 29 Gamma Rays, 242 Ganglia, 233, 237
Gangrenous, 245 Gas, 205, 223, 239, 252 Gas exchange, 252 Gastrectomy, 104 Gastric, 208, 218, 222, 237 Gastric Acid, 208 Gastrin, 208, 223 Gastrointestinal, 205, 247, 248 Gastrointestinal tract, 247 Gene Deletion, 33 Gene Duplication, 29 Gene Expression, 14, 20, 24, 28, 41, 44, 62, 63, 68, 150, 151, 187, 219 Gene Products, rev, 219 Gene-modified, 26 Genes, env, 161 Genetic Code, 234 Genetic Engineering, 204, 208 Genetic testing, 164, 168, 169, 170, 171, 172, 173, 174, 179, 239 Genetic transcription, 250 Genetics, 134, 142, 153, 154, 155, 157, 159, 160, 164, 167, 168, 169, 174, 177, 178, 179, 193, 232, 237 Genital, 208 Genomics, 180 Genotype, 56, 78, 99, 238 Germ Cells, 153, 177, 230, 235, 246, 247 Germ Layers, 69 Germline mutation, 153, 219, 222 Gestation, 237, 238 Gestational, 34 Gland, 229, 230, 235, 236, 241, 244, 247, 249 Globus Pallidus, 203 Glomerular, 227 Glomerular Filtration Rate, 227 Glucose, 20, 186, 212, 221 Glucose Intolerance, 212 Glucuronic Acid, 222 Glutamic Acid, 234, 240 Glycerol, 219, 238 Glycerophospholipids, 238 Glycine, 234, 245 Glycoprotein, 21, 216, 217, 228, 249, 251 Governing Board, 240 Government Agencies, 240 Grade, 17, 26, 220 Graft, 13, 16, 32, 224, 246 Graft Rejection, 224 Grafting, 225 Graft-versus-host disease, 32
Index 261
Granule, 15, 244 Granulocyte, 46 Granulocytes, 46, 220, 228, 254 Guanine, 143, 242 H Habitat, 234 Haematoma, 220 Haematuria, 220 Haemophilia, 81, 96, 220 Haemorrhage, 96 Hair Color, 154 Half-Life, 27, 46, 57, 64, 86 Haploid, 238 Haptens, 199 Headache, 134, 220, 221 Headache Disorders, 220 Health Behavior, 56, 221 Health Education, 138 Health Promotion, 54 Health Status, 59, 221 Heart attack, 63, 134, 206 Helminthiasis, 207 Hemarthrosis, 100 Hematologist, 18 Hematology, 18, 133, 134, 135 Hematoma, 91, 96, 108 Hematopoietic Stem Cells, 14, 35, 39, 40, 44 Hematopoietic tissue, 204 Hemicrania, 221 Hemochromatosis, 170, 190 Hemodialysis, 227, 228 Hemoglobin, 144, 200, 216, 221, 248 Hemoglobin M, 221 Hemoglobinopathies, 18, 219 Hemoglobins, 221 Hemoglobinuria, 186 Hemolytic, 248 Hemorrhage, 42, 98, 104, 116, 127, 211, 214, 220, 242, 247, 248 Hemorrhaging, 127 Hemostasis, 14, 24, 27, 30, 36, 45, 46, 62, 65, 68, 83, 126, 127, 137, 249 Heparan Sulfate Proteoglycan, 57 Heparin, 236 Hepatic, 19, 24, 30, 33, 35, 40, 61, 63, 67, 69, 98, 199, 229 Hepatitis, 17, 21, 34, 78, 82, 93, 113, 114, 125, 126, 127, 222, 253 Hepatocellular, 67 Hepatocyte, 16, 25, 67, 69 Hepatocyte Growth Factor, 25
Hepatocytes, 12, 21, 25, 27, 30, 33, 35, 44, 48, 60, 62, 69, 222 Hepatovirus, 222 Hereditary, 15, 36, 79, 142, 143, 153, 162, 168, 219, 222, 244, 248 Hereditary mutation, 153, 219, 222 Heredity, 145, 218, 219 Heterodimer, 65 Heterogeneity, 49, 199, 222 Histamine, 16, 208, 222 Histidine, 222 Histology, 43 Histones, 145, 207 Homologous, 29, 60, 199, 211, 219, 245 Hormonal, 202 Hormone, 150, 199, 202, 211, 212, 218, 223, 244, 249 Hormones, 150, 199, 219, 223, 235, 245 Horny layer, 216 Human papillomavirus, 29 Humoral, 31, 48, 66, 249 Humour, 223 Hybrid, 42, 43, 82, 84, 223 Hybridization, 232 Hybridoma, 76 Hybridomas, 214, 226 Hydrogen, 200, 203, 205, 212, 213, 223, 232, 234, 237, 241, 254 Hydrolysis, 240, 241, 251 Hydrophobic, 219, 228 Hydroxylysine, 209 Hydroxyproline, 209, 223 Hyperopia, 243 Hypersensitivity, 212, 244 Hypertension, 206 Hypnotic, 119 Hypotonic Solutions, 231 I Iatrogenic, 38, 58 Ileum, 206 Iliac Artery, 217, 252 Immune response, 14, 17, 24, 26, 27, 31, 32, 35, 40, 45, 47, 48, 57, 61, 64, 67, 103, 109, 115, 200, 201, 202, 220, 224, 248, 253 Immune Sera, 224 Immune system, 67, 223, 224, 229, 232, 252, 254 Immune Tolerance, 23, 31, 126 Immunity, 17, 33, 48, 58, 224, 250 Immunization, 53, 198, 224 Immunoassay, 34, 66
262
Hemophilia
Immunodeficiency, 21, 44, 73, 78, 79, 82, 84, 92, 99, 100, 109, 114, 120, 135, 186 Immunogenic, 14, 64, 66 Immunoglobulins, 238 Immunologic, 14, 31, 34, 35, 46, 58, 67, 198, 224, 254 Immunology, 91, 138, 199, 217 Immunosuppressant, 46 Immunosuppression, 17, 58, 67, 224 Immunosuppressive, 17, 19, 27, 48, 105, 224 Immunosuppressive Agents, 19, 224 Immunosuppressive therapy, 27, 48, 105, 224 Immunotherapy, 199, 212 Impairment, 17, 216, 225, 230 Implant radiation, 243 Implantation, 14, 71, 210 In vitro, 15, 22, 24, 25, 28, 57, 61, 65, 67, 71, 74, 219, 225, 249 In vivo, 15, 16, 20, 21, 22, 24, 25, 28, 29, 30, 31, 35, 39, 40, 44, 61, 62, 63, 64, 67, 69, 113, 125, 126, 219, 222, 225, 229 Incision, 227 Incubation, 228 Incubation period, 228 Induction, 13, 14, 23, 33, 35, 44, 82, 94 Induction therapy, 82 Infancy, 180 Infarction, 102, 233, 239 Infection, 33, 34, 46, 73, 74, 78, 82, 98, 99, 100, 105, 120, 135, 203, 204, 211, 220, 224, 225, 228, 229, 234, 244, 245, 248, 254 Infections, 17, 24, 114, 175, 201, 207, 223 Inflammation, 176, 199, 216, 217, 218, 252 Informed Consent, 171, 174, 179 Infuse, 27, 45 Infusion, 22, 23, 27, 32, 33, 44, 45, 113, 210, 225, 250 Ingestion, 239 Inhalation, 239 Initiation, 15, 24, 30, 63, 250 Insertional, 29 Insight, 58, 60, 96, 103 Insulator, 232 Integrase, 67 Interferon, 17, 82, 93, 226 Interferon-alpha, 226 Interferons, 226 Interleukin-1, 17, 34 Interleukin-10, 17, 34 Interleukin-2, 226
Interleukin-6, 34 Interleukins, 224 Internal Medicine, 221 Internal radiation, 243 Intestinal, 229 Intestine, 21, 204, 228, 246 Intestines, 198, 217, 218, 226, 227 Intracellular, 16, 20, 47, 65, 225, 230 Intracellular Membranes, 230 Intracranial Hemorrhages, 248 Intracranial Hypertension, 220 Intrahepatic, 17, 42 Intramuscular, 23, 33, 37, 220, 236 Intramuscular injection, 23, 37 Intraperitoneal, 39 Intravascular, 14, 26, 27, 37, 45 Intravenous, 16, 17, 21, 22, 42, 225, 236 Intrinsic, 27, 38, 45, 57, 64, 127, 199, 203, 236 Introns, 25, 227, 242, 251 Intussusception, 96 Invasive, 224, 229 Invertebrates, 251 Involuntary, 203, 216, 249 Ion Channels, 202 Ionizing, 199, 215 Ions, 38, 203, 213, 214, 223, 232, 241 Ipsilateral, 243 Iris, 210, 216, 227, 252 Ischemia, 68, 202 Isolated limb perfusion, 37 Isotonic, 231 K Kallidin, 205 Karyotype, 147 Karyotypes, 207 Kb, 45 Kidney Disease, 187 Kidney Failure, 156, 215, 227, 228 Kidney Failure, Acute, 227 Kidney Failure, Chronic, 227 Kidney Transplantation, 228 Kinetics, 26, 27, 45, 57, 90 L Labile, 209, 216 Laminin, 68, 203 Large Intestine, 206, 213, 226, 228, 243, 246 Larynx, 250 Lens, 253 Lenses, 243 Lentivirus, 39, 69 Leptospirosis, 65
Index 263
Lethal, 30 Leucine, 237 Leucocyte, 199 Leukapheresis, 201 Leukemia, 186, 198, 219 Leukopenia, 254 Life Expectancy, 44 Ligament, 241, 247 Ligaments, 210 Limb perfusion, 37, 227 Linkage, 113 Linkages, 58, 213, 221, 223, 237, 254 Lipid, 20, 125, 219, 228, 232 Lipoprotein, 228, 229 Liposome, 126 Liver, 17, 19, 20, 21, 24, 25, 26, 30, 32, 33, 34, 35, 38, 39, 41, 45, 47, 48, 57, 60, 62, 67, 68, 69, 70, 97, 99, 109, 112, 113, 125, 127, 151, 198, 199, 203, 208, 211, 217, 221, 222, 226, 229 Liver cancer, 199 Liver Regeneration, 69 Liver Transplantation, 19, 97, 99 Localized, 57, 220, 221, 225, 228, 238 Locomotion, 238 Low-density lipoprotein, 57, 228 Lucida, 228 Lymph, 33, 215, 223, 229 Lymph node, 33, 229 Lymph nodes, 33, 229 Lymphatic, 215, 225, 229, 231, 239, 247, 249 Lymphatic system, 229, 247, 249 Lymphocyte Depletion, 224 Lymphocytes, 17, 23, 32, 57, 112, 201, 208, 224, 226, 228, 229, 247, 249, 254 Lymphoid, 201, 228, 229 Lymphoma, 186 Lysine, 223, 251 Lytic, 245 M Macrophage, 153, 226 Magnetic Resonance Imaging, 84 Malabsorption, 186 Malformation, 83, 108 Malignancy, 58, 236 Malignant, 18, 186, 233 Malnutrition, 199, 202, 232 Mammary, 230 Mammography, 161 Mandible, 207 Mastitis, 245
Maximum Tolerated Dose, 214 Mediate, 30, 58 Mediator, 226 Medical Records, 161, 174 MEDLINE, 183 Megakaryocytes, 14, 16, 26, 204, 249 Meiosis, 152 Melanin, 227 Melanocytes, 230 Melanoma, 186, 251 Melanosomes, 230 Membrane, 13, 64, 85, 143, 200, 202, 207, 209, 216, 228, 230, 232, 234, 238, 240, 243, 244, 250, 253 Membrane Lipids, 238 Membranes, 205, 214, 230, 231, 234, 248 Memory, 32, 212, 230 Meninges, 207, 211 Menorrhagia, 56 Menstruation, 212 Mental, 166, 168, 170, 207, 210, 212, 230, 242, 244, 252 Mental Health, 242 Mental Processes, 213, 242 Mental Retardation, 166, 168, 170 Mentors, 18 Mercury, 217, 231 Mesencephalic, 243 Mesenchymal, 35 Mesenteric, 58 Mesentery, 231, 237 Meta-Analysis, 77 Metabolite, 213 Metastasis, 24 Metastasize, 244 Metastatic, 244 Mice Minute Virus, 236 Microbe, 250 Microbiology, 198, 202 Microglia, 202 Microorganism, 208, 236, 253 Micro-organism, 245 Microscopy, 43, 64, 203 Millimeter, 231 Minority Groups, 51 Miscarriage, 173 Mitochondria, 143, 144, 156, 162, 231, 251 Mitochondrial Swelling, 233 Mitosis, 152, 201 Modeling, 38, 44
206, 235,
236,
213,
235,
264
Hemophilia
Modification, 44, 66, 213, 219, 242, 254 Molecular, 19, 34, 38, 42, 44, 60, 96, 101, 103, 109, 111, 147, 149, 151, 183, 185, 187, 204, 210, 214, 217, 222, 232, 250, 251 Molecular Probes, 214 Molecular Structure, 39 Molecule, 35, 66, 127, 143, 144, 145, 150, 201, 203, 209, 213, 216, 223, 225, 232, 239, 243, 250, 252 Monitor, 19, 51, 52, 111, 234, 236 Monoclonal, 31, 43, 79, 113, 243, 244 Monocytes, 24, 226 Mononuclear, 17, 232, 251 Monophosphate, 213 Monosomy, 156, 200 Morphological, 19, 215, 230 Morphology, 221 Morula, 204 Mosaicism, 90, 153 Motility, 206 Motor Cortex, 243 Movement Disorders, 248 Mucosa, 232, 247 Multiple sclerosis, 35 Muscle Fibers, 37, 232 Muscular Atrophy, 186 Musculoskeletal System, 235 Mutagen, 233 Mutagenesis, 29, 44, 57 Mutagenic, 61 Mutagens, 218, 232 Mycoplasma, 207 Mycoplasma Infections, 207 Myelin, 232 Myelodysplastic Syndromes, 18 Myeloma, 223 Myeloproliferative Disorders, 18 Myocardial infarction, 253 Myocardium, 233 Myopia, 243 Myotonic Dystrophy, 165, 186, 251 N Nausea, 252 NCI, 208, 237 Necrosis, 127, 201, 225, 233 Needs Assessment, 53 Neonatal, 25, 27, 42, 48, 110 Neoplasia, 186 Neoplasm, 236 Neoplasms, 199, 205 Nephropathy, 227 Nervous System, 165, 207, 233, 237
Networks, 18, 31, 50, 52 Neural, 217, 223, 233 Neural tube defects, 217, 233 Neurodegenerative Diseases, 203 Neurons, 41, 212, 218 Neuropathy, 162, 237 Neurotransmitter, 198, 205, 220, 222, 234, 248 Neutrons, 199, 234, 242 Neutropenia, 46 Neutrophil, 25 Neutrophils, 234 Niacin, 251 Niche, 63 Nitrogen, 200, 227, 251 Norepinephrine, 234 Nuclear, 20, 143, 203, 214, 216, 218, 233, 234, 242, 251 Nuclear Envelope, 143, 234 Nuclear Pore, 234 Nuclear Proteins, 218, 234 Nuclei, 199, 214, 219, 223, 227, 229, 231, 234, 235, 241 Nucleic acid, 29, 203, 205, 211, 213, 219, 233, 242, 244, 254 Nucleic Acids, 203, 211, 233, 242, 244 Nucleus, 143, 144, 145, 150, 156, 175, 178, 201, 203, 207, 211, 215, 216, 229, 230, 232, 234, 241, 247, 248 Nurse Practitioners, 171 O Oliguria, 227 Oncogene, 186, 222, 234, 247 Oncogenic, 228 Oncology, 18, 133 Open Reading Frames, 228 Optic Chiasm, 235 Optic Nerve, 235, 243, 244 Organ Culture, 249 Organelles, 142, 143, 211, 230, 232, 239 Organizations, 73, 192, 210 Orgasm, 214 Orthopaedic, 139 Osmosis, 235 Osmotic, 199, 231 Osteotomy, 74 Outpatient, 68 Ovalbumin, 33 Ovaries, 170, 235, 245 Ovary, 247 Overdose, 115 Overweight, 51, 53, 59
Index 265
Ovum, 212, 219, 254 Oxidation, 211, 221 Oxidative Phosphorylation, 144 Oxygen Consumption, 243 Oxygenation, 85, 235 P P-32, 82 Palliative, 249 Palsy, 75 Pancreas, 21, 198, 221, 235, 236, 251 Pancreatic, 186 Pancreatic cancer, 186 Papilloma, 72 Papillomavirus, 29, 223 Paradoxical, 17 Parenchyma, 67 Parenteral, 17 Parietal, 237 Paroxysmal, 186, 221 Partial remission, 243 Partial response, 236 Partial Thromboplastin Time, 19 Particle, 125, 228, 250 Parvovirus, 96, 231 Paternity, 170 Pathogen, 15, 65, 92, 225 Pathologic, 201, 204, 210, 223 Pathologic Processes, 201 Pathophysiology, 17, 46 Patient Advocacy, 58 Patient Education, 36 Patient Satisfaction, 36 PDQ, 181, 237 Peduncle, 243 Pelvic, 241 Pelvis, 198, 223, 235, 237, 252 Penis, 214 Pepsin, 208 Pepsin A, 208 Peptide, 43, 237, 240, 241 Perfusion, 228, 237 Pericarditis, 77 Pericardium, 237 Perinatal, 112 Peripheral blood, 44, 57, 127, 226 Peripheral Nervous System, 234, 235, 237, 248 Peripheral Neuropathy, 254 Peripheral stem cells, 220, 237 Peritoneal, 226 Peritoneal Cavity, 226 Peritoneum, 231, 237, 244
Petechiae, 220 PH, 46 Pharmacokinetic, 18 Pharmacokinetics, 41 Pharmacologic, 31, 200, 220, 250 Phenotype, 19, 21, 23, 25, 27, 32, 37, 44, 45, 49, 56, 60, 62, 86, 218, 238 Phenotypes, 115 Phenylalanine, 237 Phospholipids, 38, 95, 217, 228, 230 Phosphorus, 205, 235, 238 Phosphorylation, 144 Photocoagulation, 208 Physical Examination, 168 Physiologic, 16, 204, 220, 238, 243 Physiology, 205, 221 Pigment, 203, 207, 230 Pigments, 239 Placenta, 24, 252 Plants, 205, 207, 219, 232, 250, 251 Plasma, 15, 18, 20, 22, 25, 34, 44, 49, 57, 60, 73, 94, 117, 125, 126, 127, 143, 199, 201, 206, 215, 216, 221, 222, 227, 228, 233, 236, 238, 239, 241, 245, 253 Plasma cells, 201, 233 Plasma protein, 60, 199, 215, 241 Plasmapheresis, 201 Plasmid, 25, 30, 32, 68, 105 Plasmids, 40, 68, 214 Plastids, 235 Platelet Activation, 43 Platelet Count, 46 Plateletpheresis, 201 Platelets, 12, 14, 15, 20, 26, 46, 64, 85, 86, 92, 239, 249 Plexus, 75 Pneumonia, 210 Pneumothorax, 74 Point Mutation, 19, 65 Poisoning, 132, 205, 231 Polyarteritis Nodosa, 76 Polycystic, 187 Polymerase, 77, 79, 239 Polymerase Chain Reaction, 77, 79 Polymers, 64 Polymorphism, 101, 172 Polypeptide, 200, 208, 217, 237, 248, 254 Polysaccharide, 201 Posterior, 202, 207, 227, 235, 244 Postnatal, 247 Postpartum Hemorrhage, 72 Post-translational, 65
266
Hemophilia
Post-traumatic, 221 Potassium, 214 Potentiates, 226 Practice Guidelines, 184 Precipitating Factors, 221 Preclinical, 18, 26, 41, 43, 45, 47, 48, 58, 63, 105, 131 Precursor, 16, 215, 241, 251 Prenatal, 75, 117, 170, 173, 215 Prenatal Diagnosis, 75, 117 Presynaptic, 234 Prevalence, 34, 97, 118, 158, 215 Primary endpoint, 240 Prion, 207 Progeny, 29, 41 Program Evaluation, 53 Progression, 17, 34, 41, 47, 82, 200 Progressive, 156, 208, 212, 227, 233, 239 Projection, 235, 243 Proline, 209, 223 Promoter, 12, 30, 40, 44, 47 Prone, 61, 156, 165 Prophylaxis, 42, 49, 52, 54, 55, 56, 63, 83, 99, 106, 253 Propiolactone, 74 Prospective study, 31 Prostate, 186 Protease, 38, 64, 91, 209 Protein Conformation, 200 Protein Folding, 60 Protein Kinases, 60 Proteoglycans, 203 Proteolytic, 38, 64, 74, 199, 209, 217 Prothrombin, 24, 31, 66, 79, 117, 136, 216, 236, 241, 249 Prothrombin Time, 24, 79 Protocol, 13, 17, 23, 31, 55, 68, 176 Protons, 199, 223, 242 Protozoa, 231 Protozoan, 207 Protozoan Infections, 207 Proximal, 75, 213 Pseudogenes, 29 Psychic, 230, 245 Psychology, 213 Public Health, 51, 52, 53, 55, 56, 59, 121 Public Policy, 183 Publishing, 191, 242 Pulmonary, 63, 204, 227, 242, 253 Pulmonary Artery, 204, 242, 253 Pulmonary Edema, 227 Pulmonary Embolism, 63, 253
Pulse, 232 Pupil, 210 Purines, 203, 245 Purpura, 31, 220 Putamen, 203 Pyogenic, 245 Pyrimidines, 203, 245 Q Quality, iv, 12, 184, 242 Quality of Life, 34, 51, 52, 53, 56, 59, 64, 82, 248 Quaternary, 241 R Race, 53, 227 Radiation, 63, 198, 215, 217, 218, 224, 242, 243, 251, 252, 254 Radiation therapy, 198, 243, 252 Radioactive, 220, 223, 225, 234, 235, 243 Radiography, 84 Radiolabeled, 15, 243 Radiotherapy, 243 Randomized, 31, 103, 214 Receptor, 13, 21, 33, 49, 57, 62, 159, 198, 201, 208, 212, 222, 243 Recessive gene, 44 Recombinant, 14, 17, 22, 23, 24, 25, 27, 30, 32, 37, 38, 41, 43, 44, 45, 48, 57, 60, 62, 64, 71, 77, 81, 86, 93, 94, 95, 98, 100, 106, 109, 110, 111, 113, 115, 116, 125, 126, 127, 243, 252 Recombinant Proteins, 14, 18, 27, 44, 45 Recombination, 29, 60, 219 Rectum, 201, 204, 209, 213, 218, 228, 241 Red blood cells, 216, 221 Red Nucleus, 202 Refer, 1, 148, 152, 159, 178, 205, 209, 234, 250 Refraction, 246 Refractory, 41, 44, 46, 108, 214 Regimen, 44, 62, 214 Remission, 108, 209, 236 Reproductive cells, 156, 166, 167, 218, 219, 222 Respiration, 201, 205, 232, 243 Retina, 39, 207, 235, 252, 253 Retinal, 235 Retinal Ganglion Cells, 235 Retinoblastoma, 158, 186 Retroperitoneal, 98 Retroviral vector, 35, 44, 79, 93, 219 Rheumatoid, 82 Rheumatoid arthritis, 82
Index 267
Rhinitis, 245 Ribavirin, 17, 31, 93 Ribonucleic acid, 150 Ribose, 198 Ribosome, 150, 250 Rigidity, 238 Risk factor, 24, 34, 55, 97, 241 Risk Factors, 34, 55, 97 Rituximab, 46, 72 S Saliva, 244 Salivary, 211, 236 Salivary glands, 211 Scatter, 252 Schizophrenia, 163 Sclera, 207, 252 Sclerosis, 159, 186, 232 Screening, 53, 61, 83, 85, 161, 170, 171, 173, 208, 236, 237 Secondary tumor, 231, 244 Secretion, 17, 22, 26, 44, 57, 60, 65, 208, 222, 223, 226, 245, 252 Secretory, 15, 65 Segregation, 243 Seizures, 236, 245 Self Care, 120 Semen, 35, 214, 241 Seminiferous tubule, 247 Seminiferous Tubules, 247 Sensibility, 200 Sensory loss, 248 Sepsis, 66 Septic, 66 Septicaemia, 245 Sequence Analysis, 43 Sequencing, 178, 239 Serine, 38, 100, 251 Serologic, 14, 34, 224 Serotonin, 234, 251 Serotypes, 26, 27, 37, 42, 48, 99 Serous, 215 Serum, 64, 198, 199, 209, 224, 227, 229, 245 Sex Characteristics, 198, 245 Sex Determination, 186 Shock, 66, 245, 251 Side effect, 125, 177, 180, 199, 213, 248, 250, 254 Side effects, 125, 177, 180, 248, 250 Signs and Symptoms, 164, 165, 170, 239, 243 Skeletal, 23, 26, 27, 37, 45, 71, 84 Skeleton, 217, 246
Skin graft, 68 Skull, 211, 233 Sleep apnea, 72 Small intestine, 108, 206, 223, 226, 251 Smooth muscle, 13, 222, 248 Social Environment, 242 Social Work, 131, 167 Sodium, 214 Soft tissue, 63, 127, 204, 246 Solvent, 65, 219, 235 Soma, 246 Somatic, 29, 153, 156, 167, 198, 215, 223, 230, 231, 237 Somatic cells, 29, 153, 156, 167, 230, 231 Somatic mutations, 156 Specialist, 171, 192 Species, 103, 123, 180, 199, 203, 207, 223, 227, 228, 230, 231, 232, 236, 242, 246, 248, 251, 253, 254 Specificity, 40, 76, 199 Spectrum, 111 Sperm, 152, 153, 156, 165, 166, 167, 170, 177, 207, 219, 222, 243, 246 Spermatozoa, 245 Spina bifida, 233 Spinal cord, 202, 207, 233, 237 Spinal Nerves, 237 Spinous, 215 Spleen, 16, 211, 223, 229, 247 Splenectomy, 46 Sporadic, 244 Sputum, 79 Stabilization, 64 Stem Cell Factor, 16, 208 Stem Cells, 34, 69, 237, 252 Stent, 13, 71 Steroid, 211 Stillbirth, 168 Stimulant, 222 Stimulus, 61, 216 Stomach, 198, 213, 218, 223, 237, 246, 247 Stool, 15, 209, 228 Strained, 50 Strand, 29, 143, 239 Stress, 60, 119, 211, 244 Stroke, 63, 161, 206 Stroma, 227, 236 Stromal, 74, 75, 204 Stromal Cells, 75, 204 Subacute, 225 Subarachnoid, 220 Subcapsular, 70
268
Hemophilia
Subclinical, 225, 245 Subcutaneous, 198, 218, 220, 236 Subspecies, 246 Substance P, 231, 245 Substrate, 29, 39, 206, 215 Support group, 120, 196 Supportive care, 237 Suppression, 31, 32, 33, 254 Suppurative, 218 Symphysis, 207, 241 Symptomatic, 127 Synaptic, 234 Synergistic, 249 System, 14, 28, 32, 34, 35, 40, 41, 44, 50, 53, 54, 56, 58, 61, 62, 68, 123, 125, 133, 184, 186, 187, 189, 190, 208, 209, 214, 215, 217, 224, 229, 234, 235, 237, 245, 247, 252 Systemic, 30, 47, 58, 201, 204, 225, 250, 253 Systolic, 223 T Tamponade, 75 Telangiectasia, 186 Telencephalon, 203, 207 Telomere, 220 Temporal, 221 Terminator, 213, 254 Thalamic, 202 Thalamic Diseases, 202 Thalamus, 248 Thalassemia, 18, 40 Theophylline, 242 Therapeutics, 16, 23 Thermal, 213, 234, 239 Thigh, 217 Thoracic, 229, 254 Threonine, 245 Threshold, 223 Thrombin, 48, 80, 216, 217, 241, 249 Thrombocytes, 239 Thrombocytopenia, 12, 14, 46, 92, 113 Thromboembolism, 18 Thrombomodulin, 241 Thrombophilia, 36, 37, 49, 50 Thromboplastin, 24, 195, 241 Thrombopoietin, 46, 249 Thrombosis, 36, 39, 98, 134, 138, 241, 247, 249 Thylakoids, 207 Thymus, 208, 224, 229, 249 Thyroid, 170, 249 Thyroid Gland, 170, 249 Thyroid Hormones, 249
Thyroxine, 199 Tic, 44 Tissue, 14, 16, 24, 28, 29, 33, 34, 37, 39, 41, 43, 62, 63, 65, 69, 125, 171, 173, 175, 198, 201, 202, 203, 204, 205, 208, 214, 215, 217, 218, 220, 221, 223, 224, 228, 229, 230, 231, 232, 233, 237, 238, 239, 241, 243, 244, 245, 246, 247, 249, 250, 254 Tissue Culture, 29 Tolerance, 13, 14, 23, 31, 32, 33, 35, 44, 94, 126, 127, 198 Tooth Preparation, 198 Torsion, 225 Tourniquet, 227, 228 Toxic, 19, 60, 142, 215, 224, 234, 250, 254 Toxicity, 12, 19, 24, 30, 45, 46, 58, 60, 61, 176, 231 Toxicology, 183 Toxin, 249 Toxins, 201, 225 Trachea, 249 Transcriptase, 213, 254 Transcription Factors, 20, 151 Transduction, 25, 26, 27, 28, 29, 30, 37, 41, 45, 58, 109 Transfection, 25, 43, 204, 214, 219 Transfer Factor, 224 Transfusion, 14, 18, 42, 46, 68 Transgenes, 22, 33, 44, 62 Translating, 28 Translation, 28, 29, 60, 150, 151, 218, 242 Translational, 38, 66, 240 Translocation, 29, 75, 207 Transmitter, 202 Transplantation, 31, 32, 40, 69, 85, 110, 208, 224, 229, 252 Transposase, 45, 63 Transposons, 44, 63 Trans-Splicing, 25, 28, 61, 251 Trauma, 14, 53, 63, 68, 140, 221, 233, 251 Trauma Centers, 68 Trinucleotide Repeat Expansion, 165 Trinucleotide Repeats, 251 Trisomy, 156, 200 Tropism, 43 Trypsin, 254 Tryptophan, 209 Tuberculosis, 79 Tuberous Sclerosis, 186 Tumor Necrosis Factor, 17 Tunica, 232
Index 269
U Ultraviolet radiation, 153 Umbilical Arteries, 252 Umbilical Cord, 87, 252 Umbilical cord blood, 87, 252 Umbilical cord blood transplantation, 87 Uracil, 242 Urea, 252 Uremia, 227 Urethra, 241, 252 Urinary, 234 Urine, 195, 201, 204, 220, 221, 227, 234, 252 Uterus, 170, 212, 235, 248, 252 Uvea, 252 Uveitis, 35 V Vaccine, 46, 241 Vaccines, 241, 253 Vacuoles, 235 Vagina, 212, 248 Vascular, 13, 20, 24, 37, 43, 55, 207, 215, 221, 225, 238, 249, 252 Vasculitis, 72, 239 Vasodilator, 205, 222 Vector, 12, 16, 19, 20, 21, 22, 26, 27, 28, 30, 33, 37, 40, 42, 43, 44, 45, 48, 58, 61, 62, 82, 84, 105, 114, 175, 176, 225, 244, 250, 253 Vein, 37, 202, 203, 227, 234, 252 Veins, 204, 239, 252, 253 Venous, 18, 58, 64, 76, 103, 113, 127, 134, 202, 239, 241, 253 Venous blood, 239 Venous Thrombosis, 64, 103, 253 Ventricle, 242, 252, 253 Ventricles, 253 Ventricular, 104 Ventricular Function, 104 Venules, 204, 205, 215 Vertebrae, 247 Veterinary Medicine, 183 Vibrio, 207 Vibrio cholerae, 207
Viral, 21, 27, 28, 29, 31, 33, 34, 37, 40, 44, 45, 46, 58, 62, 67, 69, 80, 88, 126, 175, 205, 213, 218, 219, 234, 250, 253, 254 Viral Hepatitis, 27, 45 Viral Load, 47, 80, 253 Viral Proteins, 67 Viral Regulatory Proteins, 218 Viral Structural Proteins, 218 Viral vector, 28, 40, 44, 62, 69, 88, 126 Virion, 203, 218 Virulence, 250 Virus, 14, 17, 21, 23, 25, 28, 32, 34, 43, 44, 57, 61, 72, 73, 76, 78, 79, 82, 84, 92, 99, 100, 109, 114, 118, 120, 125, 135, 175, 205, 207, 215, 219, 223, 226, 244, 250, 253 Viruses, 41, 150, 175, 198, 201, 216, 231, 244, 252, 253 Viscera, 231, 246 Visceral, 237 Vitreous, 244, 253 Vitreous Body, 244, 253 Vitro, 16, 24, 25, 67, 170, 222, 225, 239 Vivo, 16, 20, 21, 23, 24, 28, 32, 44, 62, 64, 67, 125, 126, 213, 225, 229 Volition, 227 W Walkers, 59 Warts, 223 Weight-Bearing, 127, 254 Wheelchairs, 59 White blood cell, 153, 201, 220, 228, 229, 233, 234, 238 Windpipe, 249 Womb, 252 Wound Healing, 78 X Xenograft, 200 X-ray, 234, 242 X-Rays, 234, 242 Y Yeasts, 238, 254 Z Zygote, 210, 232 Zymogen, 38, 241, 254
