Myotonic Dystrophy - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

MYOTONIC DYSTROPHY A 3-in-1 Medical Reference A Bibliography and Dictionary for Physicians, Patients, and Genome Res...

Author: Philip M. Parker

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MYOTONIC DYSTROPHY A

3-in-1

Medical

Reference

A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES

MYOTONIC DYSTROPHY 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., 1960Myotonic Dystrophy: 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: 0-497-11259-0 1. Myotonic Dystrophy-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: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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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 myotonic dystrophy. 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 MYOTONIC DYSTROPHY ........................................................................... 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Myotonic Dystrophy? ...................................................................................................... 3 How Common Is Myotonic Dystrophy?........................................................................................ 4 What Genes Are Related to Myotonic Dystrophy? ....................................................................... 4 How Do People Inherit Myotonic Dystrophy? .............................................................................. 5 Where Can I Find Additional Information about Myotonic Dystrophy?...................................... 5 References....................................................................................................................................... 7 What Is the Official Name of the CNBP Gene? ............................................................................. 7 What Is the Normal Function of the CNBP Gene?........................................................................ 8 What Conditions Are Related to the CNBP Gene?........................................................................ 8 Where Is the CNBP Gene Located?................................................................................................ 8 References....................................................................................................................................... 9 What Is the Official Name of the DMPK Gene?............................................................................ 9 What Is the Normal Function of the DMPK Gene? .................................................................... 10 What Conditions Are Related to the DMPK Gene? .................................................................... 10 Where Is the DMPK Gene Located? ............................................................................................ 10 References..................................................................................................................................... 11 Federally Funded Research on Myotonic Dystrophy................................................................... 11 The National Library of Medicine: PubMed ................................................................................ 33 CHAPTER 2. ALTERNATIVE MEDICINE AND MYOTONIC DYSTROPHY ........................................... 78 Overview...................................................................................................................................... 78 National Center for Complementary and Alternative Medicine.................................................. 78 Additional Web Resources ........................................................................................................... 82 General References ....................................................................................................................... 82 CHAPTER 3. BOOKS ON MYOTONIC DYSTROPHY ........................................................................... 83 Overview...................................................................................................................................... 83 Book Summaries: Online Booksellers........................................................................................... 83 The National Library of Medicine Book Index ............................................................................. 84 APPENDIX A. HELP ME UNDERSTAND GENETICS ......................................................................... 86 Overview...................................................................................................................................... 86 The Basics: Genes and How They Work....................................................................................... 86 Genetic Mutations and Health..................................................................................................... 97 Inheriting Genetic Conditions ................................................................................................... 103 Genetic Consultation ................................................................................................................. 111 Genetic Testing .......................................................................................................................... 113 Gene Therapy ............................................................................................................................. 119 The Human Genome Project and Genomic Research................................................................. 122 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 125 Overview.................................................................................................................................... 125 NIH Guidelines.......................................................................................................................... 125 NIH Databases........................................................................................................................... 126 Other Commercial Databases..................................................................................................... 129 APPENDIX C. PATIENT RESOURCES .............................................................................................. 130 Overview.................................................................................................................................... 130 Patient Guideline Sources.......................................................................................................... 130 Finding Associations.................................................................................................................. 132 Resources for Patients and Families........................................................................................... 133

viii Contents

ONLINE GLOSSARIES................................................................................................................ 134 Online Dictionary Directories ................................................................................................... 134 MYOTONIC DYSTROPHY DICTIONARY ............................................................................. 135 INDEX .............................................................................................................................................. 180

1

FORWARD In March 2001, the National Institutes of Health issued the following warning: “The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.”1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with myotonic dystrophy 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 myotonic dystrophy, 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 myotonic dystrophy, 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 myotonic dystrophy. 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 myotonic dystrophy. 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 myotonic dystrophy, 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 myotonic dystrophy. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.

3

CHAPTER 1. STUDIES ON MYOTONIC DYSTROPHY Overview In this chapter, we will show you how to locate peer-reviewed references and studies on myotonic dystrophy. For those interested in basic information about myotonic dystrophy, 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 myotonic dystrophy 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 myotonic dystrophy is provided.2 The Genetics Home Reference has recently published the following summary for myotonic dystrophy:

What Is Myotonic Dystrophy?3 Myotonic dystrophy is an inherited disorder of the muscles and other body systems. It is the most common form of muscular dystrophy that begins in adulthood. This disorder is characterized by progressive muscle wasting and weakness, particularly in the lower legs, hands, neck, and face. People with myotonic dystrophy often have prolonged muscle tensing (myotonia) and are not able to relax certain muscles after use. For example, a person may be unable to release a grip on a doorknob or handle.

2 3

This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=myotonicdystrophy.

4

Myotonic Dystrophy

Other signs and symptoms of myotonic dystrophy include clouding of the lens of the eye (cataracts) and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). In affected men, hormonal changes may lead to balding and an inability to father a child (infertility). The features of this disorder usually develop during a person's twenties or thirties, although they can occur at any age. The severity of the condition varies widely among affected people, even among members of the same family. The two types of myotonic dystrophy are designated type 1 and type 2. The clinical features of type 2 myotonic dystrophy tend to be milder than those of type 1, and the two types are caused by mutations in different genes. A variation of type 1 myotonic dystrophy, called congenital myotonic dystrophy, can be noted at birth. The signs and symptoms include generalized weakness, weak muscle tone (hypotonia), club foot, breathing problems, developmental delays, and mental retardation. In some cases, these medical problems are severe or life-threatening.

How Common Is Myotonic Dystrophy? Myotonic dystrophy affects about 1 in 8,000 people worldwide. Type 1 is the most common form of the condition, accounting for about 98 percent of all cases. The remaining 2 percent of cases are myotonic dystrophy, type 2. The prevalence of the two types of myotonic dystrophy varies among different ethnic populations. For example, among people with German ancestry, type 2 may be as common as type 1.

What Genes Are Related to Myotonic Dystrophy? Mutations in the CNBP (http://ghr.nlm.nih.gov/gene=cnbp) and DMPK (http://ghr.nlm.nih.gov/gene=dmpk) genes cause myotonic dystrophy. Myotonic dystrophy type 1 is caused by a mutation in the DMPK gene, while a mutation in the CNBP gene is responsible for the less common myotonic dystrophy type 2. The exact function of these genes is not known. The DMPK gene may play a role in communication within cells and appears to be important for the correct functioning of cells in the heart, brain, and muscles used for movement (skeletal muscles). The protein made by the CNBP gene is primarily found in the heart and in skeletal muscles, where it probably helps regulate the function of other genes. Similar mutations in the DMPK and CNBP genes cause the two forms of myotonic dystrophy. In each case, a short segment of DNA is abnormally repeated many times, forming an unstable region in the gene. The mutated gene produces an altered version of messenger RNA, which is a molecular blueprint of the gene that is normally used for protein production. The abnormal messenger RNA forms clumps inside the cell that interfere with the production of many proteins. These changes prevent cells in muscles and other tissues from functioning normally, leading to the signs and symptoms of myotonic dystrophy.

Studies

5

How Do People Inherit Myotonic Dystrophy? Both types of myotonic dystrophy are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one affected parent. As myotonic dystrophy is passed from one generation to the next, the disorder generally begins earlier in life and signs and symptoms become more severe. This phenomenon is called anticipation. In type 1 myotonic dystrophy, anticipation is caused by an increase in the length of the unstable region in the DMPK gene. In type 2 myotonic dystrophy, a longer unstable region in the CNBP gene does not appear to influence the age of onset of the disorder. The cause of the anticipation observed in families with type 2 myotonic dystrophy is unknown.

Where Can I Find Additional Information about Myotonic Dystrophy? You may find the following resources about myotonic dystrophy helpful. These materials are written for the general public. NIH Publications - National Institutes of Health •

National Center for Biotechnology Information: Genes and Disease: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.sec tion.164

•

National Institute of Neurological Disorders and Stroke: http://www.ninds.nih.gov/disorders/md/md.htm MedlinePlus - Health Information

•

Encyclopedia: Muscular Dystrophy: http://www.nlm.nih.gov/medlineplus/ency/article/001190.htm

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Health Topic: Muscular Dystrophy: http://www.nlm.nih.gov/medlineplus/musculardystrophy.html Educational Resources - Information Pages

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Ask the Geneticist: Inheritance of myotonic dystrophy: http://www.askthegen.org/question.php?question_id=1067

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California Department of Developmental Services: http://www.ddhealthinfo.org/ggrc/doc2.asp?ParentID=3181

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Johns Hopkins Medicine: http://hopkinsneuro.org/disease_and_condition_detail.cfm?condition_id=64

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Madisons Foundation: http://www.madisonsfoundation.org/content/3/1/display.asp?did=594

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Myotonic Dystrophy

•

Orphanet: Myotonic dystrophy type 1: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=273

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Orphanet: Myotonic dystrophy type 2: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=606

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The Cleveland Clinic Health Information Center: http://www.clevelandclinic.org/health/health-info/docs/2100/2113.asp?index=8884

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University of Washington: http://depts.washington.edu/neurogen/documents/Myotonic.pdf Patient Support - for Patients and Families

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Muscular Dystrophy Association: http://www.mda.org/disease/dm.html

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Muscular Dystrophy Family Foundation: http://www.mdff.org/

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National Organization for Rare Disorders: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Dystrophy,+My otonic

•

Resource list from the University of Kansas Medical Center: http://www.kumc.edu/gec/support/myotonic.html 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=myotonicdystrophy/show/Gene+Reviews;jsessionid =5D53393D8C0EA656DA6D91029A521225

•

Gene Tests - DNA tests ordered by healthcare professionals: http://ghr.nlm.nih.gov/condition=myotonicdystrophy/show/Gene+Tests;jsessionid=5 D53393D8C0EA656DA6D91029A521225

•

ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22myotonic+dystrophy%22+OR+%22Myo tonic+Dystrophy%22?recruiting=false

•

Online Books - Medical and science texts: http://books.mcgrawhill.com/getommbid.php?isbn=0071459960&template=ommbid&c=217

•

OMIM - Genetic disorder catalog: http://ghr.nlm.nih.gov/condition=myotonicdystrophy/show/OMIM;jsessionid=5D533 93D8C0EA656DA6D91029A521225

Studies

7

References These sources were used to develop the Genetics Home Reference condition summary on myotonic dystrophy. •

Day JW, Ranum LP. RNA pathogenesis of the myotonic dystrophies. Neuromuscul Disord. 2005 Jan;15(1):5-16. Epub 2004 Nov 26. Review. PubMed citation

•

Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LP. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003 Feb 25;60(4):657-64. PubMed citation

•

Ebralidze A, Wang Y, Petkova V, Ebralidse K, Junghans RP. RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science. 2004 Jan 16;303(5656):383-7. Epub 2003 Dec 04. PubMed citation

•

Fardaei M, Rogers MT, Thorpe HM, Larkin K, Hamshere MG, Harper PS, Brook JD. Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum Mol Genet. 2002 Apr 1;11(7):805-14. PubMed citation

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Finsterer J. Myotonic dystrophy type 2. Eur J Neurol. 2002 Sep;9(5):441-7. Review. PubMed citation

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Gene Review: Myotonic Dystrophy Type 1

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Larkin K, Fardaei M. Myotonic dystrophy--a multigene disorder. Brain Res Bull. 2001 Oct-Nov 1;56(3-4):389-95. Review. PubMed citation

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Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LP. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001 Aug 3;293(5531):864-7. PubMed citation

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Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and molecular aspects of the myotonic dystrophies: a review. Muscle Nerve. 2005 Jul;32(1):1-18. Review. PubMed citation

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Meola G, Moxley RT 3rd. Myotonic dystrophy type 2 and related myotonic disorders. J Neurol. 2004 Oct;251(10):1173-82. Review. PubMed citation

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Ranum LP, Day JW. Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet. 2004 May;74(5):793-804. Epub 2004 Apr 02. PubMed citation

A summary of the genes related to myotonic dystrophy is provided below:

What Is the Official Name of the CNBP Gene?4 The official name of this gene is “CCHC-type zinc finger, nucleic acid binding protein.”

4

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=cnbp;jsessionid=5D53393D8C0EA656DA6D91029A521225.

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Myotonic Dystrophy

CNBP is the gene's official symbol. The CNBP gene is also known by other names, listed below.

What Is the Normal Function of the CNBP Gene? The CNBP gene provides instructions for making a protein called CCHC-type zinc finger, nucleic acid binding protein. This protein is found in many of the body's tissues, but is most abundant in the heart and in muscles used for movement (skeletal muscles). Although the exact function of this protein remains unclear, it probably helps regulate genes involved in the production and use of cholesterol. The protein has seven regions, called zinc finger domains, which are thought to attach (bind) to specific sites on messenger RNA (a molecule similar to DNA that forms a blueprint for making proteins). One region of the CNBP gene has a particular repeating sequence of four DNA building blocks (nucleotides), written as CCTG. The CCTG sequence is usually repeated fewer than 26 times within the gene and is called a tetranucleotide repeat.

What Conditions Are Related to the CNBP Gene? Myotonic Dystrophy - Caused by Mutations in the CNBP Gene Type 2 myotonic dystrophy is caused by an expansion of the CCTG tetranucleotide repeat in the CNBP gene. This condition occurs when the CCTG segment is abnormally repeated 75 to more than 11,000 times.

Where Is the CNBP Gene Located? Cytogenetic Location: 3q21 Molecular Location on chromosome 3: base pairs 130,371,121 to 130,385,391

The CNBP gene is located on the long (q) arm of chromosome 3 at position 21. More precisely, the CNBP gene is located from base pair 130,371,121 to base pair 130,385,391 on chromosome 3.

Studies

9

References These sources were used to develop the Genetics Home Reference gene summary on the CNBP gene. •

Botta A, Caldarola S, Vallo L, Bonifazi E, Fruci D, Gullotta F, Massa R, Novelli G, Loreni F. Effect of the [CCTG]n repeat expansion on ZNF9 expression in myotonic dystrophy type II (DM2). Biochim Biophys Acta. 2006 Mar;1762(3):329-34. Epub 2005 Dec 6. PubMed citation

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Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LP. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003 Feb 25;60(4):657-64. PubMed citation

•


•

Finsterer J. Myotonic dystrophy type 2. Eur J Neurol. 2002 Sep;9(5):441-7. Review. PubMed citation

•


•

Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LP. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001 Aug 3;293(5531):864-7. PubMed citation

•


•

Meola G, Moxley RT 3rd. Myotonic dystrophy type 2 and related myotonic disorders. J Neurol. 2004 Oct;251(10):1173-82. Review. PubMed citation

•


What Is the Official Name of the DMPK Gene?5 The official name of this gene is “dystrophia myotonica-protein kinase.” DMPK is the gene's official symbol. The DMPK gene is also known by other names, listed below.

5

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=dmpk.

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Myotonic Dystrophy

What Is the Normal Function of the DMPK Gene? The DMPK gene provides instructions for making a protein called myotonic dystrophy protein kinase. Although the exact function of this protein is not known, it appears to be important for the normal function of muscle, heart, and brain cells. This protein may be involved in communication within cells. It also appears to regulate the production and function of important structures inside muscle cells. For example, myotonic dystrophy protein kinase has been shown to turn off (inhibit) a specific subunit ( 1R12A) of a muscle protein called myosin phosphatase. Myosin phosphatase is an enzyme that plays a role in muscle tensing (contraction) and relaxation. Myotonic dystrophy protein kinase may interact with other proteins as well. One region of the DMPK gene has a particular repeating sequence of three DNA building blocks (nucleotides), written as CTG. The CTG sequence is usually repeated 5 to 35 times within the gene and is called a trinucleotide repeat.

What Conditions Are Related to the DMPK Gene? Myotonic Dystrophy - Caused by Mutations in the DMPK Gene Type 1 myotonic dystrophy is caused by an expansion of the CTG trinucleotide repeat in the DMPK gene. This condition occurs when the CTG segment is abnormally repeated from 50 to 5,000 times. The mutated DMPK gene produces an altered version of messenger RNA, which is a molecular blueprint of the gene that is normally used for protein production. Researchers have found that the altered messenger RNA interacts with certain proteins to form clumps within the cell. The abnormal clumps interfere with the production of many other proteins. These changes prevent cells in muscles and other tissues from functioning properly, leading to the signs and symptoms of type 1 myotonic dystrophy.

Where Is the DMPK Gene Located? Cytogenetic Location: 19q13.3 Molecular Location on chromosome 19: base pairs 50,964,814 to 50,977,575

The DMPK gene is located on the long (q) arm of chromosome 19 at position 13.3.

Studies

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More precisely, the DMPK gene is located from base pair 50,964,814 to base pair 50,977,575 on chromosome 19.

References These sources were used to develop the Genetics Home Reference gene summary on the DMPK gene. •


•

Ebralidze A, Wang Y, Petkova V, Ebralidse K, Junghans RP. RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science. 2004 Jan 16;303(5656):383-7. Epub 2003 Dec 04. PubMed citation

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•

Gene Review

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•


•

Salvatori S, Fanin M, Trevisan CP, Furlan S, Reddy S, Nagy JI, Angelini C. Decreased expression of DMPK: correlation with CTG repeat expansion and fibre type composition in myotonic dystrophy type 1. Neurol Sci. 2005 Oct;26(4):235-42. PubMed citation

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Ueda H, Ohno S, Kobayashi T. Myotonic dystrophy and myotonic dystrophy protein kinase. Prog Histochem Cytochem. 2000;35(3):187-251. Review. PubMed citation

Federally Funded Research on Myotonic Dystrophy The U.S. Government supports a variety of research studies relating to myotonic dystrophy. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.6

6

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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Myotonic Dystrophy

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 myotonic dystrophy. 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 myotonic dystrophy. The following is typical of the type of information found when searching the CRISP database for myotonic dystrophy: •

Project Title: A MOUSE MODEL OF RNA-INDUCED NEUROTOXCITY Principal Investigator & Institution: Margolis, Russell L.; Associate Professor of Psychiatry & Neur; Psychiatry and Behavioral Sciences; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2007; Project Start 16-MAR-2007; Project End 30-NOV-2008 Summary: (provided by applicant): Toxicity of RNA transcripts containing long CUG repeats, a novel mechanism of disease pathogenesis, was recently described in myotonic dystrophy type 1 (DM1), the most common form of adult onset muscular dystrophy. The precise mechanism by which CUG expansions lead to cell toxicity is unclear, though misregulation of splicing may be involved. Our group recently identified an autosomal dominant disorder, Huntington's disease-like 2 (HDL2), with clinical and pathological features almost identical to Huntington's disease (HD), a relentlessly progressive adult onset neurodegenerative disorder. Like HD, HDL2 is caused by a CAG/CTG expansion mutation. To our surprise, the pathogenesis of HDL2, like DM1 and unlike HD, appears to arise at least in part from the toxic effect of RNA transcripts containing long CUG repeats. To test the hypothesis that untranslated CUG expansions can lead to neurotoxicity in the mammalian brain, we propose to generate a transgenic mouse specifically expressing an expanded CUG repeat in the brain. In Specific Aim 1, we will generate CUG transgenic mice, using an untranslatable construct that contains a short fragment of JPH3 with either a normal or an expanded CTG repeat under the control of the brain-specific PrP promoter. In Specific Aim 2, the behavioral, motoric, and pathological phenotype of these mice will be examined. In Specific Aim 3, specific characteristics of CUG repeat expansion diseases will be examined in the mice, with an emphasis on RNA foci and protein aggregation. We predict that the expanded CUG repeat will lead to neurotoxicity, evident in motor behavior and neuropathology. If this prediction is correct, the mice generated here will become invaluable tools for dissecting the pathogenic pathways of DM1, HD, and HDL2. Finding the points of pathogenic convergence in these diseases may provide novel leads for the development of rational therapeutics.

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Project Title: AUTOMATED DETECTION OF GENE DUPLICATIONS OR DELETIONS Principal Investigator & Institution: Merchant, Fatima A.; Lead Research Engineer; Advanced Digital Imaging Research, Llc 2450 S Shore Blvd, Ste 305 League City, Tx 775732997 Timing: Fiscal Year 2005; Project Start 01-APR-2000; Project End 19-MAR-2007 Summary: (provided by applicant): This project will further develop automated instrumentation and image analysis techniques to detect gene duplications or deletions

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in interphase FISH, which are difficult to detect by routine cytogenetics. There is a growing list of genetic disorders that result from chromosomal anomalies, related to either duplications or deletions. These include: (1) neuropathies; Charcot-Marie-Tooth Disease (CMT1A) and Hereditary Neuropathy with Pressure Palsies (HNPP), (2) neurological disorders; Pelizaeus-Merzbacher Disease (PMD) and X-Linked Spastic Paraplegia (SPG2), (3) muscular wasting disorders; Duchene (DMD) and Becker Muscular Dystrophy (BMD), (4) contiguous-gene syndromes; Smith-Magenis Syndrome (SMS). Our approach is to use readily available DNA probes, followed by automated genetic screening to detect duplications/deletions. We will develop an imaging system for the automated identification of interphase cells, and use sophisticated image analysis for high-resolution detection and separation of microscopic rearrangements. In the Phase I project we evaluated the feasibility of newly developed imaging algorithms, for effectively and precisely identifying the separation of FISH dot duplicates. Algorithms were developed for automatically (1) segmenting dots, (2) computing the integrated fluorescence intensity of dots, (3) determining the separation distance, and (4) classifying duplicates and single dots. In Phase II we will incorporate the newly developed imaging algorithms into our automated imaging system, and test the prototype clinically. We will also develop and implement three-dimensional modeling techniques to obtain an unbiased estimate of the spatial distance between duplicated genes. Phase III will commercialize the instrument. Computer automation will make genetic screening practical on a large scale by reducing costs and relieving humans of tedious duties. This approach will be most valuable to medical genetics, particularly for screening CMT1A/HNPP, PMD/SPG2, DMD/BMD, and SMS. Duplications have also been identified for the Prader-Willi /Angelman syndrome region that result in autism. Duplications, such as for 22ql 1.2 and 17pl 1.2 have been described and result in a rather mild phenotype. But duplications of the Williams syndrome region have not been described and thus, the phenotype is unknown. The ability to screen patients for duplications by interphase FISH analysis will likely identify a large number of individuals that would benefit from medical intervention. It may uncover syndromes that previously had no identifiable etiology. This will provide a screening test and eventually a diagnostic test for those individuals with perhaps mild phenotypes, such as learning disabilities. •

Project Title: CART REGULATION OF WAKEFULNESS Principal Investigator & Institution: Rye, David B.; Associate Professor; Neurology; Emory University 1784 North Decatur Road, Suite 510 Atlanta, Ga 30322 Timing: Fiscal Year 2007; Project Start 20-JAN-2007; Project End 31-DEC-2011 Summary: (provided by applicant): CART (Cocaine and Amphetamine-Regulated Transcript) peptides appear to mediate behaviors associated with psychostimulant drugs including: hypothalamically mediated suppression of food intake, activation of the HPA axis, locomotion, and reward/motivation. We hypothesized that CARTcontaining neurons have additional anatomical/behavioral relationships (indirect or direct) with mesolimbic dopaminergic pathways and other nuclei involved in mediating wakefulness; i.e., a behavioral 'state' also associated with psychostimulants. Our preliminary studies are supportive in demonstrating that: 1) CART exhibits a diurnal rhythm in non-human primate spinal fluid that peaks in the early morning; 2) intracerebroventricular delivery in rats during their major sleep period produces profound, dose-dependent, increases in wake; 3) interference with endogenous CART signaling increases rapid-eye-movement sleep in the initial major active period of rats; and 4)and CART is depressed in non-human primates and humans afflicted with parkinsonism and other conditions characterized by impairments in wakefulness. We

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propose to further characterize the wake promoting effects of CART peptides, and explore the underlying substrates and their potential clinical significance. S.A. #1 proposes to differentiate between CART'S role as a homeostatic vs. circadian wake promoting signal by examining its daily oscillations, responsiveness to sleep deprivation, and relationship to prior sleep-wake in the diurnal (wake-active) nonhuman primate (rhesus). S.A. #2 proposes to demonostrate that endogenous CART is necessary for normal wakefulness by central delivery of CART antibodies to rats and characterizing sleep/wake state in Cart and Cart -/- mice. S.A. #3 proposes anatomical (rat, non-human primate, and human) and behavioral (rat) determination of the regional, cellular, and pharmacologic bases of CART'S wake promoting actions. Finally, S.A. #4 proposes to examine spinal fluid CART in human conditions characterized by impairments in maintaining wakefulness (e.g., narcolepsy, parkinsonism, idiopathic hypersomnia, and myotonic dystrophy). Taken together, these findings will provide new insights into the mechanisms governing wakefulness in the context of a growing recognition that the key cellular mechanisms also involve integration of additional, seemingly disparate adaptive behaviors such as energy homeostatis, feeding, reward and motivation. •

Project Title: CHCR:A PROTEIN IN MAMMALIAN MUSCLE DIFFERENTIATION Principal Investigator & Institution: Wang, Edith Harriet.; Pharmacology; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 01-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): The long-term goal of this research is to unravel the molecular mechanism of muscle differentiation and to provide new information that may lead to therapeutic approaches for myotonic dystrophy. The activation of muscle differentiation involves both positive and negative signals. While much attention has been placed on proteins that promote muscle differentiation, the importance of negative regulatory pathways has been under emphasized. Disrupting the delicate balance between positive and negative signals can lead to the development of disease. The focus of this proposal will be to investigate the function of a novel protein CHCR that we hypothesize antagonizes muscle differentiation, which is in striking contrast to its close relative Muscleblind (at 49% identity), a Drosophila protein essential for muscle formation. CHCR also displays approximately 80% homology to proteins implicated in myotonic dystrophy (DM l) and binds to expanded repeat transcripts found in the nuclei of DM1 cells. Based on our preliminary studies, we hypothesize that CHCR is an inhibitor of muscle differentiation and that its mechanism of action requires changes in gene expression mediated by direct DNA binding. To test this hypothesis, we will examine the effects of CHCR overexpression and reducing CHCR protein levels by morpholino antisense oligonucleotides and RNA interference on muscle differentiation in C2C12 mouse myoblasts. We also propose to map the part of CHCR that is required for suppression of muscle differentiation. This information will help guide the protein interaction studies described below. The techniques of suppression subtractive hybridization and DNA microarrays will be used to identify changes in gene expression mediated by CHCR function. The involvement of direct DNA binding will be investigated by chromatin immunoprecipitation followed by the probing of DNA microarrays (ChiP-chip) and a random site selection technique. A yeast two-hybrid screen and coimmunoprecipitation experiments will be carried out to identify CHCRbinding proteins required for its antagonistic effect on mammalian muscle differentiation. The identification of direct gene targets and CHCR interacting proteins will provide the tools to further investigate CHCR function in muscle differentiation. Our long-term goal is increase our understanding of negative regulatory mechanisms

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underlying mammalian muscle differentiation. Such findings may reveal new avenues for therapy development. •

Project Title: DM2: MURINE AND CELL CULTURE MODELS OF CCUG RNA TOXICITY Principal Investigator & Institution: Ranum, Laura Pw.; Professor; Genetics, Cell Biology and Development; University of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070 Timing: Fiscal Year 2005; Project Start 15-JUL-2004; Project End 31-MAY-2008 Summary: (provided by applicant): Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on chromosome 19 (DM1) or 3 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK) and the promoter region of the homeodomain gene SIX5. Although the DM1 mutation was isolated in 1992, for many years it has been difficult to understand how this mutation, which does not alter the protein-coding portion of a gene, causes this dominantly-inherited multisystemic disorder. Suggested mechanisms have included: DMPK haploinsufficiency; reduced expression of regional genes including the homeodomain gene SIX5; and pathogenic effects of the CUG expansion in RNA. Mouse models have suggested that each of these mechanisms contributes to DM1 pathogenesis and that DM1 may be a regional gene disorder. To clarify the pathogenic mechanism of DM, we have studied a second form of myotonic dystrophy that causes a strikingly similar constellation of clinical features in humans including myotonia, myopathy, iridescent cataracts, cardiac arrhythmias, and the specific set of serological changes characteristic of DM. We mapped the DM2 locus to chromosome 3q21 (Nature Genetics 19:196-198, 1998) and recently reported that DM2 is caused by a repeat expansion in intron 1 of the zinc finger protein nine (ZNF9) gene (Science, 293:864-867). Clinical and molecular parallels between DM1 and DM2 indicate that CUG and CCUG expansions expressed at the RNA but not the protein level can themselves be pathogenic and cause the multisystemic features common to both diseases. We propose generating transgenic mice and cell culture models to test the effects of CCUG repeat-containing transcripts and to better understand the molecular mechanisms involved in the disease process. Our specific aims are: (1) To generate a reversible murine model to test the pathogenicity and characterize the downstream effects of transcripts containing the CCUG expansion expressed in skeletal muscle. (2) To generate and characterize a BAC transgenic mouse model that replicates the multisystemic features of myotonic dystrophy type 2. (3) To develop a cell culture model to evaluate the molecular effects of CCUG length on the formation of RNA foci, cellular differentiation and downstream molecular changes in alternative splicing.

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Project Title: FEN-1/WRN COMPLEX IN PREVENTION OF GENETIC DISEASES Principal Investigator & Institution: Finger, L David.; City of Hope/Beckman Research Institute Office of Sponsored Projects Duarte, Ca 910103012 Timing: Fiscal Year 2006; Project Start 26-JUN-2006; Project End 25-JUN-2009 Summary: (provided by applicant): Tri-nucleotide repeat (TNR) DNA sequences occur throughout the human genome and have an intrinsic propensity to expand during replication. Expansion of such sequences is known to result in several human diseases, including Huntington's disease, spinocerebellar ataxia, and myotonic dystrophy. Errors in several DNA metabolic pathways due to the nature of TNR sequences have been implicated as the cause for TNR expansion. One mechanism for TNR expansion involves errors in Okazaki fragment maturation. Normally, 5'-flap endonuclease (FEN-1) cleaves

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the single stranded 5'-flap DNA structures generated during lagging-strand DNA synthesis. However, when the flap contains a TNR sequence, the flap can fold into a hairpin structure that has been shown to inhibit FEN-1 cleavage of the flap structures. Therefore, the inability of FEN-1 to process TNR 5'-hairpin-flaps is proposed to be one cause of TNR expansion. FEN-1 has recently been shown in vivo to proc similarities in TNR hairpin flap and fork DNA structures, it is hypothesized that the FEN-1 /WRN complex processes TNR hairpin flap structures in vivo, thereby suppressing TNR expansions in mammals. This hypothesis is consistent with the observation that deletion of the yeast FEN-1 gene results in critique one a two orders of magnitude difference in the incidence of TNR expansions. Furthermore, it is hypothesized that the unique DNA binding properties of WRN guide FEN-1 activity to TNR hairpin flap sites in addition to stimulating catalytic activity. •

Project Title: GENETIC MECHANISM OF SPINOCEREBELLAR ATAXIA TYPE 10 Principal Investigator & Institution: Topal, Michael D.; Pathology and Lab Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2006; Project Start 15-MAR-2006; Project End 28-FEB-2008 Summary: (provided by applicant): Repeat expansions in the human genome are responsible for more than thirty neurodegenerative and neuromuscular diseases, including the dominantly inherited diseases myotonic dystrophy types 1 and 2 (DM1 and DM2), Huntington's disease, and the spinocerebellar ataxias (SCAs). The repeats associated with DM1, d(CTG)n, and DM2, d(CCTG)n, lie in untranslated regions of their host gene. The repeat expansions reach dramatic sizes of thousands of repeats and generate gain-of-function "toxic" CUG repeat RNAs that accumulate in nuclear foci and interact with CUG repeat binding proteins involved in control of tissue-specific premRNA splicing. Similarly, the SCA type 10 (SCA10) d(ATTCT)n repeat expansions occur in an untranslated intron and reach dramatic sizes. This, plus our preliminary results, suggests that dominantly inherited SCA10 disease, like DM1 and DM2, may be a toxic RNA disease. In contrast, knock down of SCA10 gene expression in neurons increases cell death, suggesting that SCA10 may be a loss-of-function disease. Thus, it is entirely unclear how the expanded ATTCT repeat leads to SCA10 disease. It is unclear that the AUUCU-repeat-containing intronic RNA is stable after splicing, and the possibility of an AUUCU binding protein is provocative and could uncover a new class of proteins that regulate pre-mRNA splicing. Lack of understanding of how the d(ATTCT)n repeat expansion alters tissue-specific gene expression is a critical problem, because until this information becomes available, it will not be possible to develop new therapeutic strategies. The long-term goal of this research is to determine the biological pathways impacted by the ATTCT repeat expansion to cause SCA10 disease. The central hypothesis for the proposed research is that SCA10 disease is manifested by a toxic RNA effect that interferes with correct splicing of brain-specific pre-mRNAs. The central hypothesis will be tested by pursuing the following specific aims: 1) localize the RNAs transcribed from SCA10 d(ATTCT)n repeat expansions; 2) identify proteins that interact with the expanded SCA10 RNA.

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Project Title: INDUCIBLE TRANSGENIC MOUSE MODEL OF RNA TOXICITY Principal Investigator & Institution: Mahadevan, Mani S.; Assistant Professor; Pathology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 229044195 Timing: Fiscal Year 2005; Project Start 01-SEP-2005; Project End 31-AUG-2010

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Summary: (provided by applicant): Myotonic dystrophy (DM) is the most common inherited neuromuscular disorder in adults. There are two types, DM1 and DM2, both being autosomal dominant disorders caused by expansions of microsatellite repeats within non-coding regions of their respective genes. DM1 is far more common; however both forms of DM are likely to share similar pathogenic mechanisms. The DM1 mutation is an expansion of a CTG triplet repeat in the 3' untranslated region (3'UTR) of the DM protein kinase (DMPK) gene. A prevailing hypothesis in the field is that many aspects of DM are caused by the expression of the mutant mRNA. DM1 and DM2 represent the first examples of toxic RNA mediated disease pathogenesis. We have already developed and characterized extensively, a myoblast cell culture model to clearly demonstrate the toxic effects of the mutant DMPK mRNA on muscle differentiation. To study the hypothesis further, the aims of this proposal are to develop and characterize an inducible transgenic mouse model of RNA toxicity for DM type 1 (DM1) and to develop a siRNA (small interfering RNA) therapeutic approach to get rid of the toxic RNA which can be tested in both our cell culture and transgenic animal models. The development of transgenic mouse models will aid in understanding disease pathogenesis and will also provide a system with which to test out potential therapeutic.strategies. The ability to control gene expression through an inducible system will enable better characterization of and better correlation with the onset and levels of expression of the toxic RNA in DM1 and disease outcomes. Most importantly, because of this property, this model will be one of the first in which we can directly test, at the level of a whole organism, if ablation of expression of the toxic RNA after a period of exposure can reverse its toxic effects. All DM patients have endured exposure to the toxic RNA from birth and thus a model such as this one will be able to provide valuable and relevant insight into this therapeutic strategy. •

Project Title: INSTABILITY OF TRIPLET REPEATS IN MAMMALIAN CELLS Principal Investigator & Institution: Wilson, John H.; Assistant Professor; Biochem and Molecular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 01-APR-1987; Project End 30-JUN-2006 Summary: Expansions of trinucleotide (triplet) repeats at specific sites in the human genome cause a number of neurological diseases, including myotonic dystrophy, Huntington disease, fragile X syndrome, and several others. At the myotonic dystrophy locus, normal individuals have up to 30-40 CTG/CAG repeats, whereas affected individuals may have up to several thousand repeats. CTG/CAG repeats have a propensity to form a variety of stable secondary structures in vitro, and it is thought that these unusual structures interfere with aspects of DNA metabolism in cells, leading to repeat expansion and disease. Studies in E. coli and S. cerevisiae have shown that triplet repeat stability is sensitive to processes that expose single strands of DNA, including transcription, replication, repair, and recombination. This application seeks to develop novel selective systems for investigation CTG/CAG triplet repeat stability in vertebrate cells. Instability during recombination and the effects of triplet repeats on the recombination processes, which have already been demonstrated at the APRT locus in CHO cells, will be defined using a variety of tandem duplication substrates, I-SceImediated double-strand breaks, and ERCC1-deficient cells. Instability of repeats due to all causes will be investigated using a novel, direct-selection assay based on the lengthdependent effects on gene expression by intronic CAG repeats, which have already been demonstrated. Long repeats placed in the intron of the HPRT minigene, which render it HPRT , can be used to select for repeat contractions (HPRT- to HPRT+). Similarly, short CAG repeats that are compatible with gene expression can be used to select for repeat contractions (HPRT- to HPRT+). Similarly, show CAG repeats that are compatible with

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gene expression can be used to select for expansions (HPRT- to HPRT+). The boundaries for these lengthdependent effects will be defined, the mechanism of interference will be determined, and appropriate CAG-containing, HPRT-minigene substrates will be deposited in the chromosomes of vertebrate cells. These substrates will allow testing of the effects of genes involved in replication, repair, and in recombination and cell treatments that stress these processes. In summary, we propose and integrated and comprehensive set of experiments to define the molecular basis of the CTG/CAG repeat instability that underlies myotonic dystrophy and other neurological diseases. These studies will also provide a set of experimental reagents that will e useful in the design and evaluation of potential therapeutic strategies directed at preventing expansion or promoting contraction of CTG/CAG repeats. •

Project Title: INTERACTIONS OF MYOTONIC DYSTROPHY PROTEIN KINASE Principal Investigator & Institution: Epstein, Henry F.; Professor; Neuroscience and Cell Biology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2004; Project Start 01-MAY-1996; Project End 31-MAY-2007 Summary: (adapted from applicant's abstract): Myotonic Dystrophy Protein Kinase (DMPK) is encoded by the Myotonic Dystrophy 1 (DM1) locus. Studies on human tissues and cultured cells suggest that haploinsufficiency affecting DMPK expression is a significant consequence affecting DMPK expression is a significant consequence of the dCTG repeat expansion mutations that cause DM1. These mutations may affect other genes as well by several mechanisms. Studies of the DMPK knockout and transgenic mice have reported skeletal and cardiac myopathy, cardiac arrhythmias, and in our preliminary results, altered synaptic plasticity in the central nervous system. Knockout of the neighboring gene, Six5 or DMAHP (DM associated homeodomain protein) leads to cataracts. The CUG expansion in mRNA may sequester proteins required for splicing of the RNAs of multiple genes. On the other hand, loss-of-function mutations in other serine-threonine protein kinases can also lead to autosomal dominant traits with variable expressivity and pleiotropy such as in Coffin-Lowry and Peutz-Jeghers Syndromes. These results support continued study of DMPK with respect to understanding the pathogenesis of DM1. DMPK is also representative of a new group of serine-threonine protein kinases active in cell-cycle control, cell differentiation, and cytoskeleton organization. At least two other human protein kinases are also members. Preliminary studies in our laboratory suggest that DMPK may serve as a nexus for cross-talk or convergence between distinct signaling networks. DMPK can interact with two well known proteins that mark distinct signaling pathways: chemically stimulated Raf-1 kinase and the cytoskeleton-linked Rho family GTPase Rac-1. In order to more rigorously establish the biochemical, cellular, and physiological significance of these interactions and further understand the responsible mechanisms, we propose the following Specific Aims: 1) to study the interactions of Rac-1 and Raf-1 kinase with DMPK as purified recombinant proteins as tests for direct functional activation and synergy and their structural basis in the DMPK molecule; 2) to test for cross-talk or convergence of Rac-1 and Raf-1 kinase signaling upon DMPK in cultured myogenic and neurogenic cells in culture and verify its structural basis in the DMPK molecule; and 3) to verify cross-talk in vivo between Rac-1 and Raf-1 kinase upon DMPK in brain and muscle by constructing and studying mutant mouse lines derived from crosses of wildtype controls or DMPK knockouts with dominant negative mutant transgenes expected to alter the activation of DMPK by Rac-1 and/or Raf-1 kinase. Accomplishment of these objectives would suggest that DMPK integrates different signals in its modulation of function in muscle and nerve. These results would clearly provide a foundation for

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better understanding of the role that DMPK may play in the pathogenesis of DM1 and for a potentially rational design of therapeutics. •

Project Title: LOCALIZED WATER INFLUX DURING CRYPTOSPORIDIUM INVASION Principal Investigator & Institution: O'hara, Steven P.; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2007; Project Start 01-JAN-2007; Project End 31-DEC-2009 Summary: (provided by applicant): My long-term career objectives are to apply fundamental concepts of cell and molecular biology to understand the role of cholangiocytes, the epithelial cells lining intrahepatic bile ducts, in health and disease. The current proposal focuses on the interactions between cholangiocytes and Cryptosporidium parvum, a coccidian parasite in the phylum Apicomplexa that has been associated with infection of the gastrointestinal, biliary, and respiratory epithelium. The primary goal of this proposal is to understand the mechanism and physiological consequences of localized, pathogen-induced water influx at the apical membrane of cholangiocytes, a process that may have broad implications in plasma membrane remodeling. Our preliminary observations support the central hypothesis that C. parvum cellular invasion requires efficient host cell membrane remodeling involving Myosin ll-dependent, exocytic insertion of vesicles containing Aquaporin 1 (Aqp1) and Na+/Glucose Cotransporter (Sglt1). We will employ complementary biochemical, molecular, and morphological approaches to address three Specific Aims to test the hypotheses that: (i) Myosin IIa and IIb are involved in the docking and fusion of vesicles containing Aqp1 and Sglt1 at infection sites on the apical cholangiocyte membrane via the direct interactions between Myosin II isoforms and vesicles containing Sglt1 and Aqp1; (ii) The Cdc42 effector Myotonic Dystrophy Kinase-Related Cdc42-binding kinase (MRCK) and Myosin Light Chain Kinase (MLCK) contribute to the localized phosphorylation of Myosin Light Chain at C. parvum invasion sites; and, (iii) Myosin ll-mediated exocytic insertion of Aqp1 and Sglt1 containing vesicles into the cholangiocyte apical membrane is involved in C. parvum induced localized water influx, a process facilitating localized membrane protrusion via promoting efficient actin dynamics at the site of infection. Thus, the proposed experiments will define the molecular mechanism by which the host actomyosin cytoskeleton facilitates exocytic insertion of Aqp1 and Sglt1 at the infection sites on the apical membrane of cholangiocytes, and how the resultant water influx contributes to efficient membrane protrusion required for C. parvum cellular invasion, a phenomenon relevant to the molecular mechanisms of apical membrane modifications in general.

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Project Title: MECHANISM OF MIS-SPLICING IN MYOTONIC DYSTROPHY 1 Principal Investigator & Institution: Kuyumcu-Martinez, Muge N.; Pathology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2008 Summary: (provided by applicant): Myotonic dystrophy (DM) is an autosomal dominant disorder affecting 1 in 8500 people worldwide. Individuals with DM exhibit progressive muscular dystrophy, arrhythmias and CNS damage. Mutations are expanded CTG or CCTG repeats in untranslated regions of DMPK and ZNF9 genes respectively. The expanded repeats are expressed as CUG (DM1) or CCUG (DM2) repeat RNA, which accumulate as discrete foci in nuclei. The pathogenesis of DM1 involves misregulation of alternative splicing resulting in expression of inappropriate protein isoforms causing specific symptoms. However, the mechanism by which

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expanded repeats alter pre-mRNA alternative splicing is unclear. Two RNA binding proteins have been implicated in DM1 pathogenesis: MBNL1 and CUG-BP1. CUG-BP1 regulates alternative splicing of cardiac troponin T (cTNT), insulin receptor (IR) and chloride channel (CIC-1) pre-mRNAs that are mis-spliced in DM1 striated muscle. The functional consequences of mis-splicing of CIC-1 and IR directly correlate with myotonia and insulin resistance, respectively, observed in DM1. The splicing patterns observed for these pre-mRNAs are consistent with increased CUG-BP1 activity observed in DM1 striated muscle. MBNL proteins bind and colocalize with the foci of expanded CUG repeat RNA in DM1 cells. MBNL proteins directly regulate splicing of cTNT and IR alternative exons. Therefore, MBNL1 and CUG-BP1 proteins are the major regulators of alternative splicing of pre-mRNAs that are misregulated in DM1. The goal of this proposal is to understand how expanded CUG repeat RNA disrupts the regulation by CUG-BP1 and MBNL1. In this study I will: i) establish and characterize stable cell lines which inducibly express CUG repeat RNA, ii) characterize the effects of CUG repeat RNA on steady state levels and nuclearcytoplasmic distribution of CUG-BP1 and MBNL1, iii) determine whether CUG repeat RNA affects post-translational modifications of CUG-BP1 and MBNL1 and characterize the significance of these modifications on alternative splicing. •

Project Title: MECHANISMS OF GENETIC INSTABILITES OF TRIPLET REPEATS Principal Investigator & Institution: Wells, Robert D.; Director; Center for Genome Research; Texas A&M University Health Science Ctr Research Foundation College Station, Tx 778433578 Timing: Fiscal Year 2005; Project Start 01-JUN-2001; Project End 31-MAY-2008 Summary: (Applicant's abstract): Genetic instabilities (expansion and deletions of simple repeating sequences) are important in the life cycles of both prokaryotic and eukaryotic cells. This fundamental mechanism of mutagenesis has been found in mycoplasma, bacteria, yeast, mammalian cells, and in humans. In lower organisms, these genetic polymorphisms are the basis for phase variations which control the expression of genes. In humans, the expansions and deletions of simple repeating sequences are closely tied to the etiologies of cancers as well as hereditary neurological diseases. Prior work has revealed that expansions are mediated by DNA replication and repair by the slippage of the complementary strands of the repeats to form hairpin loop structures with differing relative stabilities. The principal investigator has recently demonstrated that recombination is a powerful mechanism for generating large expansions. To the extent that this work can be extrapolated to human diseases, recombination may be an important mechanism for the large expansions found in fragile X syndrome, myotonic dystrophy, and SCA8. The first Specific Aim is to elucidate the mechanisms of genetic recombination which mediate the triplet repeat sequence (TRS) expansions. Specific Aim 2 will evaluate the role of recombinational repair of double strand breaks in genetic instabilities. The third Specific Aim is to establish a genetic assay for determining the recombination frequency. Specific Aim 4 will investigate tandem duplication-based instabilities in vivo in recA- cells. In summary, the principal investigator will investigate the molecular mechanisms (replication, recombination, repair) that cause genetic instabilities in simple repeat sequences.

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Project Title: MOLECULAR GENETIC CHARACTERIZATION OF MYOTONIC DYSTROPHY Principal Investigator & Institution: Krahe, Ralf; Molecular Genetics; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009

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Timing: Fiscal Year 2005; Project Start 24-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): The myotonic dystrophies (DM) are now collectively recognized as a clinically and genetically heterogeneous group of neuromuscular disorders, characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multi-system involvement. Recent work by others and us indicates at least two more DM loci in addition to DM1, the (CTG)n expansion in chromosome 19q13.3. Multiple families with clinically variable presentation from predominantly distal to exclusively proximal muscle involvement show linkage to a locus in 3q21, designated DM2. However, several families with similar presentations have been excluded from this region. Thus, there is at least a third DM locus (DM3), which has yet to be mapped. The long-term goal of this proposal is the identification of DM2 in the families mapping to 3q21, and the mapping and cloning of the remaining gene(s) in the DM2-unlinked families. The characterization of the underlying mutations will be the basis for phenotype/genotype correlations. Three specific aims are proposed: (1) to clone and characterize DM2 in 3q21; (2) to clone and characterize the gene(s) in DM2unlinked/DM3 families, and (3) to globally expression profile DM muscle with DNA microarrays. Collaborating with clinical groups from the USA and Europe, we have ascertained 57 families with clinically similar phenotypes, which are negative for the DM1 (CTG)n expansion or any of the other known myotonia loci. Ten of 21 families suitable for linkage analysis show linkage to 3q21, while 11 are unlinked. We have substantially narrowed the DM2 critical region, generated a physical transcript map and started to examine functional-positional candidate genes, using various mutation detection assays. For DM3 we propose the same strategy of positional cloning that has proved successful for DM2. Genome-wide expression profiling of DM muscle will identify dysregulated genes and provide valuable functional clues about potential candidate genes and complex cellular candidate pathways, the overall pathophysiology of DM, and potential molecular therapeutic targets. The identification of these novel genes and the characterization of their mutations and pathophysiological role(s) are the first step in developing potential therapies for patients suffering from these inherited myotonic dystrophies. Moreover, as the cellular pathologies among the different myotonic dystrophies show considerable overlap, the identification of the genes underlying DM2 and DM3 and their corresponding expression profiles may also provide valuable insights into the pathology of DM1, which continues to elude researchers. •

Project Title: MOLECULAR MECHANISMS OF MYOTONIC DYSTROPHY Principal Investigator & Institution: Berglund, John A.; None; University of Oregon Eugene, or 97403 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2011 Summary: (provided by applicant): Myotonic dystrophy (DM) is caused by nucleotide expansions of CUG and CCUG in the non-coding regions of the dystrophia myotonia protein kinase gene (DMPK) and the Zn finger 9 gene (ZNF9) respectively. Patients with the CUG expansions have type I myotonic dystrophy (DM1) and patients with the CCUG expansions have type II myotonic dystrophy (DM2). Patients with DM1 and DM2 display the same symptoms, suggesting both CUG and CCUG expansions cause DM through the same mechanism. The hypothesis for how these non-coding expansions cause DM is through an RNA gain-of-function mechanism; the expanded CUG and CCUG repeat RNAs sequester the MBNL RNA binding protein and also indirectly increase the protein levels of another RNA binding protein (CUG-BP), which disrupts the normal cellular function of MBNL and CUG-BP. MBNL and CUG-BP are pre-mRNA

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Myotonic Dystrophy

splicing factors that appear to function antagonistically. Changing their "active" concentration results in the mis-regulation of alternative splicing of multiple transcripts with a final outcome of DM for people with CUG and CCUG expansions. The focus of this proposal is to determine the role of MBNL in the disease state (DM) as well as in normal cells. To accomplish these goals we are using a combination of bioinformatics, biochemical, biophysical and structural methods. Aim 1. Identify cellular targets of MBNL and determine the mechanisms through which MBNL regulates pre- mRNA splicing. Aim 2. Biochemical and structural characterization of CUG and CCUG repeats alone and in complex with MBNL. Our goal is to understand the molecular mechanisms that cause DM. This understanding will help lead to the development of therapies to help the many people (1 in 8000) that have this most common form of adult onset muscular dystrophy. •

Project Title: MOLECULAR RESULTS IN DM

MECHANISMS WHEREBY CTG

EXPANSION

Principal Investigator & Institution: Reddy, Sita; Biochem and Molecular Biology; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 01-SEP-2000; Project End 31-AUG-2007 Summary: (Adapted from the Investigator's Abstract): Expansion of a CTG repeat sequence located in a gene rich region on chromosome 19ql3.3 results in the neuromuscular disorder, myotonic dystrophy (DM). As the expansion is not found in the coding region of a gene the mechanistic basis of DM has remained a puzzle. Two current models hypothesize that CTG expansion may result in deleterious cis-effects that alter gene transcription in its vicinity and/or have toxic effects that are intrinsic to the repeat sequence. To test these mechanistic models mouse strains encoding large CTG expansions have been developed. Transgenic mice in which CTG expansions have been knocked into the dm locus will be used to characterize the phenotypic consequence of the cis effects of CTG expansion and the intrinsic toxicity of the repeat sequences. Mice encoding expansions of 500 and 2000 repeats at the dm locus will be used to test the hypothesis that cis effects that alter gene transcription in the vicinity of the expansion, progressively spread across the chromosome to boundaries that are dictated by the size of the repeat tract. Toxic effects of the CTG/CUG repeat expansion will be independently characterized in mice encoding expanded CTG tracts integrated at random loci in the genome under the transcriptional control of the human beta actin promoter. We will test the hypothesis that an increased frequency of double-strand breaks in the CTG repeat tracts or pre-mRNA splicing abnormalities resulting from the titration of the splicing factor CUG-BP by the expanded CUG repeats are the molecular mechanism whereby expanded CTG/CUG repeats result in DM pathology. •

Project Title: MOLECULAR PATHOGENESIS OF MYOTONIC DYSTROPHY Principal Investigator & Institution: Cooper, Thomas; Professor; Pathology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 08-FEB-1999; Project End 28-FEB-2009 Summary: (provided by applicant): Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy affecting 1 in 8500 people worldwide. It is dominantly inherited and affects multiple organ systems. Causative mutations are expanded tri-(CTG) and tetra-(CCTG) nucleotide repeats in transcribed but nontranslated genomic regions. A major pathogenic mechanism of DM involves a toxic RNA gain-of-function caused by expression of RNA transcripts from the expanded

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alleles. The goal in this proposal is to determine the molecular mechanism by which RNA containing the expanded repeats causes progressive skeletal muscle dystrophy and cardiac arrhythmias, the predominant causes of mortality and morbidity. In the previous funding period we demonstrated that the pathogenic mechanism involves misregulation of alternative splicing and we identified target genes responsible for specific symptoms. We also found, that these targets are regulated antagonistically by two families of RNA binding proteins both identified previously based on CUG RNA binding activity. We will define the mechanism by which expanded CUG RNA induces pathogenesis with specific emphasis on the roles of individual members of these two protein families. First, while it is clear that CUG repeat RNA is pathogenic, the specific form of the RNA required for pathogenicity is unknown. We will use an established assay to define the sequence, protein binding, and structural features of RNA required for induction of splice-misregulation in trans. Proteins whose direct interactions with the RNA correlate with aberrant RNA processing will be identified. Second, genes whose mis-regulation contributes to myopathy and arrhythmias will be identified using novel biochemical and subtractive approaches. Third, stable cell lines inducibly expressing expanded CUG RNA will be used to characterize the distribution and metabolism of toxic RNA and the consequences on the expression of the RNA binding proteins that are relevant to cell toxicity. Fourth, we will develop versatile lines of transgenic mice using a Cre/LoxP strategy to induce high levels of expanded CUG RNA in specific tissues and in early development. These studies will provide cellular and mouse models to define altered regulatory pathways and the genes affected by this novel disease mechanism. •

Project Title: MOLECULAR PATHWAY TO CARDIAC CONDUCTION DEFECTS Principal Investigator & Institution: Housman, David E.; Professor; Massachusetts Institute of Technology 77 Massachusetts Ave Cambridge, Ma 02139 Timing: Fiscal Year 2005; Project Start 01-DEC-2004; Project End 30-NOV-2005 Summary: The overall goal of Project IV (Housman) is to utilize the DMPK deficient mouse to analyze the genetic interactions that lead to cardiac conduction defects and heart block in this model system. The DMPK knockout mouse was developed to model characteristics of myotonic dystrophy, an inherited disorder in which cardiac conduction defects in the AV node and infra-Hisian and supra-Hisian tissue are a primary cause of premature death. The DMPK knockout mouse model strikingly resembles this pattern of cardiac conduct defect. Mice with absence of function for DMPK show normal cardiac conduction during the first two months of life. Between two and five months these animals develop lengthening of PR interval, lengthening of HIV interval and secondary and tertiary heart block. To define the molecular pathways that lead to this pathological outcome, we will carry out focused efforts to 1) determine the substrates for the protein kinase activity of DMPK 2) resolve the relative roles of two alternative splices splice forms of DMPK that show differential subcellular localization and 3) investigate the role of novel genes identified by transcriptional profiling, proteomic analysis and genetic modifier screens. We will develop a baseline for proteomic analysis of mouse cardiac development and pathology that will be applicable to other Projects in this program. We will also develop for executing mouse modifier gene mapping that will support the efforts of other Projects in this program in identifying gene interactions through genetic modifier mapping.

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Myotonic Dystrophy

Project Title: MUSCULAR DYSTROPHY COOPERATIVE RESEARCH CENTER Principal Investigator & Institution: Chamberlain, Jeffrey S.; Professor; Neurology; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2005; Project Start 26-SEP-2003; Project End 31-JUL-2008 Summary: This MDCRC application is designed to advance our abilities to treat the muscular dystrophies by capitalizing on the breadth and depth of expertise at our collaborating institutions in the fields of neuromuscular disease research and patient care, molecular genetics, immunology, and gene therapy. The participating researchers include scientists and clinicians from the University of Washington Medical Center, Children's Hospital and Regional Medical Center, Fred Hutchinson Cancer Research Center, and the VA Medical Center, Seattle. Our goals are to provide an interactive environment that will advance knowledge of and treatments for the muscular dystrophies by promoting collaborations, providing shared resources, advancing basic research, stimulating translational research, fostering outreach activities, developing greater patient awareness of basic and clinical research and enabling their participation in clinical trials, and by facilitating the development gene therapy for the muscular dystrophies. Our Center is composed of four research projects and three Core laboratories, and includes a membership of more than 30 faculty members in the Seattle area with interests in neuromuscular disease research. The director and codirector are J Chamberlain and S Tapscott, researchers with a long history of genetic and clinical studies of the muscular dystrophies. Project 1 (J Chamberlain, S Tapscott and S Froehner) will conduct pre-clinical studies in dystrophic mice that lead to a phase I clinical tdal of gene therapy for Duchenne muscular dystrophy (DMD). Project2 (M-T Little and S Tapscott) will study the canine model for DMD to address pre-clinical issues related to DMD therapy by emphasizing immunological, safety and allometdc issues important for the evelopment of therapies for DMD. Project 3 (S Hauschka) explores issues important for regulating gene expression vectors in muscles of humans, mice and dogs, and will develop animal and cell culture models for human muscle gene transfer. Project 4 (S. Tapscott) will study abnormal gene expression in cells from individuals with myotonic dystrophy, and will explore the clinical significance of methylation at the DM1 locus in adult onset myotonic dystrophy. Core A (Chamberlain) is an administrative core to coordinate and organize collaborative and interactive activities within and outside of our center. Core B (Chamberlain, J Allen) is a viral vector core and a scientific research resource core that will facilitate the availability of research and clinical grade gene transfer vectors for basic research and the development of gene therapies for the muscular dystrophies. Finally, Core C (T Bird) is a genetic counseling core for patients and families with muscular dystrophy that will also allow increased participation of patients in studies of a variety of types of muscular dystrophy.

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Project Title: MUSCULAR DYSTROPHY COOPERATIVE RESEARCH CENTER Principal Investigator & Institution: Moxley, Richard T.; Professor; Neurology; University of Rochester 517 Hylan Bldg., Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2005; Project Start 30-SEP-2003; Project End 31-MAY-2008 Summary: A major strength of the University of Rochester MDCRC is having a large group of highly motivated, well-characterized patients with myotonic dystrophy (DM1 & DM2) and facioscapulohumeral muscular dystrophy (FSHD), eager to support basic research and participate in clinical studies, and a group of enthusiastic investigators with a longstanding expertise in these diseases. These assets have led us to make "The Dominantly Inherited Muscular Dystrophies: Pathophysiology and Treatment" the major focus of our 3 scientific projects and 2 scientific cores. Our primary emphases are

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on DM1 and FSHD. Project 1 explores the "Role of RNA Toxicity and Muscleblind Proteins in the Pathophysiology of DM". Using muscleblind knockout mice and studies of alternative splicing of the skeletal muscle chloride channel Project 1 examines a toxic RNA model for the myotonic dystrophies. It tests the hypothesis that the abnormally expanded mRNA alleles in DM1 & DM2 sequester certain dsRNA-binding factors, the muscleblind proteins, and that this leads to myotonia and myopathy. Project 2 investigates a potential new treatment in DM1 and hopes to prove that SomatoKine (insulin-like growth factor-1 [IGF1] complexed with recombinant IGF binding protein-3) is safe, well-tolerated, and promising as a therapy. This project tests the hypothesis that deficient activation by IGF1 contributes to the atrophy in DM1, and that maintaining high blood levels of IGF1 will correct this deficiency. Project 3 strives to increase our knowledge of the molecular and cellular pathophysiology of FSHD. It uses microarray analysis of muscle biopsy specimens to test two hypotheses: in FSHD: a) deletion of D4Z4 heterochromatic repeats does not alter adjacent 4q35 genes; and, b) aberrant overexpression of smooth muscle genes is an important contributor to the pathophysiology. One Scientific Core is an Imaging Center. It provides specialized muscle histochemical and immunological techniques, fluorescent in situ hybridization, confocal microscopy, and electron microscopy. Projects 1 & 3 make extensive use of this Core. The other Scientific Core is a Repository of resources for research on Muscular Dystrophy. This Core maintains: a) myoblast cell lines for DM1 and FSHD; b) transgenic model cell lines; c) plasmids; d) antibodies; e) autopsy tissue DM1; and f) gene expression data on DM1 & FSHD patients. Projects 1, 2, & 3 interact with the Repository Core and this Core will interact with the other MDCRCs. •

Project Title: MYOTONIC DYSTROPHY LOCUS CONTROL Principal Investigator & Institution: Tapscott, Stephen J.; Professor of Neurology and Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 981091024 Timing: Fiscal Year 2005; Project Start 01-SEP-1998; Project End 30-JUN-2008 Summary: (provided by applicant): The most prevalent form of myotonic dystrophy is caused by the expansion of a CTG triplet repeat in agene-rich region of chromosome 19 at the DM1 locus. The CTG repeat is in the non-coding region of the DMPK gene and adjacent to the regulatory region of the neighboring SIX5 gene. Its expansion alters the processing of the DMPK RNA, suppresses expression of the adjacent SIX5 gene, and produces a mutant RNA with an expanded CUG repeat. Our broad and long-term goal is to identify the normal role of the CTG repeats and associated CTCF binding sites at the DM1 locus. Our broad hypothesis is that these elements regulate regional gene expression through combination of insulator activity and regional chromatin organization. Our specific aims will: (Aim 1) Test the hypothesis that the combination of CTCF binding sites and CTG repeats insulate the DMPK promoter from the SIX5 enhancer, and that loss of this insulator function causes the congenital form of DM. (Aim 2) Test the alternative hypotheses that CTG-mediated chromatin condensation occurs through the recruitment of specific chromatin modifying factors, or, alternatively, occurs through tight structural packaging of the nucleosomes in the repeat sequence. (Aim 3) Test the hypothesis that the positioning of a nucleosome by the CTG repeat is critical to the function of the DM1 insulator and contributes to regulating regional promoter usage and gene silencing. The significance of this proposal is that we will determine the role of CAG/CTG repeat sequences in organizing the structure and expression of the human genome. The health relatedness is that understanding the normal role of CTG/CAG repeats in the genome will give new insight into their role in generating tissue specific diseases.

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Myotonic Dystrophy

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

Project Title: MYOTONIC DYSTROPHY TYPE 2 Principal Investigator & Institution: Timchenko, Lubov; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 15-JUL-2005; Project End 31-MAY-2010 Summary: (provided by applicant): Myotonic Dystrophy 2 (DM2) is a common muscular disease clinically related to Myotonic Dystrophy 1 (DM1). DM2 is caused by expansion of CCTG repeats in intron 1 of the zinc finger factor encoding gene, ZNF9, located on chromosome 3q. While some symptoms in the patients with DM1 and DM2 are similar, others are specific just for one type of disease. DM2 specific features include a lack of congenital form of disease, lack of developmental brain abnormalities, lack of retardation and significantly milder symptoms in skeletal muscle. The main focus of research in my laboratory is the investigation of molecular bases for DM1 and DM2. In the course of our studies on DM1, we found that expansion of CTG triplet repeats in DMPK gene causes DM1 pathology through un-translated RNA CUG repeats. CUG repeat expansion affects two RNA-binding proteins, CUGBP1 and MNBL. DM2 is also caused by expansion of untranslated CCTG repeats suggesting similar RNA-dependent mechanisms for DM1 and DM2. However, specific features of DM2 phenotype suggest that molecular mechanisms of DM2 are not identical to those of DM1. We found that RNA CCUG repeats in DM2 interact with distinct RNA-binding proteins and with large protein-protein complexes, designated as Mega Protein-Protein Complexes (MPPC). These complexes bind specifically to CCUG repeats but not to CUG repeats. MPPC are observed in cytoplasm and in nuclei of DM2 cells. The amounts of cytoplasmic MPPC are increased in DM2 myoblasts, while the levels of nuclear MPPC are reduced in DM2 patients. The major hypothesis of this application is that CCUG repeats cause DM2 pathology via changes of biological functions of large protein-protein complexes. Three Specific Aims are designed to test this hypothesis. We have found that cytoplasmic MPPC contains 9 proteins including CUGBP1, eJF-2a and eIF-2p, all three proteins are involved in the regulation of translation of mRNAs. Specific Aim 1 will identify other protein components of cytoplasmic MPPC and examine the role of cytoplasmic MPPC in mRNA translation. Specific Aim 2 will determine identity of proteins within nuclear MPPC, examine if this complex plays a role in splicing and investigate if the alterations in nuclear MPPC cause abnormal splicing in DM2. Specific Aim 3 will study the mechanisms by which expansion of CCUG repeats increases amounts of MPPC in cytoplasm of DM2 cells and reduces amounts of MPPC in nuclei.

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Project Title: NON-INVASIVE CARDIO-PULMONARY MONITOR FOR MICE Principal Investigator & Institution: Baruch, Martin Carl.; Empirical Technologies Corporation Box 8175, 3046A Berkmar Drive Charlottesville, Va 229068175 Timing: Fiscal Year 2006; Project Start 01-JAN-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The results of the Phase I effort, during the course of which the physiological signals of eight mice were determined and correlated with established "golden standard" techniques, have demonstrated the feasibility of monitoring and identifying clearly distinguishable physiological signals by measuring the mouse's chest movements with a saddle-type sensor. More importantly, the results clearly established that this sensor can answer the need for the long-term and continuous monitoring of mobile mice, particularly those animals whose state of health is so precarious as a result of genetic intervention and age that invasive monitoring means are not an option. As part of the Phase II effort the system will be miniaturized so

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27

that the entire sensing assembly can be moved onto the mouse and a miniature wireless transmission system will be integrated into the sensor system. The real-time signal processing algorithms will be optimized and a computer-based graphical user interface (GUI) completed. In order to validate the performance of the sensing system, two studies will be performed at the University of Virginia on mouse populations whose fragile state of health does not permit invasive monitoring. One study will involve mice with inducible myotonic dystrophy, while the other will study asthmatic mice. An alliance has been formed with a well-known manufacturer of physiological monitoring equipment to commercialize the product. The need for the long-term monitoring of cardiopulmonary rhythms in mice is growing along with an increasing population of mice strains that are being used to test drug responses, genetic engineering attempts, and other factors that can affect these biological rhythms. This sensor technology can answer the need for the long-term and continuous monitoring of mobile mice, particularly those animals whose state of health is precarious as a result of genetic intervention and age that invasive monitoring means are not an option. •

Project Title: EXPRESSION

NUCLEAR

AND

GENOMIC

ORGANIZATION

OF

GENE

Principal Investigator & Institution: Lawrence, Jeanne B.; Professor; Cell Biology; Univ of Massachusetts Med Sch Worcester Worcester, Ma 01655 Timing: Fiscal Year 2005; Project Start 01-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): Research proposed is directed to understanding the interplay between complex nuclear structure, gene expression, and genomic organization. It is increasingly recognized that the mammalian nucleus is more complex than earlier envisioned, with a number of distinct intranuclear compartments or "domains" whose functions are yet to be uncovered. Our focus is on the functional relationship of specific gone loci and mRNAs (or pre-mRNAs) with SC35 domains, regions rich in poly (A) RNA and mRNA metabolic factors. A substantial subset of active protein-coding genes position at the immediate periphery of these domains. This positioning is correlated with cell-type specific gene regulation. In contrast, some inactive genes localize to a heterochromatic compartment. In addition, Cajal Bodies associate with snRNA and histone genes while PML domains are known to associate with DNA viruses. Hence, genes are expressed (or repressed) in different nuclear environments. This concept has far-reaching but unexplored implications for gone expression. In Aim 1 we will investigate what sequences or properties of a gene locus determine association with SC35 domains, which we suggest may be reciprocally related to localization in the heterochromatic compartment. The cause and effect relationships between domain association and gene transcription, and the possible influence of "nuclear neighborhood" will be examined. Aim 2 investigates the hypothesis that passage of some largely spliced mRNAs through an SC35 domain is a previously unrecognized step in early transport from the gene, and can be blocked in conditions that perturb nuclear trafficking. Strategies include the analysis of specific human disease mutations that block transport of mutant transcripts, applied specifically to nuclear RNAs carrying triplet repeats in myotonic dystrophy. Aim 3 proposes development of a novel approach that couples bioinformatic analysis of genomic sequence with molecular cytology to investigate potential inter-relationships between chromosomal linkage, gene expression, and nuclear compartments. Hypotheses tested have potential to elucidate the functional evolution of the karyotype and such features as cytogenetic bands and conserved gene clusters, which may associate with distinct intranuclear compartments.

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Project Title: RNA DOMINANCE IN HUMAN DISEASE Principal Investigator & Institution: Swanson, Maurice S.; Professor; Molecular Genetics & Microbiol; University of Florida 219 Grinter Hall Gainesville, Fl 32611 Timing: Fiscal Year 2005; Project Start 01-APR-2000; Project End 31-MAR-2010 Summary: (provided by applicant): Although myotonic dystrophy (DM) is the most prevalent muscular dystrophy in adults, a more severe form of this neuromuscular disease is congenital DM (COM). While the two characterized types of adult-onset DM, DM1 and DM2, are caused by unstable microsatellite (CTG)n and (CCTG)n expansions in the DMPK and ZNF9 genes, respectively, CDM is only associated with >1,000 CTG repeats in the DMPK gene. The longterm goals of the proposed research are to elucidate the molecular events which result in CDM and use this information to develop novel therapeutic strategies for this disease. According to the RNA dominance model, DM is an RNA gain-of-function disease in which mutant DMPK and ZNF9 RNAs are retained in the nucleus where they inhibit the functions of the muscleblind-like (MBNL) proteins. MBNL proteins are alternative splicing factors and current evidence suggests that DM disease is caused by the retention of neonatal protein isoforms in the adult. The objective of this proposal is to use both knockout and transgenic mouse models to extend the RNA dominance model to CDM using four experimental aims. First, the hypothesis that specific Mbnl proteins are sequestered during embryogenesis by (CUG)n expansions will be tested using a new transgenic mouse model for CDM. Second, CDM is characterized by neonatal hypotonia and mental retardation so potential roles for Mbnl proteins in the regulation of pre-mRNA processing during embryonic muscle and brain development will be investigated. Third, CDM is only associated with DMPK CTG repeat expansions and previous studies have reported changes in the expression of DMPK, as well as the linked genes DMWD and SIX5, in CDM. Therefore, several mouse knockout lines will be generated to test the hypothesis that CDM results from coordinate loss of MBNL and one, or several, of these DMPK associated genes. Fourth, overexpression of DMPK RNA inhibits myogenic differentiation so the hypothesis that CDM results from co-sequestration of MBNL and DMPK RNA-binding proteins will be evaluated.

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Project Title: DYSTROPHIES

RNA-MEDIATED

MECHANISMS

IN

THE

MYOTONIC

Principal Investigator & Institution: Thornton, Charles A.; Neurology; University of Rochester 517 Hylan Bldg., Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2005; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The myotonic dystrophies [DM], including myotonic dystrophy type 1 [DM 1] and myotonic dystrophy type 2 [DM2], are dominantly inherited, multisystem diseases that share the major disease manifestations of myotonia, wasting ad weakness. DM1 is caused by an unstable CTG repeat expansion on chromosome 19q13.3 and DM2 by an unstable CCTG repeat expansion 3q21. The cause for the skeletal muscle findings in these disorders remains a mystery. We hypothesize that they result from toxic effect of mutant RNA, a RNA mediated gain of function. Support for our hypothesis comes from studies in a mouse model of DM1. The muscles of the mice show a focal accumulation of expanded CUG repeats in the nucleus. These nuclear foci closely resemble the RNA foci of expanded CUG repeats in DM1 and expanded CCUG repeats in DM2. Expression of the expanded CUG repeat in the transgenic model causes myotonia, like that seen in DM1 and DM2. We have obtained evidence that myotonia in the transgenic model results from aberrant splicing of the chloride channel 1(CIC-1) pre-mRNA, and consequent loss of CIC-1 protein and

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chloride conductance from the muscle membrane. We hypothesize that a similar RNAmediated disturbance of RNA processing underlines myotonia and other disease manifestations in DM1. To test this hypothesis we will evaluate patients with DM1 and DM2, disease controls, and normals using clinical and electromyographic testing, needle muscle biopsy, tissue culture techniques, studies of RNA expression and splicing, immunofluorescence microscopy, and microarray analysis to address four specific aims. These aims are: 1) define the mechanism of myotonia - analyze splicing of CIC1 inDM1 and DM2; 2) determine the extent of mis-splicing (beyond CIC1) in DM1 and DM2; 3) examine the structure/distribution/protein binding characteristics of the nuclear foci containing the expanded repeats in DM1 and DM2; and, 4) assess the expression profile of mRNA inDM1 and DM2. The results of these investigations will shed light on the possibility that RNA gain-of-function represents a fundamental, shared disease mechanism in all forms of myotonic dystrophy. The findings may also help to explain the common clinical manifestations that occur in DM1, DM2, and other myotonic dystrophy like disorders. Ultimately our results may improve our understanding of the pathophysiology of DM and guide us toward the development of new approaches to treatment. •

Project Title: STABILITY & FRAGILITY OF TRINUCLEOTIDE REPEATS IN YEAST Principal Investigator & Institution: Freudenreich, Catherine H.; Assistant Professor; Biology; Tufts University Medford 20 Professors Row Medford, Ma 02155 Timing: Fiscal Year 2005; Project Start 01-MAY-2001; Project End 31-JAN-2007 Summary: (Verbatim from the applicant's abstract): Expansion of trinucleotide repeat (TNR) sequences is the causative mutation for a number of hereditary diseases, including myotonic dystrophy, the most common dystrophy in adults, Fragile X syndrome, the most common form of inherited mental retardation, and neurodegenerative diseases such as Huntington's and the spinocerebellar ataxias. The mechanism of TNR instability is interesting both for understanding the etiology and inheritance of the triplet repeat diseases, and for a basic understanding of genome stability in humans. In addition, expanded CGG/CCG and CTGICAG sequences are sites of chromosome fragility, areas prone to breakage in vivo. Chromosome breakage is implicated in the generation of translocations and deletions found in many types of cancer. The aim of this proposal is to elucidate the mechanisms involved in TNR instability and fragility, and determine how these two unusual characteristics are interrelated using Saccharomyces cerevisiae. A novel genetic assay has been developed that produces a selectable phenotype when a TNR tract expands or breaks. This assay will be used to screen for proteins whose over-expression influences TNR expansion or fragility. The proteins found to influence TNRs will be characterized to determine both their normal cellular functions and their influence on repeat maintenance. In addition, the hypothesis that TNR expansions occur by aberrant lagging strand replication will be tested by analyzing tract stability (by PCR) and fragility (by genetic and physical analysis) in specific yeast replication mutants. The role of the G2IM checkpoint in detecting TNR tract damage and preventing chromosome breakage will be investigated by comparing rates of TNR tract breakage in wild-type and cheokpoint-defective cells. Lastly, these analyses will be extended to other types of minisatellite sequences that act as fragile sites in human cells. The proposed experiments are designed to elucidate not only how simple repeats expand to cause human disease, but also the consequences of and cellular response to expanded tracts, with the goal of understanding how genomic instability can affect human health.

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Project Title: STRUCTURAL AND FUNCTIONAL CNS CHANGES IN MYOTONIC DYSTROPHY TYPES 1 AND 2 Principal Investigator & Institution: Day, John W.; Neurology; University of Minnesota Twin Cities 450 Mcnamara Alumni Center Minneapolis, Mn 554552070 Timing: Fiscal Year 2007; Project Start 01-APR-2007; Project End 31-MAR-2012 Summary: (provided by applicant): Myotonic Dystrophy (DM), one of the most common forms of muscular dystrophy, is a multisystemic disorder caused by mutations on either chromosome 19 (DM1) or chromosome 3 (DM2). The pathophysiological effects of the DM1 mutation have been controversial because it is an untranslated CTG expansion in the 3' region of a gene, and thus causes this severe dominantly inherited disease without affecting the coding portion of a gene. The discovery that DM2 is caused by a similarly untranslated CCTG expansion, along with other discoveries about DM1 pathogenesis, have helped define a new disease mechanism in which both diseases are caused by a toxic RNA mechanism: transcripts with CUG or CCUG expansions collect in nuclei and affect cell function, at least in part by altering splicing of downstream genes. Our comparisons of DM1 and DM2 have shown that the features common to both diseases likely result from these RNA effects. Much of DM morbidity results from CMS deficits, most dramatically the mental retardation that is only seen in DM1. Because CMS effects differ in DM1 and DM2, whether they are caused by altered RNA processing is controversial. Our preliminary quantitative studies now show comparable MRI and functional CNS changes in DM1 and DM2, implying a toxic RNA cause these effects: 1) loss of frontal lobe volume; 2) frontal white matter abnormalities measured by diffusion tensor imaging; 3) trends toward altered executive, function consistent with the frontal lobe structural changes. Because DM2 is purely late-onset, CNS effects that are common to both forms of DM are likely caused by neurodegeneration, which we will characterize, in addition to defining neurodevelopmental DM1 effects, by cross-sectional and longitudinal studies of four strictly defined groups of adults: adult-onset DM1, adult-onset DM2, congenital DM1, and normal controls. These studies will identify CNS features common to DM1 and DM2 that likely result from RNA toxicity, as well as differences for which pathophysiological mechanisms will need to be clarified. We will also genetically characterize subjects, and maintain cell cultures, which with our ongoing collection of autopsy material will help in future molecular and cellular studies. Our large population of DM subjects, and our unique imaging and neuropsychological capabilities, will now help us understand the devastating CNS features of DM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURE AND FUNCTION OF CTCF: MOUSE MODEL STUDIES Principal Investigator & Institution: Filippova, Galina N.; Staff Scientist; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 981091024 Timing: Fiscal Year 2005; Project Start 05-JUN-1996; Project End 30-JUN-2008 Summary: (provided by applicant): CTCF is a highly conserved 11 Zn finger (ZF) transcription factor and insulator protein. CTCF is involved in multiple aspects of gene regulation including promoter activation and repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Moreover, our recent discovery of a methylationsensitive CTCF insulator at the DM1 locus that might be responsible for the severe phenotype of Congenital Myotonic Dystrophy (Filippova et al.,2001), and our preliminary data on the role of CTCF

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insulators in X chromosome inactivation strongly suggest a link between CTCF and epigenetic regulation in development. Several findings also point to a role for CTCF as a tumor suppressor gene in both cancer epigenetics and genetics. Aberrant methylation of certain CTCF target sites, that is predicted to prevent CTCF-binding, has been demonstrated in a number of tumors. CTCF maps to human chromosome 16q22, within a region that displays frequent cancer-associated deletions (Filippova et al.,1998). We have observed somatic missense mutations within the CTCF 11ZF DNA-binding domain in breast, prostate and Wilms' tumors (Filippova et al.,2002). CTCF +/- mice exhibit enhanced tumor development in multiple tissues. Homozygous deletion of the CTCF results in early embryonic lethality, whereas the CTCF heterozygous mice exhibit decreased embryonic survival. Our broad and longterm hypothesis is that certain functions of CTCF are essential in early development and maintaining cell viability, whereas its other functions, when lost, result in the malignant phenotype. To test this hypothesis our specific aims will: Extend our studies on the role of CTCF in tumorigenesis (Aim 1) and early embryonic development (Aim 2). We will determine what genetic and epigenetic mechanisms are involved in CTCF haploinsufficiency. And finally (Aim 3), we will use the Cre-loxP system to generate a conditional CTCF mutant allele, that in combination with various tissue-specific Cre transgenic mice will allow us to test the hypothesis that complete loss of CTCF function leads to cell death in both normal and/or malignant cells, whereas loss of one CTCF allele in somatic tissue predisposes to tumor development. We will also generate knock-in mice harboring CTCF Zn finger point mutations that we have observed in human tumors to determine the functional significance of such mutated alleles in tumor predisposition. The significance of this proposal is that identifying the mechanisms of the CTCF haploinsufficiency will provide new insight into the broad spectrum of clinical human cancer phenotypes associated with LOH at 16q22.1 where CTCF maps. The healthrelatedness is that the identified mechanisms can be targeted for both cancer prevention and therapeutic intervention. •

Project Title: SUPPORTING RNASTRUCTURE: SOFTWARE FOR RNA ANALYSIS Principal Investigator & Institution: Mathews, David H.; Dentistry; University of Rochester 517 Hylan Bldg., Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 30-JUN-2010 Summary: (provided by applicant): RNA plays many important roles in cellular function. In the Central Dogma of Biology, RNA serves as a transient carrier of genetic information and as the adapter molecule that reads the code. RNA catalyzes reactions and serves in post-transcriptional gene regulation, development, and immunity. RNA also plays roles in human disease, including Prader-Willi and myotonic dystrophy. Understanding and harnessing the power of RNA, e.g. with RNAi, antisense technology, or with therapeutic ribozymes, requires an understanding of the structures of these RNA sequences. RNAstructure is a software package for RNA secondary structure prediction and analysis. It is available at: http://rna.urmc.rochester.edu and has been downloaded by a total of over 11,000 users. The specific aims of this proposal include both development and maintenance for the RNAstructure package: 1) Develop enthalpy nearest neighbor parameters for RNA secondary structure formation to allow structure prediction and analysis at other temperatures. 2) Construct a web server to provide RNA secondary structure nearest neighbor parameters and offer tutorials on their use. 3) Add RNAML support to the existing software to improve interoperability with other software packages. 4) Port RNAstructure to Unix, Linux, and Macintosh OS X using the Java runtime library to build a user-interface. 5) Provide high quality Adobe Acrobat File (pdf) output directly from RNAstructure, so that predicted structures can

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be edited for publication. 6) Update RNAstructure for 64-bit Microsoft Windows Vista. 7) Provide source code for download under an open license. 8) Construct a web server for the OligoWalk algorithm for predicting equilibrium binding affinities to an RNA target. Web servers are highly popular because of there ease of use. 9) Offer an email reflector for communication by the RNAstructure user community. This work has broad implications for human health. The computer tools contained in RNAstructure are used by others to determine RNA sequences that are good drug targets. RNAstructure is also useful for the design of RNA-based Pharmaceuticals. •

Project Title: THE ROLE OF CTG REPEATS IN DM1 LOCUS REGULATION Principal Investigator & Institution: Georges, Sara A.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 981091024 Timing: Fiscal Year 2005; Project Start 01-SEP-2005; Project End 31-AUG-2007 Summary: (provided by applicant): Myotonic Dystrophy (DM1) is caused by expansion of CTG repeats located within an insulator element at the DM1 locus. My central hypothesis is that the precise establishment of chromatin structure by wild type CTG repeats and CTCF binding sites at the DM1 insulator is critical for the maintenance of transcriptional regulation at the DM1 locus, and that CTG expansion-mediated alterations in chromatin structure and the loss of CTCF binding are critical events in the onset of myotonic dystrophy. I propose to test this central hypothesis through three interrelated specific aims: 1) determine the influence of CTG repeats, and CTG repeat expansion, on the chromatin structure of the DM1 locus, 2) determine how CTG repeats, CTG repeat expansion, and CTCF binding affect DM1 insulator function, and 3) determine the contribution of CTCF binding to the DM1 insulator to the congenital DM1 phenotype using a mouse model. The long term objective of this research is to increase our understanding of the molecular mechanisms underlying the development of both adult-onset and congenital myotonic dystrophy.

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Project Title: TRIPLET REPEAT INSTABILITY IN HUMAN TISSUE CULTURE CELLS Principal Investigator & Institution: Farrell, Brian T.; Eppley Institute for Research in Cancer & Allied Diseases; University of Nebraska Medical Center 987835 Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2005; Project Start 10-APR-2003; Project End 08-JUL-2008 Summary: (provided by applicant): Trinucleotide repeat (TNR) expansions cause at least 15 neurodegenerative disorders, including Huntington's disease (HD), Friedreich ataxia, myotonic dystrophy and >90% of inherited spinocerebellar ataxias (SCAs). While these diseases are devastating and relentlessly fatal, they show several fascinating genetic properties. First, these mutations occur at a much higher frequency that spontaneous mutations, in some extreme cases with a frequency approaching 100%. Also, TNR expansions are a unique form of mutation in which repeating triplets of nucleotides linearly amplify themselves between successive generations. Amplification of the repeating sequence also produces genetic anticipation, a worsening of disease phenotype of the TNR diseases. I will use a sensitive, specific and portable genetic assay recently optimized in the laboratory of Dr. Robert Lahue to investigate the etiology of TNR instability in human cells. This work will not only enable me to receive expert training in an interesting and important area of basic science research, but will also allow me to advance our understanding of an entire class of fatal neurological diseases.

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

A 5-year follow-up study of an atypical case of myotonic dystrophy. Author(s): Macniven JA, Graham NL, Davies RR, Wilson BA. Source: Brain Injury : [bi]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16286337&query_hl=9&itool=pubmed_docsum

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A case of myotonic dystrophy associated with SIADH. Author(s): Tamaoka A, Nishimura Y. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3585431&query_hl=9&itool=pubmed_docsum

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A locus at 19cen-19q13.2 (D19S15) containing three RFLPs linked to myotonic dystrophy (DM) is recognized by probe pJSB6. Author(s): Schepens J, Hulsebos T, Smeets H, Coerwinkel M, Brunner H, Ropers HH, Wieringa B. Source: Nucleic Acids Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2882485&query_hl=9&itool=pubmed_docsum

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A long PCR-based molecular protocol for detecting normal and expanded ZNF9 alleles in myotonic dystrophy type 2. Author(s): Bonifazi E, Vallo L, Giardina E, Botta A, Novelli G. Source: Diagnostic Molecular Pathology : the American Journal of Surgical Pathology, Part B. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15322428&query_hl=9&itool=pubmed_docsum

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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A neonatal form of Steinert's myotonic dystrophy in twins after in vitro fertilization. Author(s): Garcia de Andoin N, Echeverria J, Cobo AM, Rey A, Paisan L, Lopez de Munain A. Source: Fertility and Sterility. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16169416&query_hl=9&itool=pubmed_docsum

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A pilot study of dehydroepiandrosterone sulfate in myotonic dystrophy. Author(s): Sugino M, Ohsawa N, Ito T, Ishida S, Yamasaki H, Kimura F, Shinoda K. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9710041&query_hl=9&itool=pubmed_docsum

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A reversal of misfortune for myotonic dystrophy? Author(s): Cooper TA. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17065646&query_hl=9&itool=pubmed_docsum

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A wide complex tachycardia in a woman with myotonic dystrophy: what is the tachycardia mechanism? Author(s): Veenhuyzen GD, Simpson CS, Abdollah H. Source: Journal of Cardiovascular Electrophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16101638&query_hl=9&itool=pubmed_docsum

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Abnormal liver test results in myotonic dystrophy. Author(s): Achiron A, Barak Y, Magal N, Shohat M, Cohen M, Barar R, Gadoth N. Source: Journal of Clinical Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9649014&query_hl=9&itool=pubmed_docsum

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Aerobic training in patients with myotonic dystrophy type 1. Author(s): Orngreen MC, Olsen DB, Vissing J. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15852373&query_hl=9&itool=pubmed_docsum

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Age and causes of death in adult-onset myotonic dystrophy. Author(s): de Die-Smulders CE, Howeler CJ, Thijs C, Mirandolle JF, Anten HB, Smeets HJ, Chandler KE, Geraedts JP. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9712016&query_hl=9&itool=pubmed_docsum

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Altered expression of CUG binding protein 1 mRNA in myotonic dystrophy 1: possible RNA-RNA interaction. Author(s): Watanabe T, Takagi A, Sasagawa N, Ishiura S, Nakase H. Source: Neuroscience Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15099703&query_hl=9&itool=pubmed_docsum

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Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1. Author(s): Kimura T, Nakamori M, Lueck JD, Pouliquin P, Aoike F, Fujimura H, Dirksen RT, Takahashi MP, Dulhunty AF, Sakoda S. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15972723&query_hl=9&itool=pubmed_docsum

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Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec. Author(s): Yotova V, Labuda D, Zietkiewicz E, Gehl D, Lovell A, Lefebvre JF, Bourgeois S, Lemieux-Blanchard E, Labuda M, Vezina H, Houde L, Tremblay M, Toupance B, Heyer E, Hudson TJ, Laberge C. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15883838&query_hl=9&itool=pubmed_docsum

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Anesthetic management of a patient with myotonic dystrophy for a Nissen fundoplication and gastrostomy. Author(s): Jenkins JA, Facer EK. Source: Paediatric Anaesthesia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15283832&query_hl=9&itool=pubmed_docsum

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Anterior temporal white matter lesions in myotonic dystrophy with intellectual impairment: an MRI and neuropathological study. Author(s): Ogata A, Terae S, Fujita M, Tashiro K. Source: Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9730337&query_hl=9&itool=pubmed_docsum

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Association of primary hyperparathyroidism with myotonic dystrophy in two patients. Author(s): Harada S, Matsumoto T, Ikeda K, Fukumoto S, Ihara Y, Ogata E. Source: Archives of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3827466&query_hl=9&itool=pubmed_docsum

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Association of spinal and bulbar muscular atrophy with myotonic dystrophy type 1. Author(s): Jinnai K, Nishimoto K, Itoh K, Hashimoto K, Takahashi K. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15116379&query_hl=9&itool=pubmed_docsum

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Atrial fibrillation following chemotherapy for stage IIIE diffuse large B-cell gastric lymphoma in a patient with myotonic dystrophy (Steinert's disease). Author(s): Montella L, Caraglia M, Addeo R, Costanzo R, Faiola V, Abbruzzese A, Del Prete S. Source: Annals of Hematology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15042318&query_hl=9&itool=pubmed_docsum

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Axonal function and activity-dependent excitability changes in myotonic dystrophy. Author(s): Krishnan AV, Kiernan MC. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16453325&query_hl=9&itool=pubmed_docsum

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Basal metabolic rate in myotonic dystrophy: evidence against hypometabolism. Author(s): Jozefowicz RF, Welle SL, Nair KS, Kingston WJ, Griggs RC. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3587621&query_hl=9&itool=pubmed_docsum

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Belated diagnosis of congenital myotonic dystrophy in a boy with cerebral palsy. Author(s): Jung SH, Bang MS. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17251698&query_hl=9&itool=pubmed_docsum

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Beta-adrenergic system in myotonic dystrophy. Author(s): Somer H, Maki T, Harkonen M. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1331339&query_hl=9&itool=pubmed_docsum

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Bilateral extraocular muscle atrophy in myotonic dystrophy type 1. Author(s): Yamashita T, Matsubara E, Nagano I, Shoji M, Abe K. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15326270&query_hl=9&itool=pubmed_docsum

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Bilateral optic nerve atrophy in myotonic dystrophy. Author(s): Gamez J, Montane D, Martorell L, Minoves T, Cervera C. Source: American Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11239886&query_hl=9&itool=pubmed_docsum

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Biochemical study in myotonic dystrophy. Author(s): Pendefunda G, Ciobanu M, Stefanache F. Source: Rev Med Chir Soc Med Nat Iasi. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1188215&query_hl=9&itool=pubmed_docsum

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Biomedicine. Reconstructing myotonic dystrophy. Author(s): Tapscott SJ, Thornton CA. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11486078&query_hl=9&itool=pubmed_docsum

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Biomolecular identification of (CCTG)n mutation in myotonic dystrophy type 2 (DM2) by FISH on muscle biopsy. Author(s): Cardani R, Mancinelli E, Sansone V, Rotondo G, Meola G. Source: Eur J Histochem. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15718211&query_hl=9&itool=pubmed_docsum

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Blunted coronary reserve in myotonic dystrophy. An early and gene-related phenomenon. Author(s): Annane D, Merlet P, Radvanyi H, Mazoyer B, Eymard B, Fiorelli M, Junien C, Fardeau M, Ounnoughene Z, Gajdos P, Syrota A, Duboc D. Source: Circulation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8790034&query_hl=9&itool=pubmed_docsum

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Bone anomalies in myotonic dystrophy. Author(s): Rodriguez JR, Castillo J, Leira R, Pardo J, Lema M, Noya M. Source: Acta Neurologica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1887757&query_hl=9&itool=pubmed_docsum

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Brain 1H magnetic resonance spectroscopic differences in myotonic dystrophy type 2 and type 1. Author(s): Vielhaber S, Jakubiczka S, Gaul C, Schoenfeld MA, Debska-Vielhaber G, Zierz S, Heinze HJ, Niessen HG, Kaufmann J. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16642499&query_hl=9&itool=pubmed_docsum

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Brain disease and molecular analysis in myotonic dystrophy. Author(s): Damian MS, Bachmann G, Koch MC, Schilling G, Stoppler S, Dorndorf W. Source: Neuroreport. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7696601&query_hl=9&itool=pubmed_docsum

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Brain involvement in myotonic dystrophy: MRI features and their relationship to clinical and cognitive conditions. Author(s): Censori B, Provinciali L, Danni M, Chiaramoni L, Maricotti M, Foschi N, Del Pesce M, Salvolini U. Source: Acta Neurologica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7847063&query_hl=9&itool=pubmed_docsum

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Brain magnetic resonance image changes in a family with congenital and classic myotonic dystrophy. Author(s): Kuo HC, Hsiao KM, Chen CJ, Hsieh YC, Huang CC. Source: Brain & Development. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15862193&query_hl=9&itool=pubmed_docsum

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Brain MRI features of congenital- and adult-form myotonic dystrophy type 1: casecontrol study. Author(s): Di Costanzo A, Di Salle F, Santoro L, Bonavita V, Tedeschi G. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12031621&query_hl=9&itool=pubmed_docsum

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Brain proton magnetic resonance spectroscopy and brain atrophy in myotonic dystrophy. Author(s): Akiguchi I, Nakano S, Shiino A, Kimura R, Inubushi T, Handa J, Nakamura M, Tanaka M, Oka N, Kimura J. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10190823&query_hl=9&itool=pubmed_docsum

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Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1. Author(s): Leroy O, Wang J, Maurage CA, Parent M, Cooper T, Buee L, Sergeant N, Andreadis A, Caillet-Boudin ML. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16487687&query_hl=9&itool=pubmed_docsum

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Breathing pattern awake and asleep in myotonic dystrophy. Author(s): Ververs CC, Van der Meche FG, Verbraak AF, van der Sluys HC, Bogaard JM. Source: Respiration; International Review of Thoracic Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8833986&query_hl=9&itool=pubmed_docsum

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Breathing pattern awake and asleep in patients with myotonic dystrophy. Author(s): Veale D, Cooper BG, Gilmartin JJ, Walls TJ, Griffith CJ, Gibson GJ. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7656955&query_hl=9&itool=pubmed_docsum

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Brief report: reverse mutation in myotonic dystrophy. Author(s): Brunner HG, Jansen G, Nillesen W, Nelen MR, de Die CE, Howeler CJ, van Oost BA, Wieringa B, Ropers HH, Smeets HJ. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8421477&query_hl=9&itool=pubmed_docsum

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Cardiac abnormalities in myotonic dystrophy type 1. Author(s): Finsterer J, Stollberger C. Source: American Heart Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15632870&query_hl=9&itool=pubmed_docsum

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Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): a quantitative 31P-MRS and MRI study. Author(s): Schneider-Gold C, Beer M, Kostler H, Buchner S, Sandstede J, Hahn D, Toyka KV. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15452841&query_hl=9&itool=pubmed_docsum

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Cardiovascular autonomic control in myotonic dystrophy type 1: a correlative study with clinical and genetic data. Author(s): Di Leo R, Rodolico C, De Gregorio C, Recupero A, Coglitore S, Annesi G, Toscano A, Messina C, Vita G. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14733960&query_hl=9&itool=pubmed_docsum

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Cerebral atrophy in myotonic dystrophy: a voxel based morphometric study. Author(s): Antonini G, Mainero C, Romano A, Giubilei F, Ceschin V, Gragnani F, Morino S, Fiorelli M, Soscia F, Di Pasquale A, Caramia F. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15489397&query_hl=9&itool=pubmed_docsum

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Characterization of a single nucleotide polymorphism in the ZNF9 gene and analysis of association with myotonic dystrophy type II (DM2) in the Italian population. Author(s): Vallo L, Bonifazi E, Borgiani P, Novelli G, Botta A. Source: Molecular and Cellular Probes. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15652222&query_hl=9&itool=pubmed_docsum

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Characterization of the pattern of cognitive impairment in myotonic dystrophy type 1. Author(s): Modoni A, Silvestri G, Pomponi MG, Mangiola F, Tonali PA, Marra C. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15596617&query_hl=9&itool=pubmed_docsum

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Clinical characteristics of myotonic dystrophy type 1 patients with small CTG expansions. Author(s): Arsenault ME, Prevost C, Lescault A, Laberge C, Puymirat J, Mathieu J. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16636244&query_hl=9&itool=pubmed_docsum

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Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy. Author(s): Ho TH, Savkur RS, Poulos MG, Mancini MA, Swanson MS, Cooper TA. Source: Journal of Cell Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15961406&query_hl=9&itool=pubmed_docsum

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Congenital myotonic dystrophy complicated by ventricular tachycardia--early onset in infancy. Author(s): Lee SY, Ng DK, Kwok KL, Cherk SW, Ho CS, Yuen KN. Source: Journal of Paediatrics and Child Health. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15228577&query_hl=9&itool=pubmed_docsum

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Congenital myotonic dystrophy. Author(s): Upadhyay K, Thomson A, Luckas MJ. Source: Fetal Diagnosis and Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16260886&query_hl=9&itool=pubmed_docsum

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Congenital myotonic dystrophy: a rare cause of polyhydramnios. Author(s): Jayawant S, Sinha R. Source: Indian Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15297697&query_hl=9&itool=pubmed_docsum

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Congenital myotonic dystrophy: assisted ventilation duration and outcome. Author(s): Campbell C, Sherlock R, Jacob P, Blayney M. Source: Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15060232&query_hl=9&itool=pubmed_docsum

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Congenital myotonic dystrophy: variability in muscle involvement and histopathological process. Author(s): Kuo HC, Huang CC, Chu CC, Wai YY, Hsiao KM, Chu NS. Source: Acta Neurol Taiwan. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16599279&query_hl=9&itool=pubmed_docsum

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Contrasts in clinical presentation and genetic transmission of myotonic dystrophy. Author(s): Reifer H, Sobel E. Source: Journal of the American Podiatric Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9680767&query_hl=9&itool=pubmed_docsum

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Control of E1A under an E2F-1 promoter insulated with the myotonic dystrophy locus insulator reduces the toxicity of oncolytic adenovirus Ad-Delta24RGD. Author(s): Majem M, Cascallo M, Bayo-Puxan N, Mesia R, Germa JR, Alemany R. Source: Cancer Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16498429&query_hl=9&itool=pubmed_docsum

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Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2. Author(s): Kornblum C, Reul J, Kress W, Grothe C, Amanatidis N, Klockgether T, Schroder R. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15311347&query_hl=9&itool=pubmed_docsum

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CTG repeat number at the myotonic dystrophy locus in healthy Kuwaiti individuals: possible explanation of why myotonic dystrophy is rare in Kuwait. Author(s): Alfadhli S, Elshafey AE, Bastaki L, Al-Awadi S. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15210527&query_hl=9&itool=pubmed_docsum

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Cystic insulinoma of the pancreas in a patient with myotonic dystrophy: correlation of imaging and pathologic findings. Author(s): Vandecaveye V, Verswijvel G, Colla P, Verhelst H, VanRobaeys J, Palmers Y. Source: Jbr-Btr. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14651081&query_hl=9&itool=pubmed_docsum

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Cytoplasmic and nuclear retained DMPK mRNAs are targets for RNA interference in myotonic dystrophy cells. Author(s): Langlois MA, Boniface C, Wang G, Alluin J, Salvaterra PM, Puymirat J, Rossi JJ, Lee NS. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15722335&query_hl=9&itool=pubmed_docsum

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Decreased expression of DMPK: correlation with CTG repeat expansion and fibre type composition in myotonic dystrophy type 1. Author(s): Salvatori S, Fanin M, Trevisan CP, Furlan S, Reddy S, Nagy JI, Angelini C. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16193250&query_hl=9&itool=pubmed_docsum

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Decreased hypocretin-1 (Orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness. Author(s): Martinez-Rodriguez JE, Lin L, Iranzo A, Genis D, Marti MJ, Santamaria J, Mignot E. Source: Sleep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12749547&query_hl=9&itool=pubmed_docsum

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Decreased levels of myotonic dystrophy protein kinase (DMPK) and delayed differentiation in human myotonic dystrophy myoblasts. Author(s): Furling D, Lemieux D, Taneja K, Puymirat J. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11595515&query_hl=9&itool=pubmed_docsum

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Decreased plasmalogen ratios in cultured skin fibroblasts from myotonic dystrophy. Author(s): Sakai T, Antoku Y. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3657848&query_hl=9&itool=pubmed_docsum

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Defective satellite cells in congenital myotonic dystrophy. Author(s): Furling D, Coiffier L, Mouly V, Barbet JP, St Guily JL, Taneja K, Gourdon G, Junien C, Butler-Browne GS. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11590125&query_hl=9&itool=pubmed_docsum

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Dehydroepiandrosterone sulfate (DHEAS) therapy for myotonic dystrophy type 1 and myotonia. Author(s): Sugino M. Source: Intern Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16415539&query_hl=9&itool=pubmed_docsum

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Deoxycholic acid in myotonic dystrophy. Author(s): Soderhall S, Gustafsson J, Bjorkhem I. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6122869&query_hl=9&itool=pubmed_docsum

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Deterioration of motor function in myotonic dystrophy and hereditary motor and sensory neuropathy. Author(s): Lindeman E, Leffers P, Spaans F, Drukker J, Reulen J. Source: Scandinavian Journal of Rehabilitation Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7792552&query_hl=9&itool=pubmed_docsum

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Diffuse xanthogranulomatous pyelonephritis in a patient with myotonic dystrophy and cerebral palsy. Author(s): Takayasu H, Ishimaru Y, Kisaki Y, Nakai H, Ueda Y, Ikeda H. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15948752&query_hl=9&itool=pubmed_docsum

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Diffusion tensor imaging of cerebral white matter in patients with myotonic dystrophy. Author(s): Fukuda H, Horiguchi J, Ono C, Ohshita T, Takaba J, Ito K. Source: Acta Radiologica (Stockholm, Sweden : 1987). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15841748&query_hl=9&itool=pubmed_docsum

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Dilated Virchow-Robin spaces in myotonic dystrophy: frequency, extent and significance. Author(s): Di Costanzo A, Di Salle F, Santoro L, Bonavita V, Tedeschi G. Source: European Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11598331&query_hl=9&itool=pubmed_docsum

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Discordant clinical outcome in myotonic dystrophy relatives showing (CTG)n > 700 repeats. Author(s): Novelli G, Gennarelli M, Menegazzo E, Angelini C, Dallapiccola B. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7767095&query_hl=9&itool=pubmed_docsum

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Distinct neuromuscular phenotypes in myotonic dystrophy types 1 and 2 : a whole body highfield MRI study. Author(s): Kornblum C, Lutterbey G, Bogdanow M, Kesper K, Schild H, Schroder R, Wattjes MP. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16511650&query_hl=9&itool=pubmed_docsum

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Disturbed personality and psychosocial adjustment in myotonic dystrophy: relationship to intellectual/cognitive function and underlying affective disorder (depression). Author(s): Brumback RA. Source: Psychological Reports. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3303093&query_hl=9&itool=pubmed_docsum

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DNA analysis in a suspected individual with myotonic dystrophy family history and her abortus. Author(s): Bi X, Xie H, Zheng H, Ding S, Zhang S, Wang Y, Xu Z, Ren D. Source: Chinese Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12609075&query_hl=9&itool=pubmed_docsum

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Domiciliary-assisted ventilation in patients with myotonic dystrophy. Author(s): Nugent AM, Smith IE, Shneerson JM. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11834657&query_hl=9&itool=pubmed_docsum

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Double-strand breaks in the myotonic dystrophy type 1 and the fragile X syndrome triplet repeat sequences induce different types of mutations in DNA flanking sequences in Escherichia coli. Author(s): Kosmider B, Wells RD. Source: Nucleic Acids Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17012280&query_hl=9&itool=pubmed_docsum

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Dropped head presentation in myotonic dystrophy type 1. Author(s): Grewal RP. Source: Neurology India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16010083&query_hl=9&itool=pubmed_docsum

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Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Author(s): Sergeant N, Sablonniere B, Schraen-Maschke S, Ghestem A, Maurage CA, Wattez A, Vermersch P, Delacourte A. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11590131&query_hl=9&itool=pubmed_docsum

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Early development of megarectum in myotonic dystrophy. Author(s): Meijers B, Miserez M, Veerman-Wouters G, Fryns JP. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12081728&query_hl=9&itool=pubmed_docsum

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Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy. Author(s): Frisch R, Singleton KR, Moses PA, Gonzalez IL, Carango P, Marks HG, Funanage VL. Source: Molecular Genetics and Metabolism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11592825&query_hl=9&itool=pubmed_docsum

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Effective doses of vecuronium in a patient with myotonic dystrophy. Author(s): Nishi M, Itoh H, Tsubokawa T, Taniguchi T, Yamamoto K. Source: Anaesthesia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15549982&query_hl=9&itool=pubmed_docsum

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Effects of a hand training programme in five patients with myotonic dystrophy type 1. Author(s): Aldehag AS, Jonsson H, Ansved T. Source: Occupational Therapy International. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15962697&query_hl=9&itool=pubmed_docsum

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Eight years' experience of direct molecular testing for myotonic dystrophy in Wales. Author(s): Fokstuen S, Myring J, Meredith L, Ravine D, Harper PS. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11748308&query_hl=9&itool=pubmed_docsum

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Electrophysiological evaluation in myotonic dystrophy: correlation with CTG length expansion. Author(s): Pfeilsticker BH, Bertuzzo CS, Nucci A. Source: Arquivos De Neuro-Psiquiatria. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11400022&query_hl=9&itool=pubmed_docsum

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Epidemiological and genetic studies of myotonic dystrophy type 1 in Taiwan. Author(s): Hsiao KM, Chen SS, Li SY, Chiang SY, Lin HM, Pan H, Huang CC, Kuo HC, Jou SB, Su CC, Ro LS, Liu CS, Lo MC, Chen CM, Lin CC. Source: Neuroepidemiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12902623&query_hl=9&itool=pubmed_docsum

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Epidemiology of myotonic dystrophy type 1 (Steinert disease) in Belgrade (Serbia). Author(s): Mladenovic J, Pekmezovic T, Todorovic S, Rakocevic-Stojanovic V, Savic D, Romac S, Apostolski S. Source: Clinical Neurology and Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16713671&query_hl=9&itool=pubmed_docsum

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ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I. Author(s): Leroy O, Dhaenens CM, Schraen-Maschke S, Belarbi K, Delacourte A, Andreadis A, Sablonniere B, Buee L, Sergeant N, Caillet-Boudin ML. Source: Journal of Neuroscience Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16862542&query_hl=9&itool=pubmed_docsum

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Excessive daytime somnolence and increased rapid eye movement pressure in myotonic dystrophy. Author(s): Thorpy M. Source: Curr Neurol Neurosci Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12583846&query_hl=9&itool=pubmed_docsum

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Excessive daytime somnolence and increased rapid eye movement pressure in myotonic dystrophy. Author(s): Gibbs JW 3rd, Ciafaloni E, Radtke RA. Source: Sleep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12224846&query_hl=9&itool=pubmed_docsum

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Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2). Author(s): Meola G, Sansone V, Perani D, Scarone S, Cappa S, Dragoni C, Cattaneo E, Cotelli M, Gobbo C, Fazio F, Siciliano G, Mancuso M, Vitelli E, Zhang S, Krahe R, Moxley RT. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14678804&query_hl=9&itool=pubmed_docsum

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Exercise and myotonic dystrophy: a 31P magnetic resonance spectroscopy and magnetic resonance imaging case study. Author(s): Trenell MI, Thompson CH, Sue CM. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16634010&query_hl=9&itool=pubmed_docsum

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Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel premRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Author(s): Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, Cannon SC, Thornton CA. Source: Molecular Cell. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12150905&query_hl=9&itool=pubmed_docsum

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Experienced fatigue in facioscapulohumeral dystrophy, myotonic dystrophy, and HMSN-I. Author(s): Kalkman JS, Schillings ML, van der Werf SP, Padberg GW, Zwarts MJ, van Engelen BG, Bleijenberg G. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16170086&query_hl=9&itool=pubmed_docsum

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Expression and localization of myotonic dystrophy protein kinase in human skeletal muscle cells determined with a novel antibody: possible role of the protein in cytoskeleton rearrangements during differentiation. Author(s): Beffy P, Barsanti C, Del Carratore R, Simi S, Benedetti PA, Benzi L, Prelle A, Ciscato P, Simili M. Source: Cell Biology International. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16099181&query_hl=9&itool=pubmed_docsum

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Expression of late myogenic differentiation markers in sarcoplasmic masses of patients with myotonic dystrophy. Author(s): Vattemi G, Tomelleri G, Filosto M, Savio C, Rizzuto N, Tonin P. Source: Neuropathology and Applied Neurobiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15634230&query_hl=9&itool=pubmed_docsum

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Expression of the human myotonic dystrophy kinase-related Cdc42-binding kinase gamma is regulated by promoter DNA methylation and Sp1 binding. Author(s): Ng Y, Tan I, Lim L, Leung T. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15194684&query_hl=9&itool=pubmed_docsum

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Extraocular muscle surgery in myotonic dystrophy. Author(s): Marshman WE, Adams GG, Cree I. Source: Journal of Pediatric Ophthalmology and Strabismus. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9627879&query_hl=9&itool=pubmed_docsum

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Eye movement abnormalities in myotonic dystrophy. Author(s): Versino M, Romani A, Bergamaschi R, Callieco R, Scolari S, Poli R, Lanfranchi S, Sandrini G, Cosi V. Source: Electroencephalography and Clinical Neurophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9741810&query_hl=9&itool=pubmed_docsum

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Facial emotion recognition in myotonic dystrophy type 1 correlates with CTG repeat expansion. Author(s): Winblad S, Hellstrom P, Lindberg C, Hansen S. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16421126&query_hl=9&itool=pubmed_docsum

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Faecal incontinence in myotonic dystrophy. Author(s): Abercrombie JF, Rogers J, Swash M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9436743&query_hl=9&itool=pubmed_docsum

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Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Author(s): Lin X, Miller JW, Mankodi A, Kanadia RN, Yuan Y, Moxley RT, Swanson MS, Thornton CA. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16717059&query_hl=9&itool=pubmed_docsum

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Falls and stumbles in myotonic dystrophy. Author(s): Wiles CM, Busse ME, Sampson CM, Rogers MT, Fenton-May J, van Deursen R. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16199443&query_hl=9&itool=pubmed_docsum

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Familial clustering of muscular and cardiac involvement in myotonic dystrophy type 1. Author(s): Groh WJ, Lowe MR, Simmons Z, Bhakta D, Pascuzzi RM. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15770673&query_hl=9&itool=pubmed_docsum

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Familial left ventricular hypertrabeculation in myotonic dystrophy type 1. Author(s): Finsterer J, Stollberger C, Kopsa W. Source: Herz. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12928748&query_hl=9&itool=pubmed_docsum

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Fatigue and daytime sleepiness rating scales in myotonic dystrophy: a study of reliability. Author(s): Laberge L, Gagnon C, Jean S, Mathieu J. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16170085&query_hl=9&itool=pubmed_docsum

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Fetal akinesia-hypokinesia deformation sequence (FADS) in 2 siblings with congenital myotonic dystrophy. Author(s): Lidang Jensen M, Rix M, Schroder HD, Teglbjaerg PS, Ebbesen F. Source: Clin Neuropathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7606895&query_hl=9&itool=pubmed_docsum

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Fission yeast orb6, a ser/thr protein kinase related to mammalian rho kinase and myotonic dystrophy kinase, is required for maintenance of cell polarity and coordinates cell morphogenesis with the cell cycle. Author(s): Verde F, Wiley DJ, Nurse P. 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=9636183&query_hl=9&itool=pubmed_docsum

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Fluorescence in situ hybridization analysis of the replication properties of the myotonic dystrophy protein kinase (DMPK) gene region. Author(s): Rajcan-Separovic E, Barcelo JM, Korneluk RG. Source: Cytogenetics and Cell Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9858828&query_hl=9&itool=pubmed_docsum

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Fluorescent PCR and automated fragment analysis for the clinical application of preimplantation genetic diagnosis of myotonic dystrophy (Steinert's disease). Author(s): Sermon K, De Vos A, Van de Velde H, Seneca S, Lissens W, Joris H, Vandervorst M, Van Steirteghem A, Liebaers I. Source: Molecular Human Reproduction. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9733437&query_hl=9&itool=pubmed_docsum

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Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. Author(s): Taneja KL, McCurrach M, Schalling M, Housman D, Singer RH. Source: The Journal of Cell Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7896884&query_hl=9&itool=pubmed_docsum

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Follicular cyst in a patient with myotonic dystrophy: a case of cyst with differentiation toward follicular infundibulum, isthmus, inner root sheath, and hair. Author(s): Nishie W, Iitoyo M, Miyazawa H. Source: The American Journal of Dermatopathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11801793&query_hl=9&itool=pubmed_docsum

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Founder effect and prevalence of myotonic dystrophy in South Africans: molecular studies. Author(s): Goldman A, Krause A, Ramsay M, Jenkins T. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8755933&query_hl=9&itool=pubmed_docsum

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Fragile-X syndrome and myotonic dystrophy: parallels and paradoxes. Author(s): Tapscott SJ, Klesert TR, Widrow RJ, Stoger R, Laird CD. Source: Current Opinion in Genetics & Development. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9610417&query_hl=9&itool=pubmed_docsum

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Free radicals, lipid peroxides and antioxidants in blood of patients with myotonic dystrophy. Author(s): Ihara Y, Mori A, Hayabara T, Namba R, Nobukuni K, Sato K, Miyata S, Edamatsu R, Liu J, Kawai M. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7751852&query_hl=9&itool=pubmed_docsum

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Frequency and stability of the myotonic dystrophy type 1 premutation. Author(s): Martorell L, Monckton DG, Sanchez A, Lopez De Munain A, Baiget M. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11171897&query_hl=9&itool=pubmed_docsum

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Frequency of intergenerational contractions of the CTG repeats in myotonic dystrophy. Author(s): Lopez de Munain A, Cobo AM, Saenz A, Blanco A, Poza JJ, Martorell L, Marti-Masso JF, Baiget M. Source: Genetic Epidemiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8905394&query_hl=9&itool=pubmed_docsum

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Frequency of myotonic dystrophy gene carriers in cataract patients. Author(s): Cobo AM, Poza JJ, Blanco A, Lopez de Munain A, Saenz A, Azpitarte M, Marchessi J, Marti Masso JF. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8728695&query_hl=9&itool=pubmed_docsum

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Further evidence for a major ancient mutation underlying myotonic dystrophy from linkage disequilibrium studies in the Japanese population. Author(s): Yamagata H, Nakagawa M, Johnson K, Miki T. Source: Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9852676&query_hl=9&itool=pubmed_docsum

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Gastric emptying in myotonic dystrophy. Author(s): Ronnblom A, Andersson S, Hellstrom PM, Danielsson A. Source: European Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12190956&query_hl=9&itool=pubmed_docsum

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Gastric myoelectrical activity and gut hormone secretion in myotonic dystrophy. Author(s): Ronnblom A, Hellstrom PM, Holst JJ, Theodorsson E, Danielsson A. Source: European Journal of Gastroenterology & Hepatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11474313&query_hl=9&itool=pubmed_docsum

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Gastric volvulus complicating myotonic dystrophy. Author(s): Kusunoki M, Hatada T, Ikeuchi H, Okamoto T, Sakanoue Y, Utsunomiya J. Source: Hepatogastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1483675&query_hl=9&itool=pubmed_docsum

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Gastrointestinal symptoms in myotonic dystrophy. Author(s): Ronnblom A, Forsberg H, Danielsson A. Source: Scandinavian Journal of Gastroenterology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8819213&query_hl=9&itool=pubmed_docsum

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Genealogical study of myotonic dystrophy in Istria (Croatia). Author(s): Medica I, Logar N, Mileta DL, Peterlin B. Source: Annales De Genetique. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15183746&query_hl=9&itool=pubmed_docsum

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Genetic epidemiology of myotonic dystrophy in Istria, Croatia. Author(s): Medica I, Markovic D, Peterlin B. Source: Acta Neurologica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9088385&query_hl=9&itool=pubmed_docsum

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Genetic mapping of a second myotonic dystrophy locus. Author(s): Ranum LP, Rasmussen PF, Benzow KA, Koob MD, Day JW. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9620781&query_hl=9&itool=pubmed_docsum

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Genetic risks for children of women with myotonic dystrophy. Author(s): Goodship J, Gibson DE, Burn J, Honeyman J, Cubey RB, Schofield I. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1530708&query_hl=9&itool=pubmed_docsum

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Genetic study of somatic mosaicism in a patient with myotonic dystrophy type 1: case report. Author(s): Rakocevic-Stojanovic V, Savic D, Romac S, Apostolski S. Source: Acta Myol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15088500&query_hl=9&itool=pubmed_docsum

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Genomic instability associated with myotonic dystrophy does not involve p53 expression and activity. Author(s): Gennarelli M, Lucarelli M, Amicucci P, Soddu S, Novelli G, Dallapiccola B. Source: Cell Biochemistry and Function. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9636999&query_hl=9&itool=pubmed_docsum

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Genomic organization and transcriptional units at the myotonic dystrophy locus. Author(s): Shaw DJ, McCurrach M, Rundle SA, Harley HG, Crow SR, Sohn R, Thirion JP, Hamshere MG, Buckler AJ, Harper PS, et al. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7905855&query_hl=9&itool=pubmed_docsum

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Genomic organization of human myotonic dystrophy kinase-related Cdc42-binding kinase alpha reveals multiple alternative splicing and functional diversity. Author(s): Tan I, Cheong A, Lim L, Leung T. Source: Gene. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12568720&query_hl=9&itool=pubmed_docsum

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Genotype-phenotype correlation in myotonic dystrophy. Author(s): Gharehbaghi-Schnell EB, Finsterer J, Korschineck I, Mamoli B, Binder BR. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9550357&query_hl=9&itool=pubmed_docsum

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Germline mutational dynamics in myotonic dystrophy type 1 males: allele length and age effects. Author(s): Martorell L, Gamez J, Cayuela ML, Gould FK, McAbney JP, Ashizawa T, Monckton DG, Baiget M. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14745066&query_hl=9&itool=pubmed_docsum

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GH secretion status in myotonic dystrophy. Author(s): Gomez-Saez JM, Fernandez-Real JM, Navarro MA, Martinez-Matos JA, Soler J. Source: Psychoneuroendocrinology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8516423&query_hl=9&itool=pubmed_docsum

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Giant hairpins formed by CUG repeats in myotonic dystrophy messenger RNAs might sterically block RNA export through nuclear pores. Author(s): Koch KS, Leffert HL. Source: Journal of Theoretical Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9680723&query_hl=9&itool=pubmed_docsum

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Giardia lamblia infection in a patient with myotonic dystrophy. Author(s): Mouthon L, Godmer P, Piqueras B, Cohen P, Lortholary O, HofmannRadvanyi H, Guillevin L. Source: Annales De Medecine Interne. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12610429&query_hl=9&itool=pubmed_docsum

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Glucocorticoid metabolism and adrenocortical reactivity to ACTH in myotonic dystrophy. Author(s): Johansson A, Andrew R, Forsberg H, Cederquist K, Walker BR, Olsson T. Source: The Journal of Clinical Endocrinology and Metabolism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11549662&query_hl=9&itool=pubmed_docsum

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Glucose metabolism and dopamine PET correlates in a patient with myotonic dystrophy type 2 and parkinsonism. Author(s): Sansone V, Meola G, Perani D, Fazio F, Garibotto V, Cotelli M, Cotelli M, Vitelli E. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16484664&query_hl=9&itool=pubmed_docsum

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Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm. Author(s): Jansen G, Willems P, Coerwinkel M, Nillesen W, Smeets H, Vits L, Howeler C, Brunner H, Wieringa B. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8128954&query_hl=9&itool=pubmed_docsum

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Hammerhead ribozyme-mediated destruction of nuclear foci in myotonic dystrophy myoblasts. Author(s): Langlois MA, Lee NS, Rossi JJ, Puymirat J. 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=12718910&query_hl=9&itool=pubmed_docsum

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Haplotype analysis of congenital myotonic dystrophy patients from asymptomatic DM father. Author(s): Tachi N, Ohya K, Yamagata H, Miki T, Kikuchi K, Chiba S. Source: Pediatric Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9258965&query_hl=9&itool=pubmed_docsum

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Haplotype analysis of genomic polymorphisms in and around the myotonic dystrophy locus in diverse populations of India. Author(s): Basu P, Majumder PP, Roychoudhury S, Bhattacharyya NP. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11379877&query_hl=9&itool=pubmed_docsum

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Haplotype analysis of the myotonic dystrophy type 1 (DM1) locus in Taiwan: implications for low prevalence and founder mutations of Taiwanese myotonic dystrophy type 1. Author(s): Pan H, Lin HM, Ku WY, Li TC, Li SY, Lin CC, Hsiao KM. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11528511&query_hl=9&itool=pubmed_docsum

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Health-related quality of life in myotonic dystrophy type 1 and its relationship with cognitive and emotional functioning. Author(s): Antonini G, Soscia F, Giubilei F, De Carolis A, Gragnani F, Morino S, Ruberto A, Tatarelli R. Source: Journal of Rehabilitation Medicine : Official Journal of the Uems European Board of Physical and Rehabilitation Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16702085&query_hl=9&itool=pubmed_docsum

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Heart rate turbulence as a noninvasive risk predictor of ventricular tachyarrhythmias in myotonic dystrophy type 1. Author(s): Casella M, Dello Russo A, Pace M, Pelargonio G, Ierardi C, Sanna T, Messano L, Bencardino G, Valsecchi S, Mangiola F, Lanza GA, Zecchi P, Crea F, Bellocci F. Source: Journal of Cardiovascular Electrophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16903966&query_hl=9&itool=pubmed_docsum

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Heart rate variability declines with increasing age and CTG repeat length in patients with myotonic dystrophy type 1. Author(s): Hardin BA, Lowe MR, Bhakta D, Groh WJ. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14510658&query_hl=9&itool=pubmed_docsum

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Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2. Author(s): Vihola A, Bassez G, Meola G, Zhang S, Haapasalo H, Paetau A, Mancinelli E, Rouche A, Hogrel JY, Laforet P, Maisonobe T, Pellissier JF, Krahe R, Eymard B, Udd B. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12796551&query_hl=9&itool=pubmed_docsum

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Homodimerization through coiled-coil regions enhances activity of the myotonic dystrophy protein kinase. Author(s): Zhang R, Epstein HF. Source: Febs Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12832055&query_hl=9&itool=pubmed_docsum

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Homozygosity for CCTG mutation in myotonic dystrophy type 2. Author(s): Schoser BG, Kress W, Walter MC, Halliger-Keller B, Lochmuller H, Ricker K. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15231584&query_hl=9&itool=pubmed_docsum

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Human myotonic dystrophy protein kinase effect in S. cerevisiae. Author(s): Del Carratore R, Ciucci F, Beffy P, Casella M, Puntoni M, Simi S, Simili M. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15894391&query_hl=9&itool=pubmed_docsum

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Hydrocephalus and cognitive decline in myotonic dystrophy: case report and literature review. Author(s): Moroz A, Kalva S. 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=9710180&query_hl=9&itool=pubmed_docsum

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Hyper-CK-emia as the sole manifestation of myotonic dystrophy type 2. Author(s): Merlini L, Sabatelli P, Columbaro M, Bonifazi E, Pisani V, Massa R, Novelli G. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15704146&query_hl=9&itool=pubmed_docsum

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Hyperkalaemia and selective hypoaldosteronism in myotonic dystrophy. Author(s): Misra D, DeSilva S, Fellerman H, Dufour DR, Streeten DH, Nylen ES. Source: Clinical Endocrinology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11874420&query_hl=9&itool=pubmed_docsum

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Hyperkalaemia and selective hypoaldosteronism in myotonic dystrophy. Author(s): Olsson T. Source: Clinical Endocrinology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11874404&query_hl=9&itool=pubmed_docsum

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Hypermutable myotonic dystrophy CTG repeats in transgenic mice. Author(s): Monckton DG, Coolbaugh MI, Ashizawa KT, Siciliano MJ, Caskey CT. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9020848&query_hl=9&itool=pubmed_docsum

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Hyperproliferation of synapses on spinal motor neurons of Duchenne muscular dystrophy and myotonic dystrophy patients. Author(s): Nagao M, Kato S, Hayashi H, Misawa H. Source: Acta Neuropathologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12920538&query_hl=9&itool=pubmed_docsum

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Hypersomnolence in myotonic dystrophy: demonstration of sleep onset REM sleep. Author(s): Park JD, Radtke RA. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7738575&query_hl=9&itool=pubmed_docsum

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Hypertrophic cardiomyopathy in congenital myotonic dystrophy. Author(s): Igarashi H, Momoi MY, Yamagata T, Shiraishi H, Eguchi I. Source: Pediatric Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9588538&query_hl=9&itool=pubmed_docsum

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Hypotony and aqueous humor dynamics in myotonic dystrophy. Author(s): Walker SD, Brubaker RF, Nagataki S. Source: Investigative Ophthalmology & Visual Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7076420&query_hl=9&itool=pubmed_docsum

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Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1. Author(s): Sato S, Nakamura M, Cho DH, Tapscott SJ, Ozaki H, Kawakami K. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11978764&query_hl=9&itool=pubmed_docsum

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Importance of physical rehabilitation before and after cardiac transplantation in a patient with myotonic dystrophy: a case report. Author(s): Conraads VM, Beckers PJ, Vorlat A, Vrints CJ. 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=11994815&query_hl=9&itool=pubmed_docsum

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Improved method for molecular diagnosis of myotonic dystrophy type 1 (DM1). Author(s): Erginel-Unaltuna N, Akbas F. Source: Journal of Clinical Laboratory Analysis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14730559&query_hl=9&itool=pubmed_docsum

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Incomplete manifestations of myotonic dystrophy in a large kinship in Labrador. Author(s): Pryse-Phillips W, Johnson GJ, Larsen B. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6956246&query_hl=9&itool=pubmed_docsum

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Increased (CTG/CAG)(n) lengths in myotonic dystrophy type 1 and Machado-Joseph disease genes in idiopathic azoospermia patients. Author(s): Pan H, Li YY, Li TC, Tsai WT, Li SY, Hsiao KM. Source: Human Reproduction (Oxford, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12042281&query_hl=9&itool=pubmed_docsum

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Increased levels of tPA antigen and tPA/PAI-1 complex in myotonic dystrophy. Author(s): Johansson A, Boman K, Cederquist K, Forsberg H, Olsson T. Source: Journal of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11422656&query_hl=9&itool=pubmed_docsum

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Increased plasma concentration of atrial natriuretic hormone in myotonic dystrophy. Author(s): Parlapiano C, Antonini G, Vichi R, Fragola PV, Campana E, Rota C, Borgia MC, Tonnarini G, Negri M. Source: European Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9635476&query_hl=9&itool=pubmed_docsum

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Increased risk for abnormal placentation in women affected by myotonic dystrophy. Author(s): Rudnik-Schoneborn S, Rohrig D, Zerres K. Source: Journal of Perinatal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9773377&query_hl=9&itool=pubmed_docsum

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Influence of relatives on fatigue experienced by patients with facioscapulohumeral dystrophy, myotonic dystrophy and HMSN-I. Author(s): Kalkman JS, Schillings ML, Zwarts MJ, van Engelen BG, Bleijenberg G. Source: European Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16914927&query_hl=9&itool=pubmed_docsum

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Inheritance of a novel RYR1 mutation in a family with myotonic dystrophy type 1. Author(s): Gambelli S, Malandrini A, Berti G, Gaudiano C, Zicari E, Brunori P, Perticoni G, Orrico A, Galli L, Sorrentino V, Lunardi J, Federico A, Dotti MT. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17204054&query_hl=9&itool=pubmed_docsum

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Inhibition of naloxone-stimulated adrenocorticotropin release by alprazolam in myotonic dystrophy patients. Author(s): Joyner JM, Grice JE, Hockings GI, Torpy DJ, Crosbie GV, Walters MM, Jackson RV. Source: Journal of Neuroendocrinology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9663654&query_hl=9&itool=pubmed_docsum

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Instability in the normal CTG repeat range at the myotonic dystrophy locus. Author(s): Meiner A, Thamm B, Strenge S, Froster U. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9733048&query_hl=9&itool=pubmed_docsum

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Instability in the transmission of the myotonic dystrophy CTG repeat in human oocytes and preimplantation embryos. Author(s): Dean NL, Tan SL, Ao A. Source: Fertility and Sterility. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16716318&query_hl=9&itool=pubmed_docsum

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Instability of a premutation allele in homozygous patients with myotonic dystrophy type 1. Author(s): Abbruzzese C, Costanzi Porrini S, Mariani B, Gould FK, McAbney JP, Monckton DG, Ashizawa T, Giacanelli M. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12325072&query_hl=9&itool=pubmed_docsum

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Insulin receptor splicing alteration in myotonic dystrophy type 2. Author(s): Savkur RS, Philips AV, Cooper TA, Dalton JC, Moseley ML, Ranum LP, Day JW. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15114529&query_hl=9&itool=pubmed_docsum

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Insulin receptors in myotonic dystrophy: a study with mononuclear leucocytes and erythrocytes. Author(s): Fratino P, Bellomo G, Bellazzi R, Nicotera PL, Sandrini G, Nappi G. Source: Italian Journal of Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6749756&query_hl=9&itool=pubmed_docsum

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Intergenerational changes of CTG repeat depending on the sex of the transmitting parent in myotonic dystrophy type 1. Author(s): Rakocevic-Stojanovic V, Savic D, Pavlovic S, Lavrnic D, Stevic Z, Basta I, Romac S, Apostolski S. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15693817&query_hl=9&itool=pubmed_docsum

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Intermolecular and intramolecular interactions regulate catalytic activity of myotonic dystrophy kinase-related Cdc42-binding kinase alpha. Author(s): Tan I, Seow KT, Lim L, Leung T. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11283256&query_hl=9&itool=pubmed_docsum

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Internal auditory canal hyperostosis in myotonic dystrophy. Author(s): Lassaletta L, Fernandez-Zubilaga A, Gonzalez T, Gavilan J. Source: Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15793424&query_hl=9&itool=pubmed_docsum

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Isolation of a polymorphic DNA sequence pJSB11 (D19S16) from the human chromosome 19cen-q13.2 region linked to the myotonic dystrophy (DM) gene. Author(s): Schepens J, Smeets H, Hulsebos T, Brunner H, Wieringa B. Source: Nucleic Acids Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2882484&query_hl=9&itool=pubmed_docsum

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Knowledge, views, and experience of 25 women with myotonic dystrophy. Author(s): Faulkner CL, Kingston HM. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9863600&query_hl=9&itool=pubmed_docsum

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Laboratory abnormalities in ambulatory patients with myotonic dystrophy type 1. Author(s): Heatwole CR, Miller J, Martens B, Moxley RT 3rd. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16908743&query_hl=9&itool=pubmed_docsum

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Lack of rapid enhancement of insulin action after oral glucose challenge in myotonic dystrophy. Author(s): Moxley RT 3rd, Kingston WJ, Griggs RC, Livingston JN. Source: Diabetes. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3552801&query_hl=9&itool=pubmed_docsum

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Laparoscopic cholecystectomy in a patient with myotonic dystrophy. Author(s): Takhar AS, Thaper A, Byrne A, Lobo DN. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15173332&query_hl=9&itool=pubmed_docsum

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Late presentation of myotonic dystrophy. Author(s): Clark C, Petty RK, Strong AM. Source: Clinical and Experimental Dermatology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9667115&query_hl=9&itool=pubmed_docsum

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Late-onset cytoplasmic body myopathy resembling myotonic dystrophy. Author(s): Morris HR, Landon D, Morgan-Hughes J, Brown P. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10366237&query_hl=9&itool=pubmed_docsum

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Left posterior fascicular ventricular tachycardia in myotonic dystrophy. Author(s): Ng KS, Ng WL, Chia BL. Source: International Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10912441&query_hl=9&itool=pubmed_docsum

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Left ventricular hypertrabeculation in myotonic dystrophy type 1. Author(s): Finsterer J, Stollberger C, Wegmann R, Jarius C, Janssen B. Source: Herz. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11479941&query_hl=9&itool=pubmed_docsum

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Lens epithelial changes and mutated gene expression in patients with myotonic dystrophy. Author(s): Abe T, Sato M, Kuboki J, Kano T, Tamai M. Source: The British Journal of Ophthalmology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10434869&query_hl=9&itool=pubmed_docsum

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Leptin after IGF-I generation test in a patient with hypopituitarism and myotonic dystrophy disease. Author(s): Gomez JM, Martinez-Matos JA. Source: Pituitary. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11081190&query_hl=9&itool=pubmed_docsum

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Leukocyte CTG repeat length correlates with severity of myotonia in myotonic dystrophy type 1. Author(s): Logigian EL, Moxley RT 4th, Blood CL, Barbieri CA, Martens WB, Wiegner AW, Thornton CA, Moxley RT 3rd. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15079005&query_hl=9&itool=pubmed_docsum

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Localization of myotonic dystrophy protein kinase in human and rabbit tissues using a new panel of monoclonal antibodies. Author(s): Pham YC, Man N, Lam LT, Morris GE. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9811941&query_hl=9&itool=pubmed_docsum

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Localization of the sites of conduction abnormalities in a mouse model of myotonic dystrophy. Author(s): Saba S, Vanderbrink BA, Luciano B, Aronovitz MJ, Berul CI, Reddy S, Housman D, Mendelsohn ME, Estes NA 3rd, Wang PJ. Source: Journal of Cardiovascular Electrophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10517654&query_hl=9&itool=pubmed_docsum

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Long CTG tracts from the myotonic dystrophy gene induce deletions and rearrangements during recombination at the APRT locus in CHO cells. Author(s): Meservy JL, Sargent RG, Iyer RR, Chan F, McKenzie GJ, Wells RD, Wilson JH. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12697816&query_hl=9&itool=pubmed_docsum

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Long CTG.CAG repeats from myotonic dystrophy are preferred sites for intermolecular recombination. Author(s): Pluciennik A, Iyer RR, Napierala M, Larson JE, Filutowicz M, Wells RD. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12087090&query_hl=9&itool=pubmed_docsum

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Long-term follow-up of arrhythmias in patients with myotonic dystrophy treated by pacing: a multicenter diagnostic pacemaker study. Author(s): Lazarus A, Varin J, Babuty D, Anselme F, Coste J, Duboc D. Source: Journal of the American College of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12427418&query_hl=9&itool=pubmed_docsum

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Loss of catecholaminergic neurons in the medullary reticular formation in myotonic dystrophy. Author(s): Ono S, Takahashi K, Jinnai K, Kanda F, Fukuoka Y, Kurisaki H, Mitake S, Inagaki T, Yamano T, Shimizu N, Nagao K. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9781540&query_hl=9&itool=pubmed_docsum

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Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Author(s): Charlet-B N, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA. Source: Molecular Cell. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12150906&query_hl=9&itool=pubmed_docsum

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Low incidence of myotonic dystrophy in Chinese Hans is associated with a lower number of CTG trinucleotide repeats. Author(s): Sizhong Z, Hui W, Agen P, Cuiying X, Ge Z, Yiping H, Jiayou C. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10898927&query_hl=9&itool=pubmed_docsum

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Low-dose metformin improves hyperglycaemia related to myotonic dystrophy. Author(s): Kouki T, Takasu N, Nakachi A, Tamanaha T, Komiya I, Tawata M. Source: Diabetic Medicine : a Journal of the British Diabetic Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15717887&query_hl=9&itool=pubmed_docsum

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Lower gastrointestinal tract disturbance in congenital myotonic dystrophy. Author(s): Kerr TP, Robb SA, Clayden GS. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12269262&query_hl=9&itool=pubmed_docsum

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MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. Author(s): de Haro M, Al-Ramahi I, De Gouyon B, Ukani L, Rosa A, Faustino NA, Ashizawa T, Cooper TA, Botas J. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16723374&query_hl=9&itool=pubmed_docsum

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Mechanisms of sustained ventricular tachycardia in myotonic dystrophy: implications for catheter ablation. Author(s): Merino JL, Carmona JR, Fernandez-Lozano I, Peinado R, Basterra N, Sobrino JA. Source: Circulation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9714111&query_hl=9&itool=pubmed_docsum

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Misregulation of alternative splicing causes pathogenesis in myotonic dystrophy. Author(s): Kuyumcu-Martinez NM, Cooper TA. Source: Prog Mol Subcell Biol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17076268&query_hl=9&itool=pubmed_docsum

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Muscle chloride channel dysfunction in two mouse models of myotonic dystrophy. Author(s): Lueck JD, Mankodi A, Swanson MS, Thornton CA, Dirksen RT. Source: The Journal of General Physiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17158949&query_hl=9&itool=pubmed_docsum

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Mutagenic stress modulates the dynamics of CTG repeat instability associated with myotonic dystrophy type 1. Author(s): Pineiro E, Fernandez-Lopez L, Gamez J, Marcos R, Surralles J, Velazquez A. Source: Nucleic Acids Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14627806&query_hl=9&itool=pubmed_docsum

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Myotonic dystrophy and pain management of a patient undergoing total abdominal hysterectomy in a metropolitan general hospital. Author(s): Sivathondan D. Source: Anaesthesia and Intensive Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16913352&query_hl=9&itool=pubmed_docsum

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Myotonic dystrophy in Otago, New Zealand. Author(s): Ford C, Kidd A, Hammond-Tooke G. Source: N Z Med J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16964297&query_hl=9&itool=pubmed_docsum

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Myotonic dystrophy is a significant cause of idiopathic polyhydramnios. Author(s): Esplin MS, Hallam S, Farrington PF, Nelson L, Byrne J, Ward K. Source: American Journal of Obstetrics and Gynecology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9790382&query_hl=9&itool=pubmed_docsum

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Myotonic dystrophy. Author(s): Waring JD, Korneluk RG. Source: Results Probl Cell Differ. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9670315&query_hl=9&itool=pubmed_docsum

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Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Author(s): Cho DH, Tapscott SJ. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16876389&query_hl=9&itool=pubmed_docsum

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Myotonic dystrophy: practical issues relating to assessment of strength. Author(s): Whittaker RG, Ferenczi E, Hilton-Jones D. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17043296&query_hl=9&itool=pubmed_docsum

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Neonatal respiratory failure due to myotonic dystrophy. Author(s): Simpson K. Source: Archives of Disease in Childhood. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1167072&query_hl=9&itool=pubmed_docsum

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Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophy. Author(s): Oyamada R, Hayashi M, Katoh Y, Tsuchiya K, Mizutani T, Tominaga I, Kashima H. Source: Neuropathology : Official Journal of the Japanese Society of Neuropathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16708543&query_hl=9&itool=pubmed_docsum

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Neuropsychological findings in myotonic dystrophy. Author(s): Woodward JB 3rd, Heaton RK, Simon DB, Ringel SP. Source: J Clin Neuropsychol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7174839&query_hl=9&itool=pubmed_docsum

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New methods for molecular diagnosis and demonstration of the (CCTG)n mutation in myotonic dystrophy type 2 (DM2). Author(s): Sallinen R, Vihola A, Bachinski LL, Huoponen K, Haapasalo H, Hackman P, Zhang S, Sirito M, Kalimo H, Meola G, Horelli-Kuitunen N, Wessman M, Krahe R, Udd B. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15019706&query_hl=9&itool=pubmed_docsum

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No association of the SCA1 (CAG)31 allele with Huntington's disease, myotonic dystrophy type 1 and spinocerebellar ataxia type 3. Author(s): Hellenbroich Y, Kaulich M, Opitz S, Schwinger E, Zuhlke C. Source: Psychiatric Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15167689&query_hl=9&itool=pubmed_docsum

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Non-B DNA conformations formed by long repeating tracts of myotonic dystrophy type 1, myotonic dystrophy type 2, and Friedreich's ataxia genes, not the sequences per se, promote mutagenesis in flanking regions. Author(s): Wojciechowska M, Napierala M, Larson JE, Wells RD. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16793772&query_hl=9&itool=pubmed_docsum

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Noncompaction in myotonic dystrophy type 1 on cardiac MRI. Author(s): Finsterer J, Stolberger C, Kopsa W. Source: Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15785023&query_hl=9&itool=pubmed_docsum

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Normal muscle spindle morphology in myotonia congenita: the spindle abnormality in myotonic dystrophy is not due to myotonia alone. Author(s): Swash M, Schwartz MS. Source: Clin Neuropathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6221849&query_hl=9&itool=pubmed_docsum

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Normal pressure hydrocephalus in a patient with myotonic dystrophy: case report with a 10-year follow-up. Author(s): Delavallee M, Raftopoulos C. Source: Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16575302&query_hl=9&itool=pubmed_docsum

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Nuclear RNA foci in the heart in myotonic dystrophy. Author(s): Mankodi A, Lin X, Blaxall BC, Swanson MS, Thornton CA. Source: Circulation Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16254211&query_hl=9&itool=pubmed_docsum

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Occlusive hydrocephalus in congenital myotonic dystrophy. Author(s): Rettwitz-Volk W, Wikstroem M, Flodmark O. Source: Brain & Development. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11248461&query_hl=9&itool=pubmed_docsum

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Ocular findings in myotonic dystrophy. Author(s): Raitta C, Karli P. Source: Ann Ophthalmol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7125455&query_hl=9&itool=pubmed_docsum

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Ocular motor myotonic phenomenon in myotonic dystrophy. Author(s): Versino M, Colnaghi S, Sandrini G, Cosi V. 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=11960825&query_hl=9&itool=pubmed_docsum

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Ocular motor myotonic phenomenon in myotonic dystrophy. Author(s): Versino M, Rossi B, Beltrami G, Sandrini G, Cosi V. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11796775&query_hl=9&itool=pubmed_docsum

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Orofacial dysfunction in children and adolescents with myotonic dystrophy. Author(s): Sjogreen L, Engvall M, Ekstrom AB, Lohmander A, Kiliaridis S, Tulinius M. Source: Developmental Medicine and Child Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17209971&query_hl=9&itool=pubmed_docsum

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Outcome and effect of pregnancy in myotonic dystrophy type 2. Author(s): Rudnik-Schoneborn S, Schneider-Gold C, Raabe U, Kress W, Zerres K, Schoser BG. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16505316&query_hl=9&itool=pubmed_docsum

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Outcome in pregnancies complicated by myotonic dystrophy: a study of 31 patients and review of the literature. Author(s): Rudnik-Schoneborn S, Zerres K. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15099870&query_hl=9&itool=pubmed_docsum

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Outcome of pregnancy in women with myotonic dystrophy and analysis of CTG gene expansion. Author(s): Erikson A, Forsberg H, Drugge U, Holmgren G. Source: Acta Paediatrica (Oslo, Norway : 1992). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7795352&query_hl=9&itool=pubmed_docsum

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Overexpression of human myotonic dystrophy protein kinase in Schizosaccharomyces pombe induces an abnormal polarized and swollen cell morphology. Author(s): Sasagawa N, Kino Y, Takeshita Y, Oma Y, Ishiura S. Source: Journal of Biochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14607980&query_hl=9&itool=pubmed_docsum

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Oxidative stress in myotonic dystrophy type 1. Author(s): Toscano A, Messina S, Campo GM, Di Leo R, Musumeci O, Rodolico C, Aguennouz M, Annesi G, Messina C, Vita G. Source: Free Radical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16036357&query_hl=9&itool=pubmed_docsum

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Postabsorptive and insulin-stimulated energy and protein metabolism in patients with myotonic dystrophy type 1. Author(s): Perseghin G, Comola M, Scifo P, Benedini S, De Cobelli F, Lanzi R, Costantino F, Lattuada G, Battezzati A, Del Maschio A, Luzi L. Source: The American Journal of Clinical Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15277156&query_hl=9&itool=pubmed_docsum

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Posterior correction and fusion for severe cervical kyphosis in a patient with myotonic dystrophy: a case report. Author(s): Yuzawa Y, Hashimoto T, Takahashi J, Nakamura I, Hirabayashi H, Ebara S. Source: Spine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16985447&query_hl=9&itool=pubmed_docsum

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Prenatal diagnosis of congenital myotonic dystrophy and counseling of the pregnant mother: case report and literature review. Author(s): Geifman-Holtzman O, Fay K. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9677060&query_hl=9&itool=pubmed_docsum

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Presence of palmar xanthomas in myotonic dystrophy identifies different patterns of linkage disequilibrium between the apolipoprotein E and myotonic dystrophy protein kinase loci. Author(s): Brisson D, Mathieu J, Vohl MC, Gaudet D. 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=15775763&query_hl=9&itool=pubmed_docsum

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Prevalence of structural cardiac abnormalities in patients with myotonic dystrophy type I. Author(s): Bhakta D, Lowe MR, Groh WJ. Source: American Heart Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14760317&query_hl=9&itool=pubmed_docsum

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Proximal myotonic dystrophy associated with parkinsonism. Author(s): Celik Y, Turgut N, Balci K, Kabayel L. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16459082&query_hl=9&itool=pubmed_docsum

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Proximal myotonic dystrophy mimicking progressive muscular atrophy. Author(s): Rotondo G, Sansone V, Cardani R, Mancinelli E, Krahe R, Stangalini D, Meola G. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15679706&query_hl=9&itool=pubmed_docsum

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Psychopathological and emotional deficits in myotonic dystrophy. Author(s): Bungener C, Jouvent R, Delaporte C. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9728948&query_hl=9&itool=pubmed_docsum

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Psychosocial impact of predictive testing for myotonic dystrophy type 1. Author(s): Prevost C, Veillette S, Perron M, Laberge C, Tremblay C, Auclair J, Villeneuve J, Tremblay M, Mathieu J. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15039975&query_hl=9&itool=pubmed_docsum

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Psychostimulants for hypersomnia (excessive daytime sleepiness) in myotonic dystrophy. Author(s): Annane D, Moore DH, Barnes PR, Miller RG. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16855999&query_hl=9&itool=pubmed_docsum

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Quadriceps strength and timed motor performances in myotonic dystrophy, CharcotMarie-Tooth disease, and healthy subjects. Author(s): Lindeman E, Leffers P, Reulen J, Spaans F, Drukker J. Source: Clinical Rehabilitation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9619654&query_hl=9&itool=pubmed_docsum

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Quantification of brain atrophy in patients with myotonic dystrophy and proximal myotonic myopathy: a controlled 3-dimensional magnetic resonance imaging study. Author(s): Kassubek J, Juengling FD, Hoffmann S, Rosenbohm A, Kurt A, Jurkat-Rott K, Steinbach P, Wolf M, Ludolph AC, Lehmann-Horn F, Lerche H, Weber YG. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12902021&query_hl=9&itool=pubmed_docsum

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Quantitative analysis of the "warm-up" phenomenon in myotonic dystrophy type 1. Author(s): Logigian EL, Blood CL, Dilek N, Martens WB, Moxley RT 4th, Wiegner AW, Thornton CA, Moxley RT 3rd. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15880468&query_hl=9&itool=pubmed_docsum

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Quantitative assessment of speech in myotonic dystrophy. Author(s): Maassen B, ter Bruggen JP, Nanninga-Korver A, van Spaendonck K, WeynBanningh L, Gabreels F. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7751865&query_hl=9&itool=pubmed_docsum

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Quantitative assessment of the total myocardial uptake ratio of 123I-BMIPP by using the Ishii-MacIntyre method is useful for predicting cardiac complications in patients with mitochondrial encephalomyopathy or myotonic dystrophy. Author(s): Ohkusu Y, Takahashi N, Ishikawa T, Sumita S, Kobayashi T, Matsushita K, Yamakawa Y, Uchino K, Kimura K, Inoue T, Umemura S. Source: Nuclear Medicine Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12548043&query_hl=9&itool=pubmed_docsum

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Quantitative motor assessment in myotonic dystrophy. Author(s): Mathieu J, Boivin H, Richards CL. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12774952&query_hl=9&itool=pubmed_docsum

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Quantitative testing of handgrip strength, myotonia, and fatigue in myotonic dystrophy. Author(s): Torres C, Moxley RT, Griggs RC. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6875612&query_hl=9&itool=pubmed_docsum

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Recurrent fascicular ventricular tachycardia in myotonic dystrophy. Author(s): Nageh MF. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16635990&query_hl=9&itool=pubmed_docsum

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Re-entry circuit in ventricular tachycardia due to focal fatty-fibrosis in a patient with myotonic dystrophy. Author(s): Muraoka H, Negoro N, Terasaki F, Nakakoji T, Kojima S, Hoshiga M, Sugino M, Hosokawa T, Ishihara T, Hanafusa T. Source: Intern Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15750273&query_hl=9&itool=pubmed_docsum

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Relation of CTG expansion and clinical variables to electrocardiogram conduction abnormalities and sudden death in patients with myotonic dystrophy. Author(s): Sabovic M, Medica I, Logar N, Mandic E, Zidar J, Peterlin B. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14678805&query_hl=9&itool=pubmed_docsum

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Relationship between diffusion tensor imaging and brain morphology in patients with myotonic dystrophy. Author(s): Ota M, Sato N, Ohya Y, Aoki Y, Mizukami K, Mori T, Asada T. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16978781&query_hl=9&itool=pubmed_docsum

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Respiratory training for patients with myotonic dystrophy. Author(s): Abe K, Matsuo Y, Kadekawa J, Inoue S, Yanagihara T. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9710064&query_hl=9&itool=pubmed_docsum

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Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Author(s): Kanadia RN, Shin J, Yuan Y, Beattie SG, Wheeler TM, Thornton CA, Swanson MS. 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=16864772&query_hl=9&itool=pubmed_docsum

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Rhabdomyolysis caused by tocolysis with oral ritodrine hydrochloride in a pregnant patient with myotonic dystrophy. Author(s): Nasu K, Sugano T, Yoshimatsu J, Narahara H. Source: Gynecologic and Obstetric Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16192734&query_hl=9&itool=pubmed_docsum

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Ribonuclear inclusions in skeletal muscle in myotonic dystrophy types 1 and 2. Author(s): Mankodi A, Teng-Umnuay P, Krym M, Henderson D, Swanson M, Thornton CA. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14681885&query_hl=9&itool=pubmed_docsum

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RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Author(s): Ebralidze A, Wang Y, Petkova V, Ebralidse K, Junghans RP. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14657503&query_hl=9&itool=pubmed_docsum

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Rubeosis iridis after bilateral cataract surgery and its spontaneous regression in a patient with myotonic dystrophy. Author(s): Kuroda T, Katai N, Yoshida N, Murata T. Source: Journal of Cataract and Refractive Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16765808&query_hl=9&itool=pubmed_docsum

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Saccadic slowing in myotonic dystrophy and CTG repeat expansion. Author(s): Osanai R, Kinoshita M, Hirose K. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9776468&query_hl=9&itool=pubmed_docsum

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Severe capsulorhexis contracture after cataract surgery in myotonic dystrophy. Author(s): Newman DK. Source: Journal of Cataract and Refractive Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9795861&query_hl=9&itool=pubmed_docsum

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Severe cardiac arrhythmias in young patients with myotonic dystrophy type 1. Author(s): Bassez G, Lazarus A, Desguerre I, Varin J, Laforet P, Becane HM, Meune C, Arne-Bes MC, Ounnoughene Z, Radvanyi H, Eymard B, Duboc D. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15557517&query_hl=9&itool=pubmed_docsum

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Sevoflurane for oesophagoscopy in a patient with myotonic dystrophy. Author(s): Shirley PJ, McFarlane H. Source: Canadian Journal of Anaesthesia = Journal Canadien D'anesthesie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9793677&query_hl=9&itool=pubmed_docsum

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Simple procedure for automatic detection of unstable alleles in the myotonic dystrophy and Huntington's disease loci. Author(s): Falk M, Vojtiskova M, Lukas Z, Kroupova I, Froster U. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16792511&query_hl=9&itool=pubmed_docsum

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Sleep disorders in childhood-onset myotonic dystrophy type 1. Author(s): Quera Salva MA, Blumen M, Jacquette A, Durand MC, Andre S, De Villiers M, Eymard B, Lofaso F, Heron D. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16934465&query_hl=9&itool=pubmed_docsum

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Somatic instability of the CTG repeat in mice transgenic for the myotonic dystrophy region is age dependent but not correlated to the relative intertissue transcription levels and proliferative capacities. Author(s): Lia AS, Seznec H, Hofmann-Radvanyi H, Radvanyi F, Duros C, Saquet C, Blanche M, Junien C, Gourdon G. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9668171&query_hl=9&itool=pubmed_docsum

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Subtle cognitive dysfunction in adult onset myotonic dystrophy type 1 (DM1) and type 2 (DM2). Author(s): Gaul C, Schmidt T, Windisch G, Wieser T, Muller T, Vielhaber S, Zierz S, Leplow B. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16864839&query_hl=9&itool=pubmed_docsum

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Sudden cardiac death in myotonic dystrophy type 2. Author(s): Schoser BG, Ricker K, Schneider-Gold C, Hengstenberg C, Durre J, Bultmann B, Kress W, Day JW, Ranum LP. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15623712&query_hl=9&itool=pubmed_docsum

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Survival and mortality of myotonic dystrophy type 1 (Steinert's disease) in the population of Belgrade. Author(s): Mladenovic J, Pekmezovic T, Todorovic S, Rakocevic-Stojanovic V, Savic D, Romac S, Apostolski S. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16722967&query_hl=9&itool=pubmed_docsum

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Target-controlled infusion of propofol for a patient with myotonic dystrophy. Author(s): Morimoto Y, Mii M, Hirata T, Matayoshi H, Sakabe T. Source: Journal of Anesthesia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16261476&query_hl=9&itool=pubmed_docsum

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Temperament and character in patients with classical myotonic dystrophy type 1 (DM-1). Author(s): Winblad S, Lindberg C, Hansen S. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15792867&query_hl=9&itool=pubmed_docsum

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The correlation of CTG repeat length with material and social deprivation in myotonic dystrophy. Author(s): Laberge L, Veillette S, Mathieu J, Auclair J, Perron M. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17204048&query_hl=9&itool=pubmed_docsum

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The myotonic dystrophy type 1 triplet repeat sequence induces gross deletions and inversions. Author(s): Wojciechowska M, Bacolla A, Larson JE, Wells RD. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15489504&query_hl=9&itool=pubmed_docsum

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Thrombolytic treatment of acute pulmonary embolism in myotonic dystrophy. Author(s): Jabr FI. Source: The Journal of Emergency Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16567263&query_hl=9&itool=pubmed_docsum

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Transcriptional properties of RNA polymerase II within triplet repeat-containing DNA from the human myotonic dystrophy and fragile X loci. Author(s): Parsons MA, Sinden RR, Izban MG. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9756950&query_hl=9&itool=pubmed_docsum

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Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy. Author(s): O'Cochlain DF, Perez-Terzic C, Reyes S, Kane GC, Behfar A, Hodgson DM, Strommen JA, Liu XK, van den Broek W, Wansink DG, Wieringa B, Terzic A. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15317754&query_hl=9&itool=pubmed_docsum

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Transmission ratio distortion in the myotonic dystrophy locus in human preimplantation embryos. Author(s): Dean NL, Loredo-Osti JC, Fujiwara TM, Morgan K, Tan SL, Naumova AK, Ao A. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16391559&query_hl=9&itool=pubmed_docsum

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Truncated ClC-1 mRNA in myotonic dystrophy exerts a dominant-negative effect on the Cl current. Author(s): Berg J, Jiang H, Thornton CA, Cannon SC. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15623702&query_hl=9&itool=pubmed_docsum

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Two infantile cases of congenital myotonic dystrophy with cholelithiasis/cholestasis. Author(s): Sumi M, Kusumoto T, Tagawa M, Kondoh T, Ohno Y, Masuzaki H, Ishimaru T, Moriuchi H. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16190971&query_hl=9&itool=pubmed_docsum

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Ultrasound imaging of the masseter muscle in myotonic dystrophy patients. Author(s): Kiliaridis S, Engvall M, Tzakis MG. Source: Journal of Oral Rehabilitation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7472735&query_hl=9&itool=pubmed_docsum

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UNC-39, the C. elegans homolog of the human myotonic dystrophy-associated homeodomain protein Six5, regulates cell motility and differentiation. Author(s): Yanowitz JL, Shakir MA, Hedgecock E, Hutter H, Fire AZ, Lundquist EA. Source: Developmental Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15282156&query_hl=9&itool=pubmed_docsum

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Unstable DNA in a patient with a severe form of congenital myotonic dystrophy. Author(s): Tachi N, Ohya K, Chiba S, Sato T. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8277332&query_hl=9&itool=pubmed_docsum

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Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype. Author(s): Shelbourne P, Winqvist R, Kunert E, Davies J, Leisti J, Thiele H, Bachmann H, Buxton J, Williamson B, Johnson K. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1307246&query_hl=9&itool=pubmed_docsum

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Unstable DNA sequence in myotonic dystrophy. Author(s): Harley HG, Rundle SA, Reardon W, Myring J, Crow S, Brook JD, Harper PS, Shaw DJ. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1349364&query_hl=9&itool=pubmed_docsum

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Unusual clinical findings and Complex III deficiency in a family with myotonic dystrophy. Author(s): Seijo-Martinez M, Castro del Rio M, Campos Y, Palau F, Arenas J, Teijeira S, Fernandez Hojas R, Navarro C. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12639730&query_hl=9&itool=pubmed_docsum

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Unusual fetal movement in congenital myotonic dystrophy. Author(s): Hsu CD, Feng TI, Crawford TO, Johnson TR. Source: Fetal Diagnosis and Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8240694&query_hl=9&itool=pubmed_docsum

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Upper airway calibre and impedance in patients with Steinert's myotonic dystrophy. Author(s): Fodil R, Lofaso F, Annane D, Falaise L, Lejaille M, Raphael JC, Isabey D, Louis B. Source: Respiratory Physiology & Neurobiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15522707&query_hl=9&itool=pubmed_docsum

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Use of an insertable loop recorder in a myotonic dystrophy patient. Author(s): Hadian D, Lowe MR, Scott LR, Groh WJ. Source: Journal of Cardiovascular Electrophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11843487&query_hl=9&itool=pubmed_docsum

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Use of RNA fluorescence in situ hybridization in the prenatal molecular diagnosis of myotonic dystrophy type I. Author(s): Bonifazi E, Gullotta F, Vallo L, Iraci R, Nardone AM, Brunetti E, Botta A, Novelli G. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16449216&query_hl=9&itool=pubmed_docsum

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Value of the electrocardiogram in determining cardiac events and mortality in myotonic dystrophy. Author(s): Colleran JA, Hawley RJ, Pinnow EE, Kokkinos PF, Fletcher RD. Source: The American Journal of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9399734&query_hl=9&itool=pubmed_docsum

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Vascular adrenergic receptor responses in skeletal muscle in myotonic dystrophy. Author(s): Mechler F, Mastaglia FL. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7235630&query_hl=9&itool=pubmed_docsum

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Velopharyngeal incompetence as the presenting symptom of myotonic dystrophy. Author(s): Salomonson J, Kawamoto H, Wilson L. Source: Cleft Palate J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3168273&query_hl=9&itool=pubmed_docsum

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Ventilatory response in myotonic dystrophy. Author(s): Carroll JE, Zwillich CW, Weil JV. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=563010&query_hl=9&itool=pubmed_docsum

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Ventricular late potentials in myotonic dystrophy. Author(s): Milner MR, Hawley RJ, Jachim M, Lindsay J Jr, Fletcher RD. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1892332&query_hl=9&itool=pubmed_docsum

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Ventricular tachycardia and sudden death in myotonic dystrophy. Author(s): Hiromasa S, Ikeda T, Kubota K, Hattori N, Coto H, Maldonado C, Kupersmith J. Source: American Heart Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3354423&query_hl=9&itool=pubmed_docsum

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Ventricular tachycardia and sudden death in myotonic dystrophy: clinical, electrophysiologic and pathologic features. Author(s): Grigg LE, Chan W, Mond HG, Vohra JK, Downey WF. Source: Journal of the American College of Cardiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4008782&query_hl=9&itool=pubmed_docsum

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Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions. Author(s): Furling D, Doucet G, Langlois MA, Timchenko L, Belanger E, Cossette L, Puymirat J. Source: Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12704419&query_hl=9&itool=pubmed_docsum

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Visualization of double-stranded RNAs from the myotonic dystrophy protein kinase gene and interactions with CUG-binding protein. Author(s): Michalowski S, Miller JW, Urbinati CR, Paliouras M, Swanson MS, Griffith J. Source: Nucleic Acids Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10446244&query_hl=9&itool=pubmed_docsum

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Warm heart operation in a patient with myotonic dystrophy. Author(s): Sakai T, Miki S, Ueda Y, Nomoto T, Hashimoto S, Takahashi K. Source: The Annals of Thoracic Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8823122&query_hl=9&itool=pubmed_docsum

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Whole body insulin resistance in myotonic dystrophy. Author(s): Moxley RT, Corbett AJ, Minaker KL, Rowe JW. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6367619&query_hl=9&itool=pubmed_docsum

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Why a positive genetic test for myotonic dystrophy type I does not always imply the right diagnosis. Author(s): Meuth SG, Kleinschnitz C, Frank M, Wessig C, Bendszus M, Kress W, Wiendl H. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17110752&query_hl=9&itool=pubmed_docsum

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Widespread electroanatomic alterations of right cardiac chambers in patients with myotonic dystrophy type 1. Author(s): Dello Russo A, Pelargonio G, Parisi Q, Santamaria M, Messano L, Sanna T, Casella M, De Martino G, De Ponti R, Pace M, Giglio V, Ierardi C, Zecchi P, Crea F, Bellocci F. Source: Journal of Cardiovascular Electrophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16426397&query_hl=9&itool=pubmed_docsum

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CHAPTER 2. ALTERNATIVE MEDICINE AND MYOTONIC DYSTROPHY Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to myotonic dystrophy. 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 myotonic dystrophy 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 myotonic dystrophy (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 myotonic dystrophy: •

A study of the facilitation of respiration in myotonic dystrophy. Author(s): Nitz J, Burke B. Source: Physiotherapy Research International : the Journal for Researchers and Clinicians in Physical Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12528578&query_hl=1&itool=pubmed_docsum

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Anaesthesia for caesarean section in a patient with myotonic dystrophy receiving warfarin therapy. Author(s): Campbell AM, Thompson N. Source: Canadian Journal of Anaesthesia = Journal Canadien D'anesthesie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7614649&query_hl=1&itool=pubmed_docsum

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Creatine monohydrate in DM2/PROMM: a double-blind placebo-controlled clinical study. Proximal myotonic myopathy. Author(s): Schneider-Gold C, Beck M, Wessig C, George A, Kele H, Reiners K, Toyka KV. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12578937&query_hl=1&itool=pubmed_docsum

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Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type 1. Author(s): Tarnopolsky M, Mahoney D, Thompson T, Naylor H, Doherty TJ. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14694498&query_hl=1&itool=pubmed_docsum

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De novo myotonic dystrophy mutation in a Nigerian kindred. Author(s): Krahe R, Eckhart M, Ogunniyi AO, Osuntokun BO, Siciliano MJ, Ashizawa T. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7726160&query_hl=1&itool=pubmed_docsum

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Dystrophia myotonica: a case report. Author(s): Hart JF. Source: Journal of Manipulative and Physiological Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3437242&query_hl=1&itool=pubmed_docsum

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Dystrophia myotonica: a case report. Author(s): Zahid MA, Washington G. Source: Journal of Manipulative and Physiological Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3559422&query_hl=1&itool=pubmed_docsum

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Event-related potentials (P300) in myotonic dystrophy. Author(s): Hanafusa H, Motomura N, Asaba H, Sakai T, Kawamura H. Source: Acta Neurologica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2816271&query_hl=1&itool=pubmed_docsum

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Letter: Exacerbation of myotonia dystrophica by vincristine. Author(s): Michalak JC, Dibella NJ. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=934199&query_hl=1&itool=pubmed_docsum

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Membership of a patients' association and well-being. A study into the relationship between membership of a patients' association, fellow-patient contact, information received, and psychosocial well-being of people with a neuromuscular disease.

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Author(s): van Haastregt JC, de Witte LP, Terpstra SJ, Diederiks JP, van der Horst FG, de Geus CA. Source: Patient Education and Counseling. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7746763&query_hl=1&itool=pubmed_docsum •

Membrane defects in Duchenne dystrophy: protease affecting sarcoplasmic reticulum. Author(s): Nagy B, Samaha FJ. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3527039&query_hl=1&itool=pubmed_docsum

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Myotonic dystrophy: an electrophysiological study of cognitive deficits. Author(s): Ragazzoni A, Pinto F, Taiuti R, Silveri MC. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1913364&query_hl=1&itool=pubmed_docsum

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Neural control of the expression of a Ca(2+)-activated K+ channel involved in the induction of myotonic-like characteristics. Author(s): Ramirez BU, Behrens MI, Vergara C. Source: Cellular and Molecular Neurobiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8714558&query_hl=1&itool=pubmed_docsum

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Neurological disorders with autosomal dominant transmission. Author(s): Simpson JM. Source: J Neurosurg Nurs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6239015&query_hl=1&itool=pubmed_docsum

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Phenytoin and membrane fluidity in myotonic dystrophy. Author(s): Roses AD, Butterfield A, Appel SH, Chestnut DB. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=168843&query_hl=1&itool=pubmed_docsum

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Platelet functions, alpha 2-adrenergic receptors and cytoplasmic free calcium are normal in the myotonic dystrophy of Steinert. Author(s): Lanza F, Cazenave JP, Hemmendinger S, Stierle A, Tranchant C, Warter JM. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3039064&query_hl=1&itool=pubmed_docsum

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Pursed lips breathing improves ventilation in myotonic muscular dystrophy. Author(s): Ugalde V, Breslin EH, Walsh SA, Bonekat HW, Abresch RT, Carter GT.

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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=10768538&query_hl=1&itool=pubmed_docsum •

Some flavonoids and DHEA-S prevent the cis-effect of expanded CTG repeats in a stable PC12 cell transformant. Author(s): Furuya H, Shinnoh N, Ohyagi Y, Ikezoe K, Kikuchi H, Osoegawa M, Fukumaki Y, Nakabeppu Y, Hayashi T, Kira J. Source: Biochemical Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15652241&query_hl=1&itool=pubmed_docsum

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Some psychosomatic considerations in dystrophia myotonica; report of a case. Author(s): WALLERSTEIN RS, RUBIN S. Source: The Journal of Nervous and Mental Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13233972&query_hl=1&itool=pubmed_docsum

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Spontaneous chromosome loss and colcemid resistance in lymphocytes from patients with myotonic dystrophy type 1. Author(s): Casella M, Lucarelli M, Simili M, Beffy P, Del Carratore R, Minichilli F, Chisari C, Simi S. Source: Cytogenetic and Genome Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14526184&query_hl=1&itool=pubmed_docsum

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Swedish views on selenium. Author(s): Bruce A. Source: Ann Clin Res. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3717875&query_hl=1&itool=pubmed_docsum

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The achilles reflex in thyroid disorders; a critical evaluation. Author(s): NUTTALL FQ, DOE RP. Source: Annals of Internal Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14204862&query_hl=1&itool=pubmed_docsum

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The changes in muscle strength and relaxation time after a comprehensive rehabilitation program for patients with myotonic dystrophy. Author(s): Moon JH, Na YM, Kang SW, Lee HS. Source: Yonsei Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8942293&query_hl=1&itool=pubmed_docsum

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The clinical effects of Ganoderma lucidum spore preparations in 10 cases of atrophic myotonia. Author(s): Fu HD, Wang ZY.

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Source: J Tradit Chin Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6765691&query_hl=1&itool=pubmed_docsum •

The psychotherapy of genetics. Author(s): McDaniel SH. Source: Family Process. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15807076&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 myotonic dystrophy; 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 Muscular Dystrophy 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. BOOKS ON MYOTONIC DYSTROPHY Overview This chapter provides bibliographic book references relating to myotonic dystrophy. 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 myotonic dystrophy. 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 myotonic dystrophy at online booksellers’ Web sites, you may discover non-medical books that use the generic term “myotonic dystrophy” (or a synonym) in their titles. The following is indicative of the results you might find when searching for myotonic dystrophy (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

CTG repeat number in the nonaffected allele of myotonic dystrophy patients is not critical for disease expression.(Brief Communication): An article from: Human Biology M. Cipollaro, U. Galderisi, G. Iacomino, and G. Galano (2005); ISBN: B00097TRMG; http://www.amazon.com/exec/obidos/ASIN/B00097TRMG/icongroupinterna

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Dystrophia Myotonica and Related Disorders J.E. Caughey and N.C. Myrianthopoulos (1963); ISBN: B000FUCGMA; http://www.amazon.com/exec/obidos/ASIN/B000FUCGMA/icongroupinterna

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Gale Encyclopedia of Medicine: Myotonic dystrophy C.G.C. Karen M. Krajewski M.S. (2004); ISBN: B00075V0YS; http://www.amazon.com/exec/obidos/ASIN/B00075V0YS/icongroupinterna

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Myotonic Dystrophy - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References ICON Health Publications (2004); ISBN: 0497007436; http://www.amazon.com/exec/obidos/ASIN/0497007436/icongroupinterna

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Myotonic Dystrophy Type 1: Cognition, Personality and Emotion Stefan Winblad (2006); ISBN: 9162869787; http://www.amazon.com/exec/obidos/ASIN/9162869787/icongroupinterna

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Reading and spelling impairments in children and adolescents with infantile myotonic dystrophy D. Cohen, M. Plaza, N. Angeard, and O. Lanthier-Gazzano (2006); ISBN: B000LKA2CU; http://www.amazon.com/exec/obidos/ASIN/B000LKA2CU/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 myotonic dystrophy (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 Medicine8: •

Family screening and molecular diagnosis of myotonic dystrophy.; Year: 1998; MontreÌ al: Conseil d’eÌ valuation des technologies de la santeÌ du QueÌ bec, [1998]; ISBN: 9782550339 http://www.amazon.com/exec/obidos/ASIN/9782550339/icongroupinterna

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Myotonic dystrophy Author: Harper, Peter S.; Year: 2001; London; New York: W. B. Saunders, 2001; ISBN: 9780702021 http://www.amazon.com/exec/obidos/ASIN/9780702021/icongroupinterna

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Studies on the metabolism of histamine in dystrophia myotonica Author: Sjaastad, Ottar.; Year: 1967; Oslo: Universitetsforlaget, c1967

8 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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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.9

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.

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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.

Help Me Understand Genetics

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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.

•

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.

•

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.10 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 10

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.

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Insertion: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.

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Deletion: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).

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Duplication: A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.

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Frameshift mutation: This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.

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Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly. Can Changes in Chromosomes Affect Health and Development?

Changes that affect entire chromosomes or segments of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and alter the proteins made by those genes. Conditions caused by a change in the number or structure of chromosomes are known as chromosomal disorders. Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes leads to a chromosomal disorder. These

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changes can occur during the formation of reproductive cells (eggs and sperm) or in early fetal development. A gain or loss of chromosomes from the normal 46 is called aneuploidy. The most common form of aneuploidy is trisomy, or the presence of an extra chromosome in each cell. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in each cell instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy—people with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell. Monosomy, or the loss of one chromosome from each cell, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in each cell instead of the normal two copies. Turner syndrome is a condition caused by monosomy. Women with Turner syndrome are often missing one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell. Chromosomal disorders can also be caused by changes in chromosome structure. These changes are caused by the breakage and reunion of chromosome segments when an egg or sperm cell is formed or in early fetal development. Pieces of DNA can be rearranged within one chromosome, or transferred between two or more chromosomes. The effects of structural changes depend on their size and location. Many different structural changes are possible; some cause medical problems, while others may have no effect on a person’s health. Many cancer cells also have changes in their chromosome number or structure. These changes most often occur in somatic cells (cells other than eggs and sperm) during a person’s lifetime. Can Changes in Mitochondrial DNA Affect Health and Development? Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision. Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson


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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. 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)

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The parts of the body affected by the condition (for example, retinoblastoma)

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The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan)


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•

A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea)

•

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.

•

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.

•

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.

•

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.

•

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.

•

Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial

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disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected. Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health. Factors that Influence the Effects of Particular Genetic Changes Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern. Reduced Penetrance Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations. Variable Expressivity Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and


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symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience lifethreatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose. What Do Geneticists Mean by Anticipation? The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation. Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation. What Is Genomic Imprinting? Genomic imprinting is a factor that influences how some genetic conditions are inherited. People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited

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from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13). What Is Uniparental Disomy? Uniparental disomy is a factor that influences how some genetic conditions are inherited. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems. Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11. Are Chromosomal Disorders Inherited? Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next. Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.


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Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional. Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next. Why Are Some Genetic Conditions More Common in Particular Ethnic Groups? Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.

Genetic Consultation This section presents information on finding and visiting a genetic counselor or other genetics professional. What Is a Genetic Consultation? A genetic consultation is a health service that provides information and support to people who have, or may be at risk for, genetic disorders. During a consultation, a genetics professional meets with an individual or family to discuss genetic risks or to diagnose, confirm, or rule out a genetic condition. Genetics professionals include medical geneticists (doctors who specialize in genetics) and genetic counselors (certified healthcare workers with experience in medical genetics and counseling). Other healthcare professionals such as nurses, psychologists, and social workers trained in genetics can also provide genetic consultations. Consultations usually take place in a doctor’s office, hospital, genetics center, or other type of medical center. These meetings are most often in-person visits with individuals or families, but they are occasionally conducted in a group or over the telephone.

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Why Might Someone Have a Genetic Consultation? Individuals or families who are concerned about an inherited condition may benefit from a genetic consultation. The reasons that a person might be referred to a genetic counselor, medical geneticist, or other genetics professional include: •

A personal or family history of a genetic condition, birth defect, chromosomal disorder, or hereditary cancer.

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Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.

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A child with a known inherited disorder, a birth defect, mental retardation, or developmental delay.

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A woman who is pregnant or plans to become pregnant at or after age 35. (Some chromosomal disorders occur more frequently in children born to older women.)

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Abnormal test results that suggest a genetic or chromosomal condition.

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An increased risk of developing or passing on a particular genetic disorder on the basis of a person’s ethnic background.

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People related by blood (for example, cousins) who plan to have children together. (A child whose parents are related may be at an increased risk of inheriting certain genetic disorders.)

A genetic consultation is also an important part of the decision-making process for genetic testing. A visit with a genetics professional may be helpful even if testing is not available for a specific condition, however. What Happens during a Genetic Consultation? A genetic consultation provides information, offers support, and addresses a patient’s specific questions and concerns. To help determine whether a condition has a genetic component, a genetics professional asks about a person’s medical history and takes a detailed family history (a record of health information about a person’s immediate and extended family). The genetics professional may also perform a physical examination and recommend appropriate tests. If a person is diagnosed with a genetic condition, the genetics professional provides information about the diagnosis, how the condition is inherited, the chance of passing the condition to future generations, and the options for testing and treatment. During a consultation, a genetics professional will: •

Interpret and communicate complex medical information.

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Help each person make informed, independent decisions about their health care and reproductive options.

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Respect each person’s individual beliefs, traditions, and feelings.

A genetics professional will NOT: •

Tell a person which decision to make.

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Advise a couple not to have children.


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Recommend that a woman continue or end a pregnancy.

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Tell someone whether to undergo testing for a genetic disorder.

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How Can I Find a Genetics Professional in My Area? To find a genetics professional in your community, you may wish to ask your doctor for a referral. If you have health insurance, you can also contact your insurance company to find a medical geneticist or genetic counselor in your area who participates in your plan. Several resources for locating a genetics professional in your community are available online: •

GeneTests from the University of Washington provides a list of genetics clinics around the United States and international genetics clinics. You can also access the list by clicking on “Clinic Directory” at the top of the GeneTests home page. Clinics can be chosen by state or country, by service, and/or by specialty. State maps can help you locate a clinic in your area. See http://www.genetests.org/.

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The National Society of Genetic Counselors offers a searchable directory of genetic counselors in the United States. You can search by location, name, area of practice/specialization, and/or ZIP Code. See http://www.nsgc.org/resourcelink.cfm.

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The National Cancer Institute provides a Cancer Genetics Services Directory, which lists professionals who provide services related to cancer genetics. You can search by type of cancer or syndrome, location, and/or provider name at the following Web site: http://cancer.gov/search/genetics_services/.

Genetic Testing This section presents information on the benefits, costs, risks, and limitations of genetic testing. What Is Genetic Testing? Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. Genetic testing is voluntary. Because testing has both benefits and limitations, the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing.

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What Are the Types of Genetic Tests? Genetic testing can provide information about a person’s genes and chromosomes. Available types of testing include: •

Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental retardation if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). Most states also test for other genetic disorders.

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Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person’s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person’s choices about health care and the management of the disorder.

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Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition.

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Prenatal testing is used to detect changes in a fetus’s genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however.

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Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques such as in-vitro fertilization. In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing them with sperm cells outside the body. To perform preimplantation testing, a small number of cells are taken from these embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.

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Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person’s risk of developing disorders with a genetic basis, such as certain types of cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder and help with making decisions about medical care.

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Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).


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How Is Genetic Testing Done? Once a person decides to proceed with genetic testing, a medical geneticist, primary care doctor, specialist, or nurse practitioner can order the test. Genetic testing is often done as part of a genetic consultation. Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person’s doctor or genetic counselor. Newborn screening tests are done on a small blood sample, which is taken by pricking the baby’s heel. Unlike other types of genetic testing, a parent will usually only receive the result if it is positive. If the test result is positive, additional testing is needed to determine whether the baby has a genetic disorder. Before a person has a genetic test, it is important that he or she understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission is called informed consent. What Is Direct-to-Consumer Genetic Testing? Traditionally, genetic tests have been available only through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers order the appropriate test from a laboratory, collect and send the samples, and interpret the test results. Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. If a consumer chooses to purchase a genetic test directly, the test kit is mailed to the consumer instead of being ordered through a doctor’s office. The test typically involves collecting a DNA sample at home, often by swabbing the inside of the cheek, and mailing the sample back to the laboratory. In some cases, the person must visit a health clinic to have blood drawn. Consumers are notified of their results by mail or over the telephone, or the results are posted online. In some cases, a genetic counselor or other healthcare provider is available to explain the results and answer questions. The price for this type of at-home genetic testing ranges from several hundred dollars to more than a thousand dollars. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins. At-home genetic tests, however, have significant risks and limitations. Consumers are vulnerable to being misled by the results of unproven or invalid tests. Without guidance from a healthcare provider, they may make important decisions about treatment or prevention based on inaccurate, incomplete, or misunderstood information about their health. Consumers may also experience an invasion of genetic privacy if testing companies use their genetic information in an unauthorized way.

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Genetic testing provides only one piece of information about a person’s health—other genetic and environmental factors, lifestyle choices, and family medical history also affect a person’s risk of developing many disorders. These factors are discussed during a consultation with a doctor or genetic counselor, but in many cases are not addressed by athome genetic tests. More research is needed to fully understand the benefits and limitations of direct-to-consumer genetic testing. What Do the Results of Genetic Tests Mean? The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, healthcare professionals consider a person’s medical history, family history, and the type of genetic test that was done. A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify an increased risk of developing a disease (such as cancer) in the future, or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health professionals typically cannot use a positive test result to predict the course or severity of a condition. A negative test result means that the laboratory did not find a change in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic mutation, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing may be required to confirm a negative result. In some cases, a negative result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been associated with a disorder in other people, it can be difficult to tell whether it is a natural polymorphism or a disease-causing mutation. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result. What Is the Cost of Genetic Testing, and How Long Does It Take to Get the Results? The cost of genetic testing can range from under $100 to more than $2,000, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members must be tested to obtain a meaningful result. For newborn


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screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant. From the date that a sample is taken, it may take a few weeks to several months to receive the test results. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. The doctor or genetic counselor who orders a particular test can provide specific information about the cost and time frame associated with that test. Will Health Insurance Cover the Costs of Genetic Testing? In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person’s doctor. Health insurance providers have different policies about which tests are covered, however. A person interested in submitting the costs of testing may wish to contact his or her insurance company beforehand to ask about coverage. Some people may choose not to use their insurance to pay for testing because the results of a genetic test can affect a person’s health insurance coverage. Instead, they may opt to pay out-of-pocket for the test. People considering genetic testing may want to find out more about their state’s privacy protection laws before they ask their insurance company to cover the costs. What Are the Benefits of Genetic Testing? Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible. What Are the Risks and Limitations of Genetic Testing? The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus. Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern.

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Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision. What Is Genetic Discrimination? Genetic discrimination occurs when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder. People who undergo genetic testing may be at risk for genetic discrimination. The results of a genetic test are normally included in a person’s medical records. When a person applies for life, disability, or health insurance, the insurance company may ask to look at these records before making a decision about coverage. An employer may also have the right to look at an employee’s medical records. As a result, genetic test results could affect a person’s insurance coverage or employment. People making decisions about genetic testing should be aware that when test results are placed in their medical records, the results might not be kept private. Fear of discrimination is a common concern among people considering genetic testing. Several laws at the federal and state levels help protect people against genetic discrimination; however, genetic testing is a fast-growing field and these laws don’t cover every situation. How Does Genetic Testing in a Research Setting Differ from Clinical Genetic Testing? The main differences between clinical genetic testing and research testing are the purpose of the test and who receives the results. The goals of research testing include finding unknown genes, learning how genes work, and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers. Clinical testing, on the other hand, is done to find out about an inherited disorder in an individual patient or family. People receive the results of a clinical test and can use them to help them make decisions about medical care or reproductive issues. It is important for people considering genetic testing to know whether the test is available on a clinical or research basis. Clinical and research testing both involve a process of informed consent in which patients learn about the testing procedure, the risks and benefits of the test, and the potential consequences of testing.


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Gene Therapy This section presents information on experimental techniques, safety, ethics, and availability of gene therapy. What Is Gene Therapy? Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including: •

Replacing a mutated gene that causes disease with a healthy copy of the gene.

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Inactivating, or “knocking out,” a mutated gene that is functioning improperly.

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Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures. How Does Gene Therapy Work? Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can’t cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patient’s cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein. Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.

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A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

Is Gene Therapy Safe? Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible. Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants. The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RAC’s public meetings.


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An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution’s potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research. What Are the Ethical Issues surrounding Gene Therapy? Because gene therapy involves making changes to the body’s set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding gene therapy include: •

How can “good” and “bad” uses of gene therapy be distinguished?

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Who decides which traits are normal and which constitute a disability or disorder?

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Will the high costs of gene therapy make it available only to the wealthy?

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Could the widespread use of gene therapy make society less accepting of people who are different?

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Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?

Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a person’s children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy. The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they can’t choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people. Is Gene Therapy Available to Treat My Disorder? Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States. Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate. You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for

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specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) patients.

The Human Genome Project and Genomic Research This section presents information on the goals, accomplishments, and next steps in understanding the human genome. What Is a Genome? A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. What Was the Human Genome Project and Why Has It Been Important? The Human Genome Project was an international research effort to determine the sequence of the human genome and identify the genes that it contains. The Project was coordinated by the National Institutes of Health and the U.S. Department of Energy. Additional contributors included universities across the United States and international partners in the United Kingdom, France, Germany, Japan, and China. The Human Genome Project formally began in 1990 and was completed in 2003, 2 years ahead of its original schedule. The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge will have a major impact in the fields of medicine, biotechnology, and the life sciences. What Were the Goals of the Human Genome Project? The main goals of the Human Genome Project were to provide a complete and accurate sequence of the 3 billion DNA base pairs that make up the human genome and to find all of the estimated 20,000 to 25,000 human genes. The Project also aimed to sequence the genomes of several other organisms that are important to medical research, such as the mouse and the fruit fly. In addition to sequencing DNA, the Human Genome Project sought to develop new tools to obtain and analyze the data and to make this information widely available. Also, because advances in genetics have consequences for individuals and society, the Human Genome Project committed to exploring the consequences of genomic research through its Ethical, Legal, and Social Implications (ELSI) program. What Did the Human Genome Project Accomplish? In April 2003, researchers announced that the Human Genome Project had completed a high-quality sequence of essentially the entire human genome. This sequence closed the


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gaps from a working draft of the genome, which was published in 2001. It also identified the locations of many human genes and provided information about their structure and organization. The Project made the sequence of the human genome and tools to analyze the data freely available via the Internet. In addition to the human genome, the Human Genome Project sequenced the genomes of several other organisms, including brewers’ yeast, the roundworm, and the fruit fly. In 2002, researchers announced that they had also completed a working draft of the mouse genome. By studying the similarities and differences between human genes and those of other organisms, researchers can discover the functions of particular genes and identify which genes are critical for life. The Project’s Ethical, Legal, and Social Implications (ELSI) program became the world’s largest bioethics program and a model for other ELSI programs worldwide. What Were Some of the Ethical, Legal, and Social Implications Addressed by the Human Genome Project? The Ethical, Legal, and Social Implications (ELSI) program was founded in 1990 as an integral part of the Human Genome Project. The mission of the ELSI program was to identify and address issues raised by genomic research that would affect individuals, families, and society. A percentage of the Human Genome Project budget at the National Institutes of Health and the U.S. Department of Energy was devoted to ELSI research. The ELSI program focused on the possible consequences of genomic research in four main areas: •

Privacy and fairness in the use of genetic information, including the potential for genetic discrimination in employment and insurance.

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The integration of new genetic technologies, such as genetic testing, into the practice of clinical medicine.

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Ethical issues surrounding the design and conduct of genetic research with people, including the process of informed consent.

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The education of healthcare professionals, policy makers, students, and the public about genetics and the complex issues that result from genomic research. What Are the Next Steps in Genomic Research?

Discovering the sequence of the human genome was only the first step in understanding how the instructions coded in DNA lead to a functioning human being. The next stage of genomic research will begin to derive meaningful knowledge from the DNA sequence. Research studies that build on the work of the Human Genome Project are under way worldwide. The objectives of continued genomic research include the following: •

Determine the function of genes and the elements that regulate genes throughout the genome.

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Find variations in the DNA sequence among people and determine their significance. These variations may one day provide information about a person’s disease risk and response to certain medications.

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Discover the 3-dimensional structures of proteins and identify their functions.

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Explore how DNA and proteins interact with one another and with the environment to create complex living systems.

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Develop and apply genome-based strategies for the early detection, diagnosis, and treatment of disease.

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Sequence the genomes of other organisms, such as the rat, cow, and chimpanzee, in order to compare similar genes between species.

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Develop new technologies to study genes and DNA on a large scale and store genomic data efficiently.

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Continue to explore the ethical, legal, and social issues raised by genomic research. What Is Pharmacogenomics?

Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Many drugs that are currently available are “one size fits all,” but they don’t work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.

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APPENDIX B. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

National Institutes of Health (NIH); guidelines consolidated across agencies available at http://health.nih.gov/

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/Publications/FactSheets.htm

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancertopics/pdq

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/health/

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/HealthInformation/Publications/

•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/Publications/

11

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/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidcr.nih.gov/HealthInformation/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/healthinformation/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 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

12

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 Medicine13: •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/index.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

13

See http://www.nlm.nih.gov/databases/index.html.

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The NLM Gateway14 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.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type myotonic dystrophy (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 4214 31 24 1 0 4270

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 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.18 Simply search by myotonic dystrophy (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists19 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. 14

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

15

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). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

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. 19 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

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Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 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.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

MD Consult: Access to electronic clinical resources, see http://www.mdconsult.com/.

•

Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

20

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. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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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 myotonic dystrophy 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 myotonic dystrophy. 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 myotonic dystrophy. 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 myotonic dystrophy:

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Bone Diseases http://www.nlm.nih.gov/medlineplus/bonediseases.html Cardiac Arrest http://www.nlm.nih.gov/medlineplus/cardiacarrest.html Muscle Disorders http://www.nlm.nih.gov/medlineplus/muscledisorders.html Muscular Dystrophy http://www.nlm.nih.gov/medlineplus/musculardystrophy.html Neuromuscular Disorders http://www.nlm.nih.gov/medlineplus/neuromusculardisorders.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: •

Muscular Dystrophy: Hope Through Research: National Institute of. Source: www.ninds.nih.gov http://www.ninds.nih.gov/disorders/md/detail_md.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 myotonic dystrophy. 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 myotonic dystrophy (or synonyms) into the search box, and click Search.

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Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMD®Health: http://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 myotonic dystrophy. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with myotonic dystrophy. 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 myotonic dystrophy. 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 myotonic dystrophy (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://healthhotlines.nlm.nih.gov/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information.

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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type myotonic dystrophy (or a synonym) into the search box, and click Submit Query.

Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families22: •

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

22

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

•

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).

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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MYOTONIC DYSTROPHY 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablate: In surgery, is to remove. [NIH] Ablation: The removal of an organ by surgery. [NIH] Actin: Essential component of the cell skeleton. [NIH] Actomyosin: A protein complex of actin and myosin occurring in muscle. It is the essential contractile substance of muscle. [NIH] Acyl: Chemical signal used by bacteria to communicate. [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] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU]

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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] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Akinesia: 1. Absence or poverty of movements. 2. The temporary paralysis of a muscle by the injection of procaine. [EU] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alternative Splicing: A process whereby multiple protein isoforms are generated from a single gene. Alternative splicing involves the splicing together of nonconsecutive exons during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form messenger RNA. The alternative forms produce proteins in which one part is common while the other part is different. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] 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]

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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] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] 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] Anomalies: Birth defects; abnormalities. [NIH] Anterior chamber: The space in front of the iris and behind the cornea. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] 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

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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] Antioxidants: Naturally occurring or synthetic substances that inhibit or retard the oxidation of a substance to which it is added. They counteract the harmful and damaging effects of oxidation in animal tissues. [NIH] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [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] Aqueous humor: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [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] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to

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strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Autopsy: Postmortem examination of the body. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Azoospermia: Absence of spermatozoa in the semen, or failure of formation of spermatozoa. [EU]

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] 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] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [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] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] 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

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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] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] 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] Brain Neoplasms: Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain. [NIH] 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] Bulbar: Pertaining to a bulb; pertaining to or involving the medulla oblongata, as bulbar paralysis. [EU] Caesarean section: A surgical incision through the abdominal and uterine walls in order to deliver a baby. [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] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Carbohydrates: The largest class of organic compounds, including starches, glycogens, cellulose, gums, and simple sugars. Carbohydrates are composed of carbon, hydrogen, and oxygen in a ratio of Cn(H2O)n. [NIH]

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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] Cardiac: Having to do with the heart. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheter Ablation: Removal of tissue with electrical current delivered via electrodes positioned at the distal end of a catheter. Energy sources are commonly direct current (DCshock) or alternating current at radiofrequencies (usually 750 kHz). The technique is used most often to ablate the AV junction and/or accessory pathways in order to interrupt AV conduction and produce AV block in the treatment of various tachyarrhythmias. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] 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]

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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 Polarity: Orientation of intracellular structures especially with respect to the apical and basolateral domains of the plasma membrane. Polarized cells must direct proteins from the Golgi apparatus to the appropriate domain since tight junctions prevent proteins from diffusing between the two domains. [NIH] Cell 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] 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] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH]

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Chemotherapy: Treatment with anticancer drugs. [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] Cholecystectomy: Surgical removal of the gallbladder. [NIH] Cholelithiasis: Presence or formation of gallstones. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]

Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] 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 Breakage: A type of chromosomal aberration which may result from spontaneous or induced breakage. Alkylating agents, various types of irradiation, and chemical mutagens have been found to cause induced chromosomal breakage. Breakage can induce base pair translocations, deletions, or chromatid breakage. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary processes: The extensions or projections of the ciliary body that secrete aqueous humor. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [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] 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 study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other

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interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] 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 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] 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] 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

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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] 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] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congenita: Displacement, subluxation, or malposition of the crystalline lens. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] 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] Contracture: A condition of fixed high resistance to passive stretch of a muscle, resulting from fibrosis of the tissues supporting the muscles or the joints, or from disorders of the muscle fibres. [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] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that

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it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] 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] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyst: A sac or capsule filled with fluid. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [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] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH]

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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, from a chemical compound. [NIH] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [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] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dinucleotide Repeats: The most common of the microsatellite tandem repeats (microsatellite repeats) dispersed in the euchromatic arms of chromosomes. They consist of two nucleotides repeated in tandem; guanine and thymine, (GT)n, is the most frequently seen. [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]

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Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diurnal: Occurring during the day. [EU] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] 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 nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Electrocardiogram: Measurement of electrical activity during heartbeats. [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] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [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]

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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] 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] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Enhancer: Transcriptional element in the virus genome. [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] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [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] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] 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] Expiration: The act of breathing out, or expelling air from the lungs. [EU]

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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] Extraocular: External to or outside of the eye. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [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] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fasciculation: A small local contraction of muscles, visible through the skin, representing a spontaneous discharge of a number of fibres innervated by a single motor nerve filament. [EU]

Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fetal Movement: Motion of the fetus perceived by the mother and felt by palpation of the abdomen. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] 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] Flexion: In gynaecology, a displacement of the uterus in which the organ is bent so far forward or backward that an acute angle forms between the fundus and the cervix. [EU] 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] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Founder Effect: The principle that when a small subgroup of a larger population establishes itself as a separate and isolated entity, its gene pool carries only a fraction of the genetic diversity of the parental population. This may result in an increased frequency of certain diseases in the subgroup, especially those diseases known to be autosomal recessive. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base

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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] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] 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] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [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 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] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes

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may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [NIH] 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] 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] 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] Glomeruli: Plural of glomerulus. [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] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

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] 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

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different for each type of cancer. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Guanine: One of the four DNA bases. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Hair Color: Color of hair or fur. [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] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatocyte: A liver cell. [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]

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Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [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] 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] Homozygotes: An individual having a homozygous gene pair. [NIH] 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] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrocephalus: Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial hypertension; headache; lethargy; urinary incontinence; and ataxia (and in infants macrocephaly). This condition may be caused by obstruction of cerebrospinal fluid pathways due to neurologic abnormalities, intracranial hemorrhages; central nervous system infections; brain neoplasms; craniocerebral trauma; and other conditions. Impaired resorption of cerebrospinal fluid from the arachnoid villi results in a communicating form of hydrocephalus. Hydrocephalus ex-vacuo refers to ventricular dilation that occurs as a result of brain substance loss from cerebral infarction and other conditions. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hyperglycaemia: Abnormally increased content of sugar in the blood. [EU] Hyperostosis: Increase in the mass of bone per unit volume. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophic cardiomyopathy: Heart muscle disease that leads to thickening of the heart walls, interfering with the heart's ability to fill with and pump blood. [NIH] Hypokinesia: Slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other

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conditions. [NIH] Hypopituitarism: Diminution or cessation of secretion of one or more hormones from the anterior pituitary gland (including LH; FSH; somatotropin; and corticotropin). This may result from surgical or radiation ablation, non-secretory pituitary neoplasms, metastatic tumors, infarction, pituitary apoplexy, infiltrative or granulomatous processes, and other conditions. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypotonia: A condition of diminished tone of the skeletal muscles; diminished resistance of muscles to passive stretching. [EU] Hysterectomy: Excision of the uterus. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH]

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Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] 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] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] 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] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [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] Intracranial Hemorrhages: Bleeding within the intracranial cavity, including hemorrhages in the brain and within the cranial epidural, subdural, and subarachnoid spaces. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result

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from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intrahepatic: Within the liver. [NIH] Intrahepatic bile ducts: The bile ducts that pass through and drain bile from the liver. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] 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] Iridis: The angle between the iris and the cornea at the periphery of the anterior chamber of the eye. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kyphosis: A deformity of the spine characterized by extensive flexion. [NIH]

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Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [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]

Leukemia: Cancer of blood-forming tissue. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipid: Fat. [NIH] Lipid Peroxides: Peroxides produced in the presence of a free radical by the oxidation of unsaturated fatty acids in the cell in the presence of molecular oxygen. The formation of lipid peroxides results in the destruction of the original lipid leading to the loss of integrity of the membranes. They therefore cause a variety of toxic effects in vivo and their formation is considered a pathological process in biological systems. Their formation can be inhibited by antioxidants, such as vitamin E, structural separation or low oxygen tension. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside

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diameter) and used in transferring microorganisms. [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] 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] 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] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [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] 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] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] 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] 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 Fluidity: The motion of phospholipid molecules within the lipid bilayer,

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dependent on the classes of phospholipids present, their fatty acid composition and degree of unsaturation of the acyl chains, the cholesterol concentration, and temperature. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mesolimbic: Inner brain region governing emotion and drives. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [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] Microsatellite Repeats: A variety of simple di- (dinucleotide repeats), tri- (trinucleotide repeats), tetra-, and pentanucleotide tandem repeats (usually less than 100 bases long). They are dispersed in the euchromatic arms of most chromosomes. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [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] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH]

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Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] 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] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] Motor Neurons: Neurons which activate muscle cells. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [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] Muscle Hypertonia: Abnormal increase in skeletal or smooth muscle tone. Skeletal muscle hypertonicity may be associated with pyramidal tract lesions or basal ganglia diseases. [NIH] Muscle Relaxation: That phase of a muscle twitch during which a muscle returns to a resting position. [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] Musculature: The muscular apparatus of the body, or of any part of it. [EU] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mycoplasma: A genus of gram-negative, facultatively anaerobic bacteria bounded by a plasma membrane only. Its organisms are parasites and pathogens, found on the mucous membranes of humans, animals, and birds. [NIH]

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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] Myopathy: Any disease of a muscle. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonia: Prolonged failure of muscle relaxation after contraction. This may occur after voluntary contractions, muscle percussion, or electrical stimulation of the muscle. Myotonia is a characteristic feature of myotonic disorders. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Natriuresis: The excretion of abnormal amounts of sodium in the urine. [EU] Natriuretic Hormone: A low-molecular weight substance, possibly from the hypothalamus, which is released due to plasma volume expansion. It causes natriuresis in part by inhibiting sodium potassium ATPase. The development of hypertension may be the consequence of an abnormality in volume regulation induced by a defect in the renal response to the natriuretic effect of the natriuretic hormone. Do not confuse with atrial natriuretic factor or cardionatrin which is a different, well characterized hormone. [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] Neonatal: Pertaining to the first four weeks after birth. [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] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Diseases: A general term encompassing lower motor neuron disease; peripheral nervous system diseases; and certain muscular diseases. Manifestations include muscle weakness; fasciculation; muscle atrophy; spasm; myokymia; muscle hypertonia, myalgias, and musclehypotonia. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon,

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and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [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] Nonverbal Communication: Transmission of emotions, ideas, and attitudes between individuals in ways other than the spoken language. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] 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] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleosomes: The repeating structural units of chromatin, each consisting of approximately 200 base pairs of DNA wound around a protein core. This core is composed of the histones H2A, H2B, H3, and H4. [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

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providing medical care under the supervision of a physician. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncolysis: The destruction of or disposal by absorption of any neoplastic cells. [NIH] Oncolytic: Pertaining to, characterized by, or causing oncolysis (= the lysis or destruction of tumour cells). [EU] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [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] 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] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Pacemaker: An object or substance that influences the rate at which a certain phenomenon occurs; often used alone to indicate the natural cardiac pacemaker or an artificial cardiac pacemaker. In biochemistry, a substance whose rate of reaction sets the pace for a series of interrelated reactions. [EU]

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Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palpation: Application of fingers with light pressure to the surface of the body to determine consistence of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. [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] Paralysis: Loss of ability to move all or part of the body. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] 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] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [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 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] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] 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 Nervous System Diseases: Diseases of the peripheral nerves external to the brain and spinal cord, which includes diseases of the nerve roots, ganglia, plexi, autonomic nerves, sensory nerves, and motor nerves. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness,

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constipation, vomiting, and moderate fever. [EU] 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] 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]

Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Apoplexy: Sudden hemorrhage or ischemic necrosis involving the pituitary gland which may be associated with acute visual loss, severe headache, meningeal signs, cranial nerve palsies, panhypopituitarism, and rarely coma. The most common cause is hemorrhage (intracranial hemorrhages) related to a pituitary adenoma. Ischemia, meningitis, intracranial hypertension, and other disorders may be associated with this condition. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Pituitary Neoplasms: Neoplasms which arise from or metastasize to the pituitary gland. The majority of pituitary neoplasms are adenomas, which are divided into non-secreting and secreting forms. Hormone producing forms are further classified by the type of hormone they secrete. Pituitary adenomas may also be characterized by their staining properties (adenoma, basophil; adenoma, acidophil; and adenoma, chromophobe). Pituitary tumors may compress adjacent structures, including the hypothalamus, several cranial nerves, and the optic chiasm. Chiasmal compression may result in bitemporal hemianopsia. [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] Placentation: Development of a site of fetomaternal union for physiologic exchange, a placenta or placenta-like organ. [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

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that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [NIH] Plasmids: Any extrachromosomal hereditary determinant. Plasmids are self-replicating circular molecules of DNA that are found in a variety of bacterial, archaeal, fungal, algal, and plant species. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [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] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Polyhydramnios: Excess of amniotic fluid greater than 2,000 ml. It is a common obstetrical complication whose major causes include maternal diabetes, chromosomal disorders, isoimmunological disease, congenital abnormalities, and multiple gestations. [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] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] 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

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convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propofol: A widely used anesthetic. [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 Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Isoforms: Different forms of a protein that may be produced from different genes, or from the same gene by alternative splicing. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to

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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] 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] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychosomatic: Pertaining to the mind-body relationship; having bodily symptoms of psychic, emotional, or mental origin; called also psychophysiologic. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [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] Pyelonephritis: Inflammation of the kidney and its pelvis, beginning in the interstitium and rapidly extending to involve the tubules, glomeruli, and blood vessels; due to bacterial infection. [EU] 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] Race: A population within a species which exhibits general similarities within itself, but is

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both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [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] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH]

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Reticular: Coarse-fibered, netlike dermis layer. [NIH] Reticular Formation: A region extending from the pons & medulla oblongata through the mesencephalon, characterized by a diversity of neurons of various sizes and shapes, arranged in different aggregations and enmeshed in a complicated fiber network. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [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] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Ritodrine: Adrenergic beta-agonist used to control premature labor. [NIH] RNA: Ribonucleic acid. One of the two types of nucleic acids found in cells. The other is DNA (deoxyribonucleic acid). RNA plays a role in sending information from DNA to the protein-forming system of the cell. [NIH] Ryanodine: Insecticidal alkaloid isolated from Ryania speciosa; proposed as a myocardial depressant. [NIH] Sarcoplasmic Reticulum: A network of tubules and sacs in the cytoplasm of skeletal muscles that assist with muscle contraction and relaxation by releasing and storing calcium ions. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] 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

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personality. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [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] 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] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep Deprivation: The state of being deprived of sleep under experimental conditions, due to life events, or from a wide variety of pathophysiologic causes such as medication effect, chronic illness, psychiatric illness, or sleep disorder. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH]

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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] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] 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] Somatotropin: A small peptide hormone released by the anterior pituitary under hypothalamic control. Somatotropin, or growth hormone, stimulates mitosis, cell growth, and, for some cell types, differentiation in many tissues of the body. It has profound effects on many aspects of gene expression and metabolism. [NIH] Somnolence: Sleepiness; also unnatural drowsiness. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [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] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH]

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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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Steady state: Dynamic equilibrium. [EU] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroids: Drugs used to relieve swelling and inflammation. [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] 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] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] 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]

Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [NIH] Supplementation: Adding nutrients to the diet. [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]

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Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Systemic: Affecting the entire body. [NIH] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] 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] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

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Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] 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] Tocolysis: Any drug treatment modality designed to inhibit uterine contractions in pregnant women at risk for preterm labor. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [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] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell

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to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [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]

Tropomyosin: A protein found in the thin filaments of muscle fibers. It inhibits contraction of the muscle unless its position is modified by troponin. [NIH] Troponin: One of the minor protein components of skeletal muscle. Its function is to serve as the calcium-binding component in the troponin-tropomyosin B-actin-myosin complex by conferring calcium sensitivity to the cross-linked actin and myosin filaments. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Untranslated Regions: The parts of the messenger RNA sequence that do not code for product, i.e. the 5' untranslated regions and 3' untranslated regions. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in

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the bladder, and leaves the body through the urethra. [NIH] Uterine Contraction: Contraction of the uterine muscle. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] 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] 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 Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH]

Dictionary 179

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] 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] Volvulus: A twisting of the stomach or large intestine. May be caused by the stomach being in the wrong position, a foreign substance, or abnormal joining of one part of the stomach or intestine to another. Volvulus can lead to blockage, perforation, peritonitis, and poor blood flow. [NIH] Wakefulness: A state in which there is an enhanced potential for sensitivity and an efficient responsiveness to external stimuli. [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] 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] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

180

INDEX 3 3-dimensional, 69, 93, 124, 135 A Abdomen, 135, 149, 150, 156, 158, 165, 174, 179 Abdominal, 63, 140, 165 Abdominal Pain, 165 Aberrant, 23, 25, 28, 29, 46 Ablate, 141 Ablation, 17, 155 Acceptor, 164 Acetylcholine, 163 Acid, 136, 163 Actin, 19, 22, 135, 161, 162, 177 Actomyosin, 19 Acyl, 160 Adaptability, 141 Adaptation, 167 Adenine, 87, 135, 169 Adenoma, 166 Adenoma, Chromophobe, 166 Adenosine, 88, 135, 166 Adenosine Triphosphate, 88, 135, 166 Adenovirus, 41, 120 Adjustment, 44, 135 Administration, iv, 11, 120, 121, 128 Adrenal Medulla, 141, 149, 163 Adrenergic, 36, 76, 80, 148, 149, 175 Adverse Effect, 172 Aerobic, 160 Affinity, 136, 173 Age of Onset, 140 Agonist, 148, 162, 171 Air Sacs, 136 Airway, 75 Akinesia, 49 Algorithms, 13, 27, 140 Alkaline, 140 Alkaloid, 171 Alleles, 23, 25, 31, 33, 72, 106, 154, 158 Allylamine, 136 Alpha Particles, 170 Alpha-1, 102, 106 Alternative medicine, 145 Alternative Splicing, 15, 19, 22, 23, 25, 28, 38, 40, 52, 62, 63, 168 Alveolar Process, 170 Alveoli, 178 Amine, 154

Amino Acid Sequence, 137, 149, 152 Amino acids, 89, 93, 99, 136, 137, 144, 152, 165, 167, 169, 171, 172, 176 Amino Acids, 89, 93, 99, 136, 137, 144, 152, 165, 167, 169, 171, 172, 176 Ammonia, 136 Amnion, 137 Amniotic Fluid, 115, 117, 137, 167 Ampulla, 143 Amygdala, 139, 175 Anaerobic, 161 Anaesthesia, 155 Analogous, 176 Anaphylatoxins, 145 Anatomical, 13, 138, 143, 155, 172 Anemia, 101, 102, 105, 106, 111 Anesthesia, 136, 168 Anesthetics, 149 Aneuploidy, 100 Animal model, 17 Anions, 157 Anomalies, 13, 37 Anterior Cerebral Artery, 142 Anterior chamber, 157 Antibacterial, 173 Antibiotic, 173 Antibodies, 14, 25, 137, 161, 167 Antibody, 47, 137, 138, 144, 154, 155, 156, 157, 161, 170 Anticoagulant, 168, 179 Antigen, 57, 137, 144, 154, 156 Antigen-Antibody Complex, 144 Antigens, 137, 155, 178 Antineoplastic, 178 Antineoplastic Agents, 178 Antioxidants, 50, 158 Anuria, 157 Anus, 144 Aorta, 178 Apoptosis, 88, 97 Aqueous, 56, 139, 143, 146, 158 Aqueous humor, 56, 143 Archaea, 160 Arginine, 154 Arterial, 142, 145, 154, 169 Arteries, 138, 140, 146, 162 Arterioles, 140 Arteriosus, 169 Artery, 138, 148, 149, 171

Index 181

Aseptic, 164, 174 Assay, 17, 20, 23, 29, 32 Astigmatism, 170 Asymptomatic, 54 Ataxia, 15, 32, 65, 138, 154, 175 Atrial, 57, 138, 145, 162, 179 Atrial Fibrillation, 179 Atrioventricular, 145 Atrium, 138, 145, 178 Atrophy, 25, 36, 38, 39, 69, 162 Atypical, 33, 110 Auditory, 59 Autonomic Nervous System, 165 Autopsy, 25, 30 Axons, 164, 171 Azoospermia, 57 B Bacteria, 20, 86, 94, 98, 135, 137, 138, 148, 150, 153, 160, 161, 173, 178 Bacterial Infections, 142 Bacterial Physiology, 135 Barbiturates, 169 Basal Ganglia, 138, 139, 140, 154, 161 Basal Ganglia Diseases, 138, 154, 161 Base, 87, 88, 91, 93, 97, 98, 99, 122, 135, 143, 146, 147, 150, 152, 157, 163, 167, 175 Base Sequence, 98, 151, 152 Basement Membrane, 150 Basophil, 166 Basophils, 153 Benign, 140, 153 Beta Rays, 148 Bewilderment, 145 Bilateral, 71 Bile, 139, 157, 158 Bile Acids, 139 Bile Acids and Salts, 139 Bile duct, 139, 157 Bile Ducts, 139, 157 Biliary, 19, 143 Binding Sites, 25, 32 Biochemical, 18, 19, 22, 23, 102, 136, 139, 157 Biological Transport, 147 Biopsy, 25, 29, 37 Biopsy specimen, 25 Biosynthesis, 172 Biotechnology, 122 Bladder, 155, 162, 168, 177, 178 Blastocyst, 145, 166 Blood Coagulation, 140, 175 Blood Coagulation Factors, 140

Blood Glucose, 153, 156 Blood pressure, 105, 141, 154, 155, 161, 173 Blood urea, 157 Blood vessel, 109, 140, 141, 142, 143, 146, 149, 157, 169, 173, 174, 176, 178 Blood Vessels, 109, 141, 142, 143, 146, 169, 173, 178 Body Fluids, 148, 164, 173 Bone Marrow, 121, 152, 159 Bowel, 156, 174 Bowel Movement, 174 Brachytherapy, 157, 170 Brain Hypoxia, 175 Brain Neoplasms, 154, 175 Brain Stem, 140 Bronchi, 140, 149, 176 Bronchial, 154 Bronchioles, 136 Buccal, 115, 117, 140 Bulbar, 35, 140 C Caesarean section, 78 Caffeine, 169 Calcium, 80, 140, 144, 148, 171, 177 Callus, 149 Capillary, 178 Carbohydrate, 167 Carbohydrates, 142 Carbon Dioxide, 147, 151, 166, 170 Carcinogenic, 156, 168 Carcinoma, 141, 143 Cardiac, 15, 18, 20, 23, 48, 57, 65, 68, 69, 71, 72, 76, 77, 138, 146, 149, 164 Cardiomyopathy, 56, 154 Cardiopulmonary, 27 Cardiovascular, 124 Cardiovascular disease, 124 Carotene, 171 Case report, 52, 55, 57, 65, 67, 79, 141, 143 Case series, 141, 143 Cataract, 50, 71, 141 Cataracts, 15, 18 Catecholamine, 148 Catecholamines, 148 Catheter, 63, 141 Catheter Ablation, 63 Cathode, 148 Cations, 157 Caudal, 155, 167 Caudate Nucleus, 139 Cause of Death, 147 Cecum, 158

182

Myotonic Dystrophy

Cell Cycle, 49, 96, 97 Cell Death, 16, 31, 97, 138, 162 Cell Differentiation, 18 Cell Division, 89, 96, 97, 109, 110, 139, 141, 142, 146, 156, 159, 160, 166, 168, 172 Cell membrane, 19, 139, 151, 166 Cell motility, 74 Cell Polarity, 49 Cell Respiration, 160, 170 Central Nervous System, 18, 140, 142, 151, 153, 154, 164, 167 Central Nervous System Infections, 153, 154 Centrioles, 168 Centromere, 89, 92 Cerebellar, 138, 170, 177 Cerebellar Diseases, 138, 177 Cerebellum, 140, 142, 167, 170 Cerebral, 36, 43, 138, 139, 140, 142, 149, 151, 154 Cerebral Cortex, 138 Cerebral hemispheres, 139, 140, 142 Cerebral Infarction, 154 Cerebral Palsy, 36, 43 Cerebrospinal, 42, 154 Cerebrospinal fluid, 42, 154 Cerebrovascular, 139, 141, 175 Cerebrovascular Disorders, 175 Cerebrum, 142 Cervical, 67, 142 Cervix, 142, 150 Character, 73 Chemotactic Factors, 145 Chemotherapy, 36 Chiasma, 146 Chin, 160 Cholecystectomy, 60 Cholelithiasis, 74 Cholestasis, 74 Cholesterol, 88, 139, 146, 160 Choroid, 171 Chromatin, 14, 25, 30, 32, 45, 138, 159, 163, 174 Chromosomal, 13, 27, 97, 99, 110, 111, 112, 114, 137, 143, 154, 161, 167, 171 Chromosomal Proteins, Non-Histone, 143 Chromosome, 3, 15, 21, 22, 25, 26, 28, 29, 30, 31, 59, 81, 89, 90, 91, 92, 93, 96, 97, 99, 100, 106, 107, 110, 111, 116, 119, 137, 142, 143, 157, 158, 161, 171, 172, 177 Chromosome Breakage, 29 Chromosome Fragility, 29, 177

Chronic, 143, 156, 157, 158, 172, 174 Ciliary, 138, 143 Ciliary Body, 143 Ciliary processes, 138 Circadian, 14 Cirrhosis, 153 CIS, 22, 81, 143, 151, 152, 171 Clear cell carcinoma, 147 Clinical Medicine, 123, 168 Clinical study, 79 Clinical trial, 12, 24, 120, 121, 124, 143, 148, 165, 169 Clinical Trials, 24, 120, 121, 124, 127, 165 Cloning, 21, 140 Coagulation, 179 Codon, 94, 144, 152 Codon, Terminator, 144 Codons, 144, 152 Cofactor, 169, 175 Collagen, 144, 150 Colon, 103, 144, 158 Colonoscopy, 105 Complement, 144, 145, 152, 157 Complementary medicine, 78 Compress, 166 Computational Biology, 127 Concentric, 163 Conception, 96, 150, 173, 174 Conduction, 23, 61, 70, 141 Cones, 171 Confusion, 103, 148, 177 Congenita, 65 Conjugated, 146, 163 Connective tissue, 140, 144, 145, 147, 151, 159 Connective Tissue, 140, 144, 145, 147, 151, 159 Connective Tissue Cells, 145 Connexins, 151 Consciousness, 147 Constipation, 166 Constriction, 89, 92, 157, 171 Consultation, 111, 112, 115, 116 Contracture, 71 Contraindications, ii Contralateral, 164, 170 Conus, 169 Cor, 155 Cornea, 137, 138, 157 Coronary, 37, 141, 146, 162 Coronary heart disease, 141

127, 143,

150, 150,

Index 183

Coronary Thrombosis, 162 Corpus, 179 Cortical, 175 Cranial, 146, 153, 156, 164, 165, 166 Cranial Nerves, 146, 166 Craniocerebral Trauma, 139, 153, 154, 175 Creatinine, 157 Cricoid Cartilage, 179 Crossing-over, 170 Cultured cells, 18 Curative, 175 Cyst, 49 Cytochrome, 164 Cytogenetics, 13, 171 Cytoplasm, 26, 86, 87, 88, 94, 138, 142, 146, 153, 159, 163, 171, 175 Cytosine, 87, 169 Cytoskeleton, 18, 19, 47 D De novo, 97 Death Certificates, 105 Decarboxylation, 154 Decidua, 166 Dehydroepiandrosterone, 34 Deletion, 16, 25, 31, 99, 138 Dementia, 100 Dendrites, 163 Dendritic, 171 Deoxyribonucleic, 87, 171 Deoxyribonucleic acid, 87, 171 Deoxyribonucleotides, 147 Deprivation, 73 Dermis, 147, 171 DES, 84 Deuterium, 154 Diabetes Mellitus, 153, 156 Dialyzer, 153 Diastolic, 154 Diastolic pressure, 154 Diffusion, 30, 70, 139 Digestion, 139, 156, 158, 174, 178 Digestive tract, 172 Dilation, 154 Dilution, 167 Dinucleotide Repeats, 160 Diploid, 137, 161, 166, 177 Direct, iii, 13, 14, 17, 18, 19, 23, 45, 115, 116, 117, 141, 142, 143, 148, 170, 175 Discrete, 19 Discrimination, 117, 118, 123 Diseases, 32, 38, 126, 131, 132, 133, 134, 139, 162, 165, 175

Disorientation, 145 Distal, 21, 141, 169 Diurnal, 13 Dominance, 28 Dopamine, 53, 163 Dorsal, 167 Dorsum, 148 Dose-dependent, 13 Double-blind, 79 Duct, 137, 139, 149 Duodenum, 139, 174 Dystrophic, 24 Dystrophy, 12, 14, 15, 17, 19, 21, 22, 24, 28, 29, 30, 32, 41, 42, 47, 54, 56, 58, 63, 64, 65, 67, 80, 82, 83, 84 E Edema, 157 Effector, 19, 144 Ejaculation, 172 Elastic, 173 Elastin, 144 Electrocardiogram, 70, 76 Electrocoagulation, 144 Electrolyte, 157, 164, 167, 173 Electrolytes, 139, 157 Electrons, 139, 148, 157, 159, 164, 170 Elementary Particles, 148, 159, 169 Emboli, 179 Embolism, 179 Embolization, 179 Embolus, 156 Embryo, 96, 97, 98, 106, 137, 140, 141, 149, 155 Embryogenesis, 28, 149 Endemic, 174 Endogenous, 13, 148, 168 Endorphins, 163 Endothelial cell, 175 Endothelial cells, 175 Endotoxins, 144 Enhancer, 25 Enkephalins, 163 Environmental Health, 126, 127 Enzymatic, 140, 144, 154, 171 Enzyme, 88, 148, 149, 152, 167, 168, 169, 175, 179 Enzymes, 88, 98, 136, 162, 165, 168 Eosinophils, 153 Epidemic, 174 Epidermis, 147 Epidural, 156 Epigastric, 165

184

Myotonic Dystrophy

Epinephrine, 135, 148, 163, 177 Epithelial, 19, 60, 139, 149 Epithelial Cells, 19, 149 Epithelium, 19, 157 Erythrocytes, 59, 137, 140, 149 Esophagus, 174 Ethnic Groups, 111, 114 Eukaryotic Cells, 20, 155, 164 Evoke, 174 Excitability, 36 Excitation, 163 Excrete, 138, 157 Exocrine, 165 Exocytosis, 175 Exogenous, 149, 168 Exon, 38, 136 Exons, 20, 46, 136, 149 Expiration, 170 External-beam radiation, 157, 170 Extracellular, 145, 150, 173 Extracellular Matrix, 145, 150 Extracellular Space, 150 Extraocular, 36 Extrapyramidal, 148 Eye Color, 98 Eye Infections, 135 F Family Planning, 127 Fasciculation, 162 Fat, 140, 145, 146, 148, 173 Fathers, 106 Fatigue, 47, 58, 69 Fats, 139, 143, 150 Fatty acids, 158 Fecal Incontinence, 155 Feces, 174 Fetal Movement, 75 Fetus, 114, 115, 117, 121, 150, 166, 168, 174, 178 Fibrillation, 36 Fibrin, 140, 165, 175 Fibrinogen, 175 Fibroblasts, 42 Fibrosis, 70, 98, 101, 105, 106, 145, 172 Filtration, 157 Flatus, 151 Flexion, 157 Fluid Therapy, 164 Fluorescence, 13, 75, 150 Fold, 16 Foramen, 143 Forearm, 140

Founder Effect, 35 Frameshift, 99 Frameshift Mutation, 99 Frontal Lobe, 30, 142 Fundus, 150 G Gallbladder, 135, 139, 143, 151 Gamma Rays, 170 Ganglia, 162, 165 Ganglion, 171 Gap Junctions, 151 Gas, 141, 147, 154, 170, 178 Gas exchange, 170, 178 Gastric, 36, 154 Gastrin, 154 Gastrointestinal, 19, 62, 149, 151, 174 Gastrointestinal tract, 62 Gastrostomy, 35 Gene, 3, 12, 14, 15, 16, 17, 18, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 37, 39, 49, 50, 59, 60, 61, 66, 77, 84, 89, 91, 92, 93, 94, 95, 97, 98, 99, 101, 102, 103, 105, 106, 107, 108, 109, 110, 114, 116, 117, 118, 119, 120, 121, 122, 135, 136, 140, 148, 150, 151, 152, 153, 154, 167, 168, 172, 173, 176, 177 Gene Duplication, 12 Gene Expression, 14, 16, 17, 24, 25, 27, 60, 94, 95, 151, 173 Gene Pool, 150 Gene Products, rev, 152 Gene Silencing, 25, 30 Gene Therapy, 24, 119, 120, 121, 122, 135, 151 Genes, 3, 13, 15, 17, 18, 19, 20, 21, 23, 25, 27, 28, 30, 45, 57, 65, 86, 88, 89, 93, 94, 95, 96, 98, 99, 101, 102, 103, 105, 106, 107, 109, 110, 111, 113, 114, 118, 119, 122, 123, 124, 146, 149, 151, 152, 158, 166, 168, 170, 178 Genes, env, 105 Genetic Code, 163 Genetic Engineering, 27, 140, 144 Genetic Screening, 13, 152 Genetic testing, 108, 112, 113, 114, 115, 116, 117, 118, 123 Genetic transcription, 176 Genetics, 13, 24, 31, 82, 86, 97, 98, 99, 101, 103, 104, 108, 111, 112, 113, 118, 121, 122, 123, 133, 146, 148, 165 Genital, 143 Genomics, 124

Index 185

Genotype, 21, 166 Germ Cells, 97, 121, 159, 164, 173, 174 Germline mutation, 97, 152, 153 Gestation, 166 Gland, 159, 165, 166, 168, 172, 174, 176 Globus Pallidus, 139 Glomerular, 157 Glomerular Filtration Rate, 157 Glomeruli, 169 Glomerulus, 152 Glucose, 60, 147, 153, 156 Glucose Intolerance, 147 Glutamic Acid, 163 Glutathione Peroxidase, 172 Glycerol, 166 Glycerophospholipids, 166 Glycine, 163, 172 Glycoprotein, 175 Governing Board, 167 Government Agencies, 167 Grade, 24, 152 Grafting, 155 Gram-negative, 161 Granule, 171 Granulocytes, 158, 179 Guanine, 87, 147, 169 H Habitual, 142 Hair Color, 98 Hair follicles, 147 Haploid, 166 Headache, 153, 154, 166 Headache Disorders, 153 Heart attack, 141 Heartbeat, 174 Helminthiasis, 142 Hematopoietic tissue, 140 Hemianopsia, 166 Hemochromatosis, 114 Hemodialysis, 157 Hemoglobin, 88, 137, 149, 153 Hemoglobin M, 153 Hemoglobinopathies, 152 Hemophilia, 106 Hemorrhage, 146, 153, 166, 174 Hepatocyte, 143 Hereditary, 20, 29, 43, 86, 87, 97, 106, 112, 152, 153, 167, 171 Hereditary mutation, 97, 152, 153 Heredity, 89, 151, 152 Heterozygotes, 148 Histamine, 84, 154

Histidine, 154 Histones, 89, 143, 163 Homologous, 136, 146, 151, 154, 172, 175 Homozygotes, 148 Hormonal, 138 Hormone, 30, 51, 94, 147, 149, 151, 154, 156, 162, 166, 173, 176 Hormones, 94, 152, 154, 155 Hybrid, 14, 154 Hybridization, 14, 154 Hydrocephalus, 65, 154, 157 Hydrogen, 136, 139, 140, 152, 154, 160, 163, 164, 169 Hydrogen Bonding, 163 Hydrogen Peroxide, 152 Hydrolysis, 167, 169 Hydroxylysine, 144 Hydroxyproline, 144 Hyperglycaemia, 62 Hyperopia, 170 Hyperostosis, 59 Hypertension, 141, 157, 162 Hypertrophic cardiomyopathy, 74 Hypertrophy, 146 Hypokinesia, 49, 165 Hypopituitarism, 61 Hypotension, 74 Hypothalamic, 173 Hypothalamus, 140, 162, 166 Hypotonia, 28 Hysterectomy, 63 I Idiopathic, 14, 57, 63 Immune response, 137, 174, 178, 179 Immune system, 155, 159, 178, 179 Immunity, 31 Immunofluorescence, 29 Immunology, 24 Impairment, 35, 40, 150, 155, 160 Implant radiation, 157, 170 Implantation, 145 In situ, 25, 49, 75 In Situ Hybridization, 25, 49, 75 In vitro, 17, 34, 152, 155, 176 In vivo, 16, 18, 20, 29, 152, 155, 158 Incision, 140, 157 Incompetence, 76 Incontinence, 48, 154, 155 Induction, 23, 80 Infancy, 40, 124, 156 Infantile, 74, 84 Infarction, 142, 155, 162

186

Myotonic Dystrophy

Infection, 19, 53, 143, 156, 159, 163, 169, 174, 179 Infections, 119, 137, 142 Infiltration, 168 Inflammation, 120, 150, 174 Informed Consent, 115, 118, 123 Infusion, 73, 156 Initiation, 176 Inotropic, 148 Insight, 17, 25, 31 Insulator, 25, 30, 32, 41 Insulin, 20, 25, 60, 67, 77, 156 Insulin-dependent diabetes mellitus, 156 Insulin-like, 25 Intermittent, 158 Internal radiation, 157, 170 Interphase, 13 Interstitial, 157 Intestine, 158, 172, 179 Intestines, 135, 151 Intracellular, 142, 156, 167, 172 Intracranial Hemorrhages, 154, 166, 175 Intracranial Hypertension, 153, 154, 166 Intrahepatic, 19 Intrahepatic bile ducts, 19 Intravenous, 156 Intrinsic, 15, 22 Invasive, 26, 155, 159 Involuntary, 139, 150, 170, 173 Ions, 139, 148, 154, 171 Ipsilateral, 170 Iridis, 71 Iris, 137, 146, 150, 157 Irradiation, 143 Ischemia, 138 K Karyotype, 27, 91 Karyotypes, 143, 152 Kidney Failure, 100, 157 Kidney Failure, Acute, 157 Kidney Failure, Chronic, 157 Kidney Transplantation, 157 Kyphosis, 67 L Labile, 144 Large Intestine, 156, 158, 170, 172, 179 Larynx, 176 Latent, 168 Lens, 138, 141, 145 Lenses, 170 Lesion, 158 Lethargy, 154

Leucocyte, 136 Leukemia, 152 Life cycle, 20 Ligament, 168 Ligaments, 146 Linkage, 21, 27, 50, 67 Linkage Disequilibrium, 50, 67 Linkages, 153, 154 Lipid, 50, 156, 158, 159 Lipid Peroxides, 50, 158 Lipopolysaccharide, 153 Lipoprotein, 153 Liver, 34, 95, 135, 139, 143, 151, 153, 157, 158 Lobe, 30, 142 Localization, 23, 27, 47 Localized, 19, 156, 166 Locomotion, 13, 166 Longitudinal Studies, 30 Long-Term Care, 19 Loop, 20, 75, 158 Lymph, 142, 159 Lymph node, 142, 159 Lymph nodes, 142, 159 Lymphatic, 156, 159 Lymphatic system, 159 Lymphocytes, 81, 138, 158, 159, 179 Lymphoid, 137, 158, 159 Lymphoma, 36 Lysine, 154 M Macrophage, 97 Magnetic Resonance Imaging, 41, 46, 69, 159 Magnetic Resonance Spectroscopy, 38, 46 Malignant, 31, 140 Malnutrition, 138, 161 Mammography, 105 Mandible, 143, 170 Medial, 164 Mediate, 13, 20, 148 Medical Records, 105, 118 MEDLINE, 127 Medullary, 62 Meiosis, 96, 175 Melanin, 157, 177 Melanocytes, 159 Melanoma, 177 Membrane, 19, 29, 80, 87, 137, 142, 144, 149, 153, 161, 163, 164, 166, 167, 171, 175, 176 Membrane Fluidity, 80

Index 187

Membrane Lipids, 166 Membranes, 158, 160, 161, 163 Memory, 147, 160 Meningeal, 166 Meninges, 142, 146 Meningitis, 166 Mental, 28, 29, 30, 110, 112, 114, 142, 143, 145, 147, 148, 150, 154, 155, 160, 169, 171, 177 Mental Disorders, 154, 169 Mental Retardation, 28, 29, 30, 110, 112, 114 Mesencephalic, 170 Mesolimbic, 13 Metastasis, 160 Metastasize, 166 Metastatic, 140, 155 Microbe, 176 Microbiology, 135, 138 Microorganism, 144, 165, 179 Microsatellite Repeats, 17, 147 Microscopy, 25, 29 Miscarriage, 117 Mitochondria, 87, 88, 100, 106, 164 Mitochondrial Swelling, 162 Mitosis, 96, 138, 160, 173 Mitotic, 53 Modeling, 13 Modification, 152, 169 Molecular, 14, 15, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 32, 33, 37, 45, 50, 57, 64, 75, 84, 91, 93, 95, 127, 129, 137, 139, 145, 146, 158, 162 Molecule, 18, 31, 87, 88, 89, 94, 138, 139, 144, 148, 160, 163, 164, 167, 170, 178 Monitor, 163 Monoclonal, 61, 157, 161, 170 Monoclonal antibodies, 61, 161 Mononuclear, 59 Monosomy, 100, 137 Morphogenesis, 49 Morphological, 19, 149 Morphology, 65, 67, 70, 141 Morula, 140 Mosaicism, 52, 53, 97 Motility, 142 Motor Cortex, 170 Motor nerve, 150, 165 Motor Neurons, 56 Movement Disorders, 175 Muscle Contraction, 171 Muscle Fibers, 161, 162, 177

Muscle Hypertonia, 162 Muscle Relaxation, 162 Muscular Atrophy, 35, 68 Muscular Diseases, 162 Musculature, 154 Mutagen, 161 Mutagenesis, 20, 65 Mutagens, 143, 151, 161 Mycoplasma, 20, 142 Mycoplasma Infections, 142 Mydriatic, 147 Myocardial infarction, 179 Myocardium, 162 Myopathy, 15, 18, 23, 25, 46, 60, 69, 74, 79 Myopia, 170 Myosin, 135, 161, 177 Myotonia, 15, 20, 21, 25, 28, 42, 61, 65, 69, 70, 79, 81 N Naloxone, 58 Narcolepsy, 14 Natriuresis, 162 Natriuretic Hormone, 57, 162 Nausea, 177 NCI, 143, 165 Necrosis, 138, 142, 156, 162, 166, 172 Neonatal, 28, 34 Neoplasm, 177 Neoplasms, 140 Nervous System, 109, 142, 162, 163, 165, 175 Networks, 18 Neurodegenerative Diseases, 29, 139 Neurogenic, 18 Neurologic, 154 Neuromuscular, 16, 17, 21, 22, 24, 28, 43, 79 Neuromuscular Diseases, 16 Neurons, 13, 16, 62, 147, 151, 171, 175 Neuropathy, 43, 106 Neurotoxicity, 12 Neurotransmitter, 135, 148, 152, 154, 163, 174 Neutrons, 157, 170 Neutrophils, 153 Nitrogen, 136, 157 Nonverbal Communication, 169 Norepinephrine, 135, 148, 163 Nuclear, 16, 26, 27, 28, 41, 53, 87, 139, 148, 149, 151, 162, 163, 171 Nuclear Envelope, 87, 163 Nuclear Pore, 53, 163

188

Myotonic Dystrophy

Nuclear Proteins, 151, 163 Nuclei, 13, 14, 19, 26, 30, 49, 148, 151, 152, 154, 159, 160, 164, 169 Nucleic acid, 139, 146, 152, 154, 155, 161, 163, 169, 171 Nucleic Acid Hybridization, 154 Nucleic Acids, 139, 146, 154, 161, 163, 169, 171 Nucleoproteins, 163 Nucleosomes, 25 Nucleus, 27, 28, 87, 88, 89, 94, 100, 119, 122, 138, 143, 146, 148, 149, 159, 161, 163, 168, 169, 174, 175 Nurse Practitioners, 115 Nutritional Support, 151 O Oliguria, 157 Oncolysis, 164 Oncolytic, 41 Oocytes, 58 Opacity, 141 Opiate, 162 Opium, 164 Opsin, 171 Optic Chiasm, 155, 164, 166 Optic Nerve, 36, 164, 171 Organ Culture, 176 Organelles, 86, 87, 146, 167 Organizations, 132 Ovaries, 114, 164 Ovary, 164 Ovulation, 164 Ovum, 158, 179 Oxidation, 138, 146, 152, 158 Oxidative Phosphorylation, 88 Oxygen Consumption, 164, 170 P Pacemaker, 62, 164 Palliative, 175 Palpation, 150, 165 Pancreas, 41, 135, 153, 156 Paralysis, 136, 140 Parasite, 19 Parkinsonism, 13, 53, 68 Particle, 173 Paternity, 114 Pathogen, 19 Pathologic, 41, 76, 138, 139, 146, 170 Pathologic Processes, 138 Pathologies, 21 Pathophysiology, 21, 25, 29 PDQ, 125, 165

Peduncle, 170 Pelvic, 168 Pelvis, 135, 164, 165, 169, 178 Peptide, 167, 168, 169, 173 Perforation, 179 Peripheral Nerves, 165 Peripheral Nervous System, 162, 163, 165, 174 Peripheral Nervous System Diseases, 162 Peritoneum, 165 Peritonitis, 179 Pharmacologic, 14, 137, 176 Phenotype, 12, 13, 21, 26, 29, 30, 32, 52, 75, 166 Phenotypes, 13, 21, 31, 43 Phenylalanine, 177 Phospholipids, 150, 160 Phosphorus, 140, 166 Phosphorylation, 19, 88 Photocoagulation, 144 Physical Examination, 112 Physiologic, 136, 139, 154, 166, 170, 177 Pigment, 159 Pigments, 167, 171 Pilot study, 34 Pituitary Apoplexy, 155 Pituitary Gland, 155, 166 Pituitary Neoplasms, 155, 166 Placenta, 166 Placentation, 57 Plants, 136, 141, 152, 161, 163, 176 Plasma, 19, 57, 87, 137, 142, 153, 157, 161, 162, 167, 172 Plasma cells, 137 Plasma Volume, 162 Plasmids, 25 Plasticity, 18, 167 Plastids, 164 Pneumonia, 145 Point Mutation, 31 Polyhydramnios, 40, 63 Polymerase, 73, 167 Polymorphic, 59 Polymorphism, 39, 116 Polypeptide, 136, 144, 154, 179 Polysaccharide, 138 Pons, 171 Posterior, 60, 138, 148, 157, 165 Post-translational, 20 Potassium, 148, 162 Practice Guidelines, 128 Precursor, 148, 149, 177

Index 189

Predisposition, 31 Prenatal, 75, 114, 117, 149, 152 Presynaptic, 163, 175 Presynaptic Terminals, 175 Prevalence, 50, 54, 102 Prion, 142 Probe, 33 Procaine, 136 Progression, 137 Progressive, 12, 19, 23, 68, 101, 143, 147, 157, 162, 177 Projection, 163, 164, 170 Proline, 144 Promoter, 12, 15, 22, 25, 30, 41, 47 Prone, 29, 100, 109 Prophase, 164, 175 Prophylaxis, 179 Propofol, 73 Prostate, 31 Protease, 80 Protein Binding, 23, 29 Protein Conformation, 136 Protein Isoforms, 19, 28, 136 Protein Kinases, 18 Proteins, 14, 16, 18, 20, 23, 25, 26, 28, 29, 86, 87, 89, 90, 94, 95, 98, 99, 113, 115, 122, 124, 136, 137, 138, 142, 143, 144, 151, 152, 153, 154, 160, 163, 165, 166, 168, 169, 171, 175, 176, 178 Proteolytic, 136, 144 Prothrombin, 175 Protocol, 33, 120 Protons, 154, 159, 170 Protozoa, 160 Protozoan, 142 Protozoan Infections, 142 Proximal, 21, 46, 69, 148, 168 Pseudotumor Cerebri, 157 Psychiatric, 172 Psychiatry, 169, 178 Psychic, 160, 169 Psychosomatic, 81 Psychotherapy, 82 Public Policy, 127 Pulmonary, 73, 140, 146, 157, 169, 178, 179 Pulmonary Artery, 140, 169, 178 Pulmonary Edema, 157 Pulmonary Embolism, 73, 179 Pulmonary hypertension, 146 Pulse, 161 Pupil, 146, 147 Purines, 139, 172

Putamen, 139 Pyelonephritis, 43 Pyramidal Tracts, 150 Pyrimidines, 139, 172 Q Quality, iv, 11, 128, 169 Quality of Life, 54, 174 R Race, 157 Radiation, 135, 148, 150, 155, 157, 170, 177, 179 Radiation therapy, 135, 157, 170 Radioactive, 154, 155, 157, 161, 163, 170 Radiolabeled, 157, 170 Radiotherapy, 157, 170 Receptor, 20, 35, 58, 76, 103, 135, 138, 148, 170 Recombinant, 18, 25, 170, 178 Recombinant Proteins, 18 Recombination, 17, 20, 61, 151 Rectum, 138, 144, 151, 155, 158, 168 Red Nucleus, 138 Refer, 1, 92, 96, 103, 122, 140, 144, 158 Reflex, 81 Refraction, 173 Reliability, 48 Reproductive cells, 100, 110, 111, 152, 153 Resorption, 154 Respiration, 78, 141, 161, 170 Respiratory failure, 64 Respiratory Physiology, 178 Reticular, 62 Reticular Formation, 62 Retina, 158, 164, 171 Retinal, 164, 171 Retinal Ganglion Cells, 164 Retinoblastoma, 102 Retinol, 171 Retroviral vector, 151 Rhodopsin, 171 Ribonucleic acid, 94 Ribose, 135 Ribosome, 94, 176 Rigidity, 165, 166 Ritodrine, 71 RNA, 31 Rods, 171 Ryanodine, 35 S Sarcoplasmic Reticulum, 80 Satellite, 42 Scatter, 177

190

Myotonic Dystrophy

Schizophrenia, 107 Sclerosis, 103 Screening, 13, 84, 105, 114, 115, 117, 144, 152, 165 Sebaceous, 147 Sebaceous gland, 147 Sebaceous Glands, 147 Secretion, 51, 52, 154, 155, 156, 172, 178 Secretory, 155 Segregation, 170 Selenium, 81 Sella, 166 Sella Turcica, 166 Semen, 139, 168 Seminiferous tubule, 174 Seminiferous Tubules, 174 Sensibility, 137 Sensor, 26 Sensory loss, 175 Sequencing, 122 Sequester, 18, 21, 25, 175 Serine, 18 Serotonin, 163 Serum, 144, 157, 165 Shock, 141, 172 Side effect, 121, 124, 136, 174, 176 Side effects, 121, 124, 174, 176 Signs and Symptoms, 108, 109, 114 Skeletal, 15, 18, 23, 25, 26, 28, 35, 39, 46, 47, 71, 76, 155, 161, 171, 173, 177 Skeleton, 135, 172 Skull, 146, 175 Sleep Deprivation, 14 Small intestine, 154, 156, 178 Smooth muscle, 25, 154, 161, 173, 174 Social Environment, 169 Social Work, 111 Sodium, 148, 162, 173 Soft tissue, 140, 172 Soma, 173 Somatic, 31, 52, 97, 100, 111, 149, 159, 160, 165 Somatic cells, 97, 100, 111, 159, 160 Somatic mutations, 100 Somatotropin, 155 Somnolence, 46 Sound wave, 145 Spasm, 162 Specialist, 115, 132, 147 Species, 124, 149, 154, 157, 159, 160, 161, 165, 167, 169, 173, 174, 177, 178, 179 Spectroscopic, 37

Spectrum, 31 Sperm, 53, 96, 97, 100, 109, 110, 111, 114, 121, 143, 152, 153, 170, 173 Spermatozoa, 139, 172 Spinal cord, 142, 143, 160, 162, 163, 165, 170 Spinal Nerves, 165 Spleen, 159 Sporadic, 162, 171 Steady state, 20 Sterility, 156 Steroids, 147 Stillbirth, 112 Stimulant, 154 Stimulus, 170, 175 Stomach, 135, 151, 154, 172, 179 Stool, 144, 155, 158 Strand, 16, 17, 20, 22, 29, 44, 87, 167 Stress, 18, 63, 67, 141, 168 Stroke, 105, 141 Stroma, 157 Stupor, 158 Subacute, 156 Subarachnoid, 153, 156 Subclinical, 156 Subspecies, 173 Sudden death, 70, 76 Supplementation, 79 Supportive care, 165 Suppression, 13, 14, 151 Sweat, 147 Sweat Glands, 147 Sympathetic Nervous System, 175 Sympathomimetic, 148, 149, 163 Symphysis, 143, 168 Synapse, 135, 168, 175, 177 Synapses, 56, 175 Synapsis, 175 Synaptic, 18, 163 System, 13, 17, 21, 26, 31, 36, 82, 128, 130, 131, 144, 148, 163, 164, 165, 171, 172 Systemic, 140, 149, 156, 157, 179 Systolic, 154 T Tachycardia, 34, 40, 60, 63, 70, 76 Telencephalon, 139, 142 Temporal, 35 Thalamic, 138 Thalamic Diseases, 138 Thalamus, 140, 175 Theophylline, 169 Therapeutics, 12, 19

Index 191

Third Ventricle, 155 Thoracic, 179 Threonine, 18, 172 Threshold, 149, 154, 175 Thrombin, 168, 175 Thrombomodulin, 168 Thrombosis, 169, 174 Thymus, 159 Thyroid, 81, 114, 176, 177 Thyroid Gland, 114, 176 Thyroid Hormones, 176, 177 Tissue, 16, 23, 25, 29, 31, 115, 117, 119, 135, 138, 139, 140, 141, 144, 148, 149, 150, 158, 159, 161, 162, 166, 170, 171, 172, 173, 174, 176, 177 Tissue Culture, 29 Tocolysis, 71 Tolerance, 135 Tone, 155, 161 Tonus, 176 Tooth Preparation, 135 Torsion, 156 Toxic, 12, 16, 17, 22, 25, 28, 30, 86, 148, 155, 158, 163, 172, 176 Toxicity, 12, 17, 22, 23, 30, 41, 62, 120 Toxicology, 127 Toxins, 138, 156, 161 Trachea, 176 Transcription Factors, 71, 95 Transfection, 140, 151 Transgenes, 18 Translation, 26, 94, 95, 151 Translational, 24, 151, 167 Translocation, 143 Transmitter, 148, 163, 175 Transplantation, 57 Trauma, 162 Tremor, 165, 177 Tricuspid Atresia, 146 Trinucleotide Repeat Expansion, 109 Trinucleotide Repeats, 62, 160, 177 Trisomy, 100, 137 Tropomyosin, 177 Troponin, 20, 177 Trypsin, 179 Tryptophan, 144 Tumor suppressor gene, 31 Tumour, 164 Tyrosine, 148 U Ultraviolet radiation, 97 Untranslated Regions, 16, 19, 177

Uracil, 169 Urea, 177 Uremia, 157 Urethra, 168, 178 Urinary, 154, 155, 164 Urine, 138, 140, 155, 157, 162, 164, 177 Uterine Contraction, 176 Uterus, 114, 142, 150, 155, 164, 178 V Vaccine, 169 Vaccines, 179 Vacuoles, 164 Vagina, 142, 147 Vascular, 147, 156, 166, 176 Vasoconstriction, 149 Vasodilator, 148, 154 Vector, 77, 119, 120, 171, 178 Vein, 157, 163, 171, 178 Veins, 140, 178 Venous, 142, 169, 179 Venous blood, 142 Venous Thrombosis, 179 Ventilation, 40, 44, 80, 178 Ventral, 167 Ventricle, 145, 169, 178 Ventricles, 142, 154 Ventricular, 40, 48, 54, 60, 63, 70, 145, 154 Venules, 140 Vertebrae, 174 Veterinary Medicine, 127 Villi, 154 Vinca Alkaloids, 178 Vincristine, 79 Viral, 24, 119, 151, 152 Viral Regulatory Proteins, 151 Viral Structural Proteins, 151 Viral vector, 24 Virion, 151 Virulence, 176 Virus, 119, 142, 149, 152, 171, 178 Viruses, 27, 94, 119, 135, 150, 160, 178, 179 Viscera, 173 Visual field, 164 Vitreous, 158, 171, 179 Vitreous Body, 171, 179 Vitro, 114, 155 Vivo, 16, 155 Volition, 157 Volvulus, 51 W Wakefulness, 13 Warfarin, 78

192

Myotonic Dystrophy

White blood cell, 97, 137, 159, 167 Windpipe, 176 Womb, 178 X Xenograft, 137 X-ray, 157, 163, 170 X-ray therapy, 157

X-Rays, 157, 163, 170 Y Yeasts, 166, 179 Z Zygote, 145, 161 Zymogen, 168, 179

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