HUNTINGTON DISEASE A
3-in-1
Medical
Reference
A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES
HUNTINGTON DISEASE 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., 1960Huntington Disease: 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: 0-497-11235-3 1. Huntington Disease-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on Huntington disease. 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 HUNTINGTON DISEASE ............................................................................ 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Huntington Disease? ....................................................................................................... 3 How Common Is Huntington Disease?......................................................................................... 4 What Genes Are Related to Huntington Disease?......................................................................... 4 How Do People Inherit Huntington Disease? ............................................................................... 4 Where Can I Find Additional Information about Huntington Disease? ....................................... 5 References....................................................................................................................................... 7 What Is the Official Name of the HD Gene?.................................................................................. 7 What Is the Normal Function of the HD Gene? ............................................................................ 7 What Conditions Are Related to the HD Gene? ............................................................................ 8 Where Is the HD Gene Located? .................................................................................................... 8 References....................................................................................................................................... 8 Federally Funded Research on Huntington Disease ...................................................................... 9 The National Library of Medicine: PubMed ................................................................................ 39 CHAPTER 2. ALTERNATIVE MEDICINE AND HUNTINGTON DISEASE ............................................ 84 Overview...................................................................................................................................... 84 National Center for Complementary and Alternative Medicine.................................................. 84 Additional Web Resources ........................................................................................................... 91 General References ....................................................................................................................... 92 CHAPTER 3. PATENTS ON HUNTINGTON DISEASE ......................................................................... 93 Overview...................................................................................................................................... 93 Patent Applications on Huntington Disease ............................................................................... 93 Keeping Current .......................................................................................................................... 94 CHAPTER 4. BOOKS ON HUNTINGTON DISEASE............................................................................. 95 Overview...................................................................................................................................... 95 Book Summaries: Online Booksellers........................................................................................... 95 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 101 Overview.................................................................................................................................... 101 The Basics: Genes and How They Work..................................................................................... 101 Genetic Mutations and Health................................................................................................... 112 Inheriting Genetic Conditions ................................................................................................... 118 Genetic Consultation ................................................................................................................. 126 Genetic Testing .......................................................................................................................... 128 Gene Therapy ............................................................................................................................. 134 The Human Genome Project and Genomic Research................................................................. 137 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 140 Overview.................................................................................................................................... 140 NIH Guidelines.......................................................................................................................... 140 NIH Databases........................................................................................................................... 141 Other Commercial Databases..................................................................................................... 144 APPENDIX C. PATIENT RESOURCES .............................................................................................. 145 Overview.................................................................................................................................... 145 Patient Guideline Sources.......................................................................................................... 145 Finding Associations.................................................................................................................. 148 Resources for Patients and Families........................................................................................... 149 ONLINE GLOSSARIES................................................................................................................ 151 Online Dictionary Directories ................................................................................................... 153
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HUNTINGTON DISEASE DICTIONARY ............................................................................... 154 INDEX .............................................................................................................................................. 202
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FORWARD In March 2001, the National Institutes of Health issued the following warning: “The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.”1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with Huntington disease 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 Huntington disease, 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 Huntington disease, 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 Huntington disease. 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 Huntington disease. 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 Huntington disease, 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 Huntington disease. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.
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CHAPTER 1. STUDIES ON HUNTINGTON DISEASE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Huntington disease. For those interested in basic information about Huntington disease, 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 Huntington disease 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 Huntington disease is provided.2 The Genetics Home Reference has recently published the following summary for Huntington disease:
What Is Huntington Disease?3 Huntington disease is a progressive brain disorder that causes uncontrolled movements, mental and emotional problems, and loss of thinking ability (cognition). Adult-onset Huntington disease, the most common form of this disorder, usually appears in a person's thirties or forties. Early signs and symptoms can include irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions. As the disease progresses, involuntary jerking movements (chorea) become more pronounced. Affected individuals may have trouble walking, speaking, and 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=huntingtondisease.
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swallowing. People with this disorder typically also experience changes in personality and a decline in thinking and reasoning abilities. Individuals with the adult-onset form of Huntington disease generally survive about 15 to 25 years after signs and symptoms begin. A less common, early-onset form of Huntington disease begins in childhood or adolescence. Although both forms of the disorder involve movement problems and mental and emotional changes, some of the features of the early-onset form differ from those of the adult-onset form. In children, signs and symptoms can include slowness, clumsiness, frequent falling, rigidity, slurred speech, and drooling. School performance often declines as thinking and reasoning abilities become impaired. Seizures occur in 30 percent to 50 percent of individuals with this condition. The course of early-onset Huntington disease may be shorter than adult-onset Huntington disease; affected individuals generally survive 10 to 15 years after signs and symptoms appear.
How Common Is Huntington Disease? Huntington disease affects an estimated 3 to 7 per 100,000 people of European ancestry. The disorder appears to be less common in some other populations, including people of Japanese, Chinese, and African descent.
What Genes Are Related to Huntington Disease? Mutations in the HD (http://ghr.nlm.nih.gov/gene=hd) gene cause Huntington disease. The HD gene provides instructions for making a protein called huntingtin. Although the function of this protein is unknown, it likely plays an important role in nerve cells. Huntington disease is caused by a mutation in which a DNA segment, known as a CAG repeat, is abnormally expanded within the HD gene. Normally, this segment is repeated 10 to 35 times within the gene. In people with Huntington disease, however, the CAG segment is repeated 36 to more than 120 times. The abnormally expanded CAG segment leads to the production of a huntingtin protein that contains a long stretch of the amino acid glutamine. (Amino acids are the building blocks of proteins.) The elongated protein disrupts the normal function of nerve cells in certain parts of the brain, and ultimately leads to the death of those cells. The dysfunction and loss of nerve cells cause the signs and symptoms of Huntington disease.
How Do People Inherit Huntington Disease? This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. An affected person usually inherits the altered gene from one affected parent. In rare cases, an individual with Huntington disease does not have a parent with the disorder. As the altered HD gene is passed from one generation to the next, the size of the CAG repeat expansion often increases in size. Larger repeat expansions are usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation.
Studies
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Where Can I Find Additional Information about Huntington Disease? You may find the following resources about Huntington disease helpful. These materials are written for the general public. NIH Publications - National Institutes of Health •
National Center for Biotechnology Information: Genes and Disease: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gn d.section.207
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National Human Genome Research Institute: Learning About Huntington's Disease: http://www.genome.gov/10001215
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National Institute of Neurological Disorders and Stroke: Huntington's Disease: Hope Through Research: http://www.ninds.nih.gov/disorders/huntington/detail_huntington.htm
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National Institute of Neurological Disorders and Stroke: Huntington's Disease Information Page: http://www.ninds.nih.gov/disorders/huntington/huntington.htm MedlinePlus - Health Information
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Encyclopedia: Huntington's Disease: http://www.nlm.nih.gov/medlineplus/ency/article/000770.htm
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Health Topic: Huntington's Disease: http://www.nlm.nih.gov/medlineplus/huntingtonsdisease.html Educational Resources - Information Pages
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Ask the Geneticist: Inheritance of Huntington disease: http://www.askthegen.org/question.php?question_id=721
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Centre for Genetics Education: http://www.genetics.com.au/factsheet/37.htm
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HOPES: Huntington's Outreach Project for Education (Stanford University): http://www.stanford.edu/group/hopes/
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Johns Hopkins Medicine: http://www.hopkinsmedicine.org/bhdc/about/
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Madisons Foundation: http://www.madisonsfoundation.org/content/3/1/display.asp?did=190
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Mayo Clinic: http://www.mayoclinic.org/huntingtons-disease/
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New York Online Access to Health (NOAH): http://www.noah-health.org/en/bns/disorders/huntington/
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Orphanet: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=399
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The Cleveland Clinic: http://www.clevelandclinic.org/health/health-info/docs/2300/2303.asp?index=9355
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The Merck Manual, Second Home Edition: http://www.merck.com/mmhe/sec06/ch091/ch091i.html
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The Wellcome Trust: http://genome.wellcome.ac.uk/doc_WTD020863.html
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University of Washington: http://depts.washington.edu/neurogen/documents/HuntingtonDis.pdf Patient Support - for Patients and Families
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Caring for People with Huntington's Disease (University of Kansas Medical Center): http://www.kumc.edu/hospital/huntingtons/
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Hereditary Disease Foundation: http://www.hdfoundation.org/
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Huntington's Disease Society of America: http://www.hdsa.org/
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Huntington Society of Canada: http://www.hsc-ca.org
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National Organization for Rare Disorders: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Huntington\
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Resource list from the University of Kansas Medical Center: http://www.kumc.edu/gec/support/huntingt.html
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WE MOVE: Worldwide Education and Awareness for Movement Disorders: http://www.wemove.org/hd/ Professional Resources
You may also be interested in these resources, which are designed for healthcare professionals and researchers. •
Gene Reviews - Clinical summary: http://www.genetests.org/query?dz=huntington
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Gene Tests - DNA tests ordered by healthcare professionals: http://www.genetests.org/query?testid=2097
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Genetic Tools - Teaching cases: http://www.genetests.org/servlet/access?fcn=y&filename=/tools/cases/huntingto n-24/
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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22huntington+disease%22?recruiting=fals
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PubMed - Recent literature: http://ghr.nlm.nih.gov/condition=huntingtondisease/show/PubMed;jsessionid=78F4B 3FEF7711555B0E8EBD6671545CEe
Studies
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OMIM - Genetic disorder catalog: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143100
References These sources were used to develop the Genetics Home Reference condition summary on Huntington disease. •
Bates GP. History of genetic disease: The molecular genetics of Huntington disease - a history. Nat Rev Genet. 2005 Aug 31; [Epub ahead of print]. PubMed citation
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Gene Review
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Kent A. Huntington's disease. Nurs Stand. 2004 Apr 21-27;18(32):45-51; quiz 52-3. Review. PubMed citation
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Scriver, Charles R; The metabolic & molecular bases of inherited disease; 8th ed.; New York : McGraw-Hill, c2001. p5677-5701. NLM Catalog
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Tost H, Wendt CS, Schmitt A, Heinz A, Braus DF. Huntington's disease: phenomenological diversity of a neuropsychiatric condition that challenges traditional concepts in neurology and psychiatry. Am J Psychiatry. 2004 Jan;161(1):28-34. No abstract available. PubMed citation
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Young AB. Huntingtin in health and disease. J Clin Invest. 2003 Feb;111(3):299-302. Review. No abstract available. PubMed citation
A summary of the gene related to Huntington disease is provided below:
What Is the Official Name of the HD Gene?4 The official name of this gene is “huntingtin (Huntington disease).” HD is the gene's official symbol. The HD gene is also known by other names, listed below.
What Is the Normal Function of the HD Gene? The HD gene provides instructions for making a protein called huntingtin. Although the exact function of this protein is unknown, it appears to play an important role in nerve cells and is essential for normal development before birth. Huntingtin is found in many of the body's tissues, with the highest levels of activity in the brain. Within cells, this protein may be involved in signaling, transporting materials, attaching (binding) to proteins and other structures, and protecting the cell from self-destruction (apoptosis). One region of the HD gene contains a particular DNA segment known as a CAG trinucleotide repeat, so called because this segment of three DNA building blocks
4
Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=hd;jsessionid=78F4B3FEF7711555B0E8EBD6671545CE.
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(nucleotides) is repeated multiple times within the gene. In most people, the number of CAG repeats ranges from 10 to 35. This repeated segment leads to the production of a huntingtin protein that contains a stretch of glutamine, an amino acid building block used in many proteins.
What Conditions Are Related to the HD Gene? Huntington Disease - Caused by Mutations in the HD Gene The inherited mutation in the HD gene that causes Huntington disease abnormally repeats the CAG segment from 36 to more than 120 times. This unstable region, called an expanded trinucleotide repeat, leads to an altered version of the huntingtin protein that contains an abnormally long stretch of the amino acid glutamine. Enzymes in the cell often cut this elongated protein into fragments that have "sticky" ends. The protein fragments form abnormal clumps inside nerve cells and may attract other, normal proteins into the clumps. These nerve cells do not function properly and ultimately die. This process is particularly likely to occur in a part of the brain that coordinates movement (the striatum) and a part of the brain that controls thinking and emotions (the cerebral cortex).
Where Is the HD Gene Located? Cytogenetic Location: 4p16.3 Molecular Location on chromosome 4: base pairs 3,046,205 to 3,215,484
The HD gene is located on the short (p) arm of chromosome 4 at position 16.3. More precisely, the HD gene is located from base pair 3,046,205 to base pair 3,215,484 on chromosome 4.
References These sources were used to develop the Genetics Home Reference gene summary on the HD gene.
Studies
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Bates G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet. 2003 May 10;361(9369):1642-4. Review. PubMed citation
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Cattaneo E. Dysfunction of wild-type huntingtin in Huntington disease. News Physiol Sci. 2003 Feb;18:34-7. Review. PubMed citation
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Gardian G, Vecsei L. Huntington's disease: pathomechanism and therapeutic perspectives. J Neural Transm. 2004 Oct;111(10-11):1485-94. Review. PubMed citation
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Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series. EMBO Rep. 2004 Oct;5(10):958-63. Review. PubMed citation
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Li SH, Li XJ. Huntingtin and its role in neuronal degeneration. Neuroscientist. 2004 Oct;10(5):467-75. Review. PubMed citation
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MacDonald ME. Huntingtin: alive and well and working in middle management. Sci STKE. 2003 Nov 4;2003(207):pe48. Review. PubMed citation
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Rangone H, Humbert S, Saudou F. Huntington's disease: how does huntingtin, an antiapoptotic protein, become toxic? Pathol Biol (Paris). 2004 Jul;52(6):338-42. Review. PubMed citation
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van Dellen A, Grote HE, Hannan AJ. Gene-environment interactions, neuronal dysfunction and pathological plasticity in Huntington's disease. Clin Exp Pharmacol Physiol. 2005 Dec;32(12):1007-19. Review. PubMed citation
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Young AB. Huntingtin in health and disease. J Clin Invest. 2003 Feb;111(3):299-302. Review. No abstract available. PubMed citation
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Federally Funded Research on Huntington Disease The U.S. Government supports a variety of research studies relating to Huntington disease. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.5 CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to Huntington disease. 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 Huntington disease. The following is typical of the type of information found when searching the CRISP database for Huntington disease:
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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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Huntington Disease
Project Title: AUTOPHAGY, DNA DAMAGE AND ONSET OF HUNTINGTON'S DISEASE. Principal Investigator & Institution: Yuan, Junying; Professor; Children's Hospital Corporation Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2011 Summary: The goal of this proposal is to test the hypothesis that the reduction of key autophagy gene expression andautophagy function as a result of DNA damage during the aging process plays a key role in mediating theonset of Huntington's disease (HD). Mouse, Drosophila and C. elegans models of HD suggest that thecytotoxicity of expanded polyglutamine is highly dependent upon protein context and protein expressionlevels of mutant Htt. Autophagy plays an important role in regulating the intracellular accumulation of mutantHtt with expanded polyQ. The expression of beclin 1, a key gene involved in autophagy, decreased in anage-dependent fashion in human brains. Since beclin 1 gene is haploid insufficient in regulatingautophagosome function, age-dependent decrease of beclin 1 expression may lead to a reduction ofautophagic activity during aging. The hypothesis is that reduction of autophagy function in aging results inboth increased oxidative stress induced DNA damage and reduced long-lived protein turnover whichpromotes the accumulation of mutant Htt. Increased accumulation of mutant Htt and oxidative stress mayplay an important role in promoting the onset of HD. This hypothesis will be tested in the following specificaims. Specific Aim 1 is to test,the hypothesis that the reduction of beclin 1 expression in aging human brainscontributes to the onset of HD by generating beclin 1+/-; HdhQ111 mice and examining if 50% reduction ofbeclin 1 expression led to an increased accumulation of mutant Htt as well as to determine theconsequence of autophagy deficiency on neuronal survival and functions. Specific Aim 2 is to examine themechanism which led to the age-dependent reduction of beclin 1 expression by testing if the promoter ofbeclin 1 is preferentially damaged in aging human brains and particularly susceptible to oxidative damage incellular models. The contribution of reduced expression of transcriptional factors regulating beclin 1expression will also be considered. Specific Aim 3 is to test the hypothesis that the reduction of autophagyfunction exacerbates the DNA damage during aging by increasing the accumulation of damagedmitochondria which further promotes the levels of intracellular ROS by examining aging beclin 1+/mice andautophagy deficient cells for evidence of increased damaged mitochondria. Specific Aim 4 is to investigatethe functional role of autophagy to oxidative DNA damage using CK-p25 mice as a model and to examinethe roles of of DNA damage and autophagy deficiency to the accumulation of mutant Htt in HdhQ111; CKp25mice. The ability of SIRT1 activating molecules (STACs) to restore the autophagy function in CKp25mice and to delay the onset of motor dysfunction in HD models will be determined. Understanding themechanism by which DNA damage negatively regulates autophagy during aging would allow us to developstrategies to maintain normal autophagy function during aging process which may delay or prevent the onsetof HD and other aging related neurodegenerative diseases.
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Project Title: BIOENERGETICS IN ANIMAL MODELS OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Beal, M Flint.; Professor; Neurology and Neuroscience; Weill Medical College of Cornell Univ 1300 York Avenue New York, Ny 10021 Timing: Fiscal Year 2005; Project Start 15-APR-1999; Project End 31-MAR-2008
Studies
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Summary: (provided by applicant): The pathogenesis of Huntington's Disease (HD) is as yet unknown but there is substantial evidence that both altered gene transcription as well as mitochondrial dysfunction play an important role. There is evidence that huntingtin binds to transcription factors which results in decreased expression of genes which may play a critical role in neuronal survival. A secondary consequence of this appears to be impaired oxidative phosphorylation and increased generation of reactive oxygen species. In our prior grant, we showed that there was impaired oxidative phosphorylation in transgenic mouse models of Huntington's disease, and that this was associated with increased oxidative damage. We also showed that agents such as creatine and coenzyme Q, which improve cellular bioenergetics, exert neuroprotective effects in transgenic mouse models of Huntington's disease. In the present proposal, we intend to extend these studies to two further unique transgenic mouse models of Huntington's disease. We will determine whether there is mitochondrial dysfunction and oxidative damage in a knock-in mouse model developed by MacDonald and colleagues. These mice are a very accurate genetic model of Huntington's disease. We will also examine the tetracycline-off model developed by Yamamoto and colleagues to determine whether there is mitochondrial dysfunction and oxidative damage with the gene turned on, which then resolves once the gone is turned off. We will carry out similar studies with an inducible cell culture model. We will investigate whether histone deacetylase (HDAC) inhibitors exert neuroprotective effects by altering gene transcription in transgenic mouse models of Huntington's disease. We will examine whether a phosphodiesterase IV inhibitor can exert neuroprotective effects in transgenic mouse models of HD by increasing cyclic AMP levels, leading to increased CREB transcriptional activity, and whether this improves mitochondrial function. Our prior studies showed that combinations of agents, which target different disease mechanisms in Huntington's disease, may exert additive neuroprotective effects. We will, therefore, examine whether a combination of creatine or coenzyme Q with either a HDAC inhibitor or a phosphodiesterase IV inhibitor can exert additive neuroprotective effects. •
Project Title: BRAIN IMAGING AND COGNITION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Reading, Sarah A.; Psychiatry and Behavioral Sciences; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2006; Project Start 01-JUL-2006; Project End 31-MAR-2011 Summary: (provided by applicant): This is an application for a mentored PatientOriented Research Career Development Award (K23). The candidate is a psychiatrist who proposes to acquire the specific skills and knowledge necessary to become an independent investigator and leader in the field of psychiatric neuroimaging. Huntington's Disease (HD) is a prototypic neuropsychiatric illness with prominent psychiatric and cognitive dysfunction, a known genetic abnormality and consistent structural pathology. The candidate will be guided by known cognitive dysfunction to investigate, using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the relationship between structure and function in early HD and in presymptomatic carriers of the HD genetic mutation. Career development activities will emphasize an integrative approach and focus on research methodology and statistics, cognitive neuropsychology, and functional and diffusion tensor neuroimaging acquisition and analysis techniques. The candidate plans to acquire skills through the study of HD that will generalize to the study of other neuropsychiatric conditions like schizophrenia. The research plan will focus on subjects in the early stages of HD and on pre-symptomatic HD mutation-positive individuals. Subjects will be recruited through the Johns Hopkins Department of Psychiatry Huntington's Disease Research Center,
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where they will have undergone rigorous clinical and cognitive evaluations. Specific Aim 1 will focus on fMRI analysis of hemodynamic activation during cognitive tasks designed to activate fronto-striatal circuits. Specific Aim 2 will use DTI data to study changes of fronto-striatal fractional anisotropy (FA), and Specific Aim 3 will investigate the relationships among clinical features, hemodynamic activation patterns and white matter changes. Future directions include the extension of this approach to patients with schizophrenia and other neuropsychiatric conditions in which cognitive symptoms manifest early and are refractory to current interventions. By working to understand the biology that subserves these cognitive processes we can approach thoughtful strategies for intervention and perhaps cure. RELEVANCE: Cognitive dysfunction is common among patients with neuropsychiatric disorders. By better understanding the biologic nature of this dysfunction, specific interventions may be developed to ease disease burden to patients, caregivers and society as a whole. •
Project Title: CEHCS AS THERAPEUTICS FOR HUNTINGTON'S DISEASE Principal Investigator & Institution: Benaksas Schwartz, Pharmaceuticals, Inc. 18085 Gentian Ave Riverside, Ca 92508
Elaine
J.;
Encore
Timing: Fiscal Year 2005; Project Start 01-SEP-2005; Project End 31-AUG-2007 Summary: (provided by applicant): Huntington's Disease (HD) is a hereditary autosomal dominant triplet-repeat disease with complete penetrance, manifest by progressive motor and cognitive deterioration. HD affects males and females in relatively equal numbers, typically presenting with symptoms in the 3rd-4th decade of life. The disorder occurs in various geographic and ethnic populations worldwide. The frequency of HD appears to vary among different populations, ranging from an estimated 4 to 10 individuals per 100,000. HD is a progressive neurological disorder usually leading to death 15-20 years after onset of neurological or psychological impairment. Recent discoveries made through the collaborative work of scientists at Encore Pharmaceuticals, Inc. and the Oklahoma Medical Research Foundation (OMRF) have demonstrated novel antioxidant, anti-inflammatory and neuroprotective activities for gamma-carboxyethyl hydroxychroman (gamma-CEHC), a natural metabolite of gamma-tocopherol. gamma-CEHC slows disease progression in a mouse model of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's Disease) even when gamma-CEHC is administered late in the disease. Because ALS and Huntington's Disease (HD) share common neuropathic features, we have begun to investigate whether gamma-CEHC might show protection in preclinical models of HD. We find that systemically administered gamma-CEHC completely protects mice against chronic 3NP-induced HD-like neurological damage, suggesting its therapeutic potential in Huntington's Disease. EncorePharma and the OMRF established complementary patent protection in the field of tocopherol analogs, specifically seven United States patents (and their foreign counterparts) in the area of gamma-tocopherol, its metabolites and derivatives, including composition of matter patents for gamma-CEHC. Recently our two entities have developed a strategic relationship in order to combine scientific and business acumen. Through this relationship we plan to capitalize on the commercial potential offered by the novel tocopherol metabolites. Expressly, through this partnership we wish to leverage our recent discoveries and initiate product commercialization efforts by further elucidating the in vivo therapeutic of gamma-CEHC. The targeted objectives of the research defined in this Phase I application are to conduct a complete evaluation of gamma-CEHC for the slowing of HD progression in an accepted mouse genetic model, the R6/2 mouse that expresses the first exon of mutant human huntingtin (Htt) containing a pathogenic polyglutamine expansion. We are uniquely positioned to perform mechanistic studies of gamma-CEHC in preclinical models of HD and to
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pursue translational research leading quickly to human clinical trials. Successful demonstration of gamma-CEHC efficacy in a mouse genetic model of HD will ultimately result in the filing of an investigational new drug (IND) application for gamma-CEHC for the treatment of HD, after performing the necessary preclinical safety studies, followed by initiation of clinical development activities with Orphan Drug Designation. Although early in the preclinical development process for this agent, few if any safety issues have been seen or are anticipated. The need to move this potential therapeutic forward for a disease that has very few treatment alternatives cannot be understated. •
Project Title: CELESTROLS FOR TREATMENT OF NEURODEGENERATIVE DISEASES Principal Investigator & Institution: Silverman, Richard B.; Charles Deering Mccormick Professor; Chemistry; Northwestern University Evanston, Il 602081110 Timing: Fiscal Year 2005; Project Start 01-JUL-2004; Project End 30-JUN-2008 Summary: (provided by applicant): The expression of molecular chaperones has been shown to suppress protein misfolding/aggregation and cellular toxicity phenotypes in model systems associated with Huntington's Disease, Alzheimer's Disease, Parkinson's Disease, and ALS. A feature common to diseases of protein conformation is the appearance of folded intermediates that self-associate to form protein aggregates and inclusions. The molecular chaperones Hsp90 and Hsp70 sequester damaged proteins that appear in cells exposed to physiological and environmental stress. The ability of molecular chaperones to suppress the cellular toxicities associated with expression of these "toxic" proteins may be due to the intrinsic properties of chaperones to capture and suppress the appearance of folded intermediates. Therefore, we propose that the identification of small molecules that elevate the expression of genes encoding heat shock proteins and molecular chaperones should lead to the development of novel therapies beneficial to the prevention of neurodegenerative diseases. The rationale for this proposal is based on results obtained by our laboratory and others who participated recently in a screening program organized by the NINDS, Huntington Disease Society of America, Hereditary Disease Foundation, and the ALSA to identify new drugs for treating these diseases. A search was carried out for drugs that activate the heat shock response; the most effective compound identified was the natural product celastrol. Synthetic analogs of celastrol will be prepared to optimize its effectiveness as a regulator of the heat shock response and a suppressor of neurotoxicity and to determine its mechanism of action as an activator of the heat shock response. To probe the function of celastrol as a potential therapy for neurodegenerative diseases, the following Specific Aims will be addressed: (1) Synthesize analogs of celastrol that induce the human heat shock response using a heat shock promoter-reporter assay in human tissue culture cells. (2) Determine the mechanism of action of celastrol (or an analog). The working model is that celastrol activates the heat shock response by inducing heat shock transcription factor HSF1. The mechanism by which HSF1 activity is induced by celastrol will be determined. It also will be determined whether celastrol, by virtue of its ability to activate the expression of chaperones, can reduce the aggregation and neurotoxicity of the Huntington Q64 protein expressed in a human SH-SY5Y neuroblastoma cell line. (3) Studies will be carried out to identify the binding target for celastrol using molecular biological and biochemical techniques. Identified target(s) will then be cloned and characterized. Results of these studies will aid in the determination of the molecular mechanism of celastrol action and in the further understanding of the heat shock response, identify new targets for therapeutic intervention, and may also lead to new therapies for neurodegeneration.
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Huntington Disease
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COENZYME Q10 IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Cudkowicz, Merit E.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 30-SEP-2005; Project End 30-NOV-2010 Summary: (provided by applicant): The study objective is to determine the efficacy of Coenzyme Q10 (CpQ) in Huntington's disease (HD). Although the genetic defect that causes HD has been identified there is no known effective treatment or cure. Rational therapeutic strategies in Huntington's disease include those that are targeted to improving cellular energy production and reducing oxidative stress. Coenzyme Q10, a co-factor involved in mitochondria! electron transfer and an anti-oxidant, is a compound that has some of these properties. Coenzyme Q10 slows progression and prolongs survival in a dose dependent manner in a transgenic mouse model of HD. Coenzyme Q10 at a dosage of 600 mg per day for 2 years appeared to slowed the functional decline in HD by approximately 13% compared to placebo. Pre-clinical and clinical studies with COQ suggest that higher dosages are more beneficial. The study hypothesis is that chronic treatment of HD patients with CoQ will slow the progressive functional decline of HD. The specific aim is to test this hypothesis by conducting a double-blind, placebocontrolled, randomized, parallel group, multi-center study of CoQ involving 608 ambulatory HD subjects who are each treated for 60 months. Eligible subjects will be randomized to CoQ 2400 mg daily or matching placebo. A CoQ dosage of 2400 mg was chosen based on dosage ranging tolerability studies in HD, amyotrophic lateral sclerosis and Parkinson's disease. The primary outcome measure will be the clinical progression of HD as measured by the change in the total functional capacity (TFC) between baseline and 60 months. Secondary measures will include changes in the other clinical rating scales of the Unified Huntington Disease Rating Scale (UHDRS), times to decline in TFC by 2 and 3 points, ability to complete the study at the assigned dosage and the frequencies of clinical and laboratory adverse events.
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Project Title: COMBINATION DRUG THERAPY IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Ferrante, Robert J.; Professor; Neurology; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 021182394 Timing: Fiscal Year 2005; Project Start 01-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for a protein of unknown function, huntingtin (htt). There is no known treatment for HD. Although the exact cause of neuronal death in HD remains unknown, it has been postulated that the abnormal aggregation of the mutant huntingtin protein may cause toxic effects in neurons, leading to pathogenic mechanisms of oxidative stress, mitochondrial dysfunction, apoptosis, energy metabolism defects, and subsequent excitotoxicity. We have identified a number of drug compounds that separately target these mechanisms and have shown that they significantly ameliorate the phenotype of HD transgenic mice. These compounds or their analogs are available for human use and represent the immediate pipeline of candidate neuroprotective agents for clinical trials in HD. We have shown that these drugs have great potential for combined use to maximize neuroprotection. Much as treatment for cancer and AIDS has evolved, the most effective neuroprotection for HD will likely come from a cocktail of medications. Such combination therapies in HD mouse models would provide critical pre-clinical data to pilot combined therapies in humans. We propose a logical series of combination
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therapeutic trials in both HD transgenic mice and HD knock-in mice with proven drug compound regimens, using phenotype analysis, histopathology, toxicology, biochemistry, and pharmacokinetics as outcome measures. We will begin with two-drug trails using creatine and coenzyme Q10. These compounds are under trial in HD patients and will serve as a foundation to build further two-drug combinations. We will continue to add compounds to both creatine and coenzyme Q10 that we have already shown to be efficacious in transgenic HD mice. Because planning is underway for cysteamine to enter early phase clinical testing, a high priority will be to combine it with creatine and coenzyme Q10. Once the best combinations with creatine and coenzyme Q10 are determined, we will select additional compound pairs based on their potential for the greatest efficacy and least toxicity in humans (ie. inhibitors of htt aggregation, histone deacetylase inhibition, and transcription dysregulation). To model medication trials in presymptomatic individuals, as well as symptomatic individuals, we will perform studies in R6/2 mice initiating treatment upon weaning and repeated with treatment initiated once symptoms are present (6 weeks, analogous to early stages of human HD). We will confirm the most efficacious single and combination drug strategies identified in the transgenic HD mice within the full-length HD knock-in mice. By modeling combination therapeutic trials in both transgenic and knock-in HD mice we expect to emerge knowing which combinations have the most promise for prospective clinical drug-trials in HD patients and will initiate treatment strategies. •
Project Title: CREATINE THERAPY FOR HUNTINGTON'S DISEASE Principal Investigator & Institution: Hersch, Steven M.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 01-SEP-2000; Project End 30-JUN-2007 Summary: Huntington's disease (HD) is a progressive and fatal neurologic disorder caused by an expanded CAG repeat in gene coding for a protein of unknown function that has been named huntington. The exact cause of neuronal death in HD is unknown, however, the leading hypothesis is that of excitotoxicity and apoptosis induced by a defect in energy metabolism that may be caused by oxidative stress. We previously demonstrated that mitochondrial inhibitors produce striatal lesions closely mimicking the phenotype of HD. We have also shown that oxidative injury is involved in these models and may be in human HD. Because of this research, there as been increasing interest in the HD field in exploring complementary agents that might prevent oxidative injury, Creatine is a widely used dietary supplement principally taken to enhance athletic performance. It is a very strong candidate neuroprotective agent for HD and other neurodegenerative disorders because of its ability to ameliorate toxin-based animal models and because of our preliminary evidence in transgenic HD mice. However, there is only limited animal experience with creatine and there has not yet been any trials in humans with neurodegenerative disorders. There are several potential mechanisms by which creatine could be an effective treatment for HD. First, there is evidence that it can be neuroprotective by relieving oxidative stress. Second, it could directly inhibit apoptotic neuronal death through its inhibitory action on the mitochondrial transition pore. Third, we have preliminary evidence that creatine treatment may be associated with reduced huntingtin aggregation, a potentially toxic process. Finally it could act peripherally to help reverse the weakness and muscle mass loss that is a major clinical problem in HD. We have preliminary evidence that creatine can extend survival in transgenic models of HD and that it can reduce brain markers of metabolic stress in humans with HD. We propose to test whether creatine can ameliorate the behavioral and neuropathologic phenotypes occurring intransgenic models of HD, examine the potential mechanisms of creatine neuroprotection, test its
16
Huntington Disease
safety and tolerability in HD patients, and collect pilot clinical data examining how creatine impacts HD symptoms and progression. These studies are intended to provide the basis of a subsequent phase III trial of creatine in HD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DISSECTING THE HUNTINGTON'S DISEASE MECHANISM Principal Investigator & Institution: Macdonald, Marcy; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114
Associate
Professor;
Timing: Fiscal Year 2004; Project Start 01-MAY-1994; Project End 30-JUN-2007 Summary: (Investigator's abstract): Huntington's disease (HD) is a dominant inherited neurodegenerative disorder that affects 1 in 10,000 in the U.S. Knowledge of the HD mutation, a CAG expansion that extends a run of glutamines in huntingtin, has spurred elucidation of the HD pathogenic mechanism and related polyglutamine disorders. Mutant huntingtin's HD pathogenic-trigger comprises two components: a novel toxicity property of polyglutamine conferred on the amino terminus and another intrinsic feature of the 350 kDa protein that renders striatal neurons especially vulnerable. By inserting HD CAG repeats into the mouse's HD gene (Hdh), we have uncovered abnormal conformational properties of full-length mutant huntingtin that precede truncated-aggregate and neuronal atrophy. The striatal neuron specificity, dominance and glutamine progressively implicate these events early in the human disease. We have demonstrated by Hdh inactivation and studies in striatal cells that huntingtin displays alternate conformations (consistent with distinct complexes) that associate with different sets of nuclear RNA and cytoplasmic membrane organelles that require its function. We have demonstrated regulation of huntingtin levels that implicates it in a diversity of physiologic adoptions to altered cellular homeostasis. In the renewal period, we aim to pursue the delineation of both components of HD pathogenesis. To investigate the specificity element, we will more precisely define huntingtin's normal function, placing it within the RNAprotein energy pathway and delineating regulatory features important to the metabolism of striatal neurons. To define the polyglutamine component, we will assess modifications and interactions unique to mutant huntingtin, test factors that modify its abnormal behaviors and assess the contribution of physiologic regulation. Our long-term goal continues to be a detailed understanding of the initial steps of the HD pathogenic cascade in order to be able to target specific processes for the development of effective therapies for this tragic disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC ANALYSIS USING SPERM TYPING Principal Investigator & Institution: Arnheim, Norman; Professor; Biological Sciences; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2005; Project Start 01-SEP-1985; Project End 31-AUG-2006 Summary: This proposal seeks to study fundamental questions concerning mutation and recombination events that lead to human disease. One aim is to determine whether expansions of the CAT/CTG tracts found in Huntington disease patients occur in germline mitotic cells or following the initiation of meiosis. Studies are also proposed to examine whether the proximity or orientation of a CAG/CTG tract relative to an origin of DNA replication influences expansion size or frequency and whether this accounts for the marked inter-locus variation in expansion mutation susceptibility. Two other aims also focus on mutation. One aim will examine human sperm to determine whether
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the mutation that causes achondroplasia, the most common cause of dwarfism, increases with the age of the father as predicted by population studies. Another will examine the role played by members of the MutL DNA repair protein family on mononucleotide repeat slippage mutations. In humans this kind of mutation has been shown to inactivate important genes in many tumors from patients with the a familial colon cancer (HNPCC). The last aim seeks to directly measure the effects of sequence length and sequence similarity on the frequency of unequal recombination between repeated sequences in the human genome. Such events have been shown to lead to a variety of human disease syndromes. •
Project Title: GENETIC SUPPRESSORS OF HUNTINGTON'S DISEASE IN MICE Principal Investigator & Institution: Yang, Xiangdong William.; Assistant Professor; None; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2005; Project Start 01-JUN-2004; Project End 31-MAY-2006 Summary: (provided by applicant): Huntington's disease (HD) is a devastating neurodegenerative disease caused by a polyglutamine expansion mutation in the Huntingtin gene (Ht). The mutant Huntingtin (mHt) exerts dominant toxicity to cause selective neuronal dysfunction and degeneration. Currently, there are very few valid drug targets for HD. One method to identify new drug targets is through genetic modifier studies. Genetic = modifier screenings in Yeast, Drosophila, C. elegans and mammalian cell culture have produced a number of genes that can be manipulated to suppress mutant Huntingtin toxicity. However, the efficacy of these genes to suppress mutant Huntingtin toxicity in the mammalian brain is unclear. This proposal seeks to establish a mouse genetic system that can readily and systematically test genetic suppressors for HD in vivo. Using a relatively novel mouse genetic technology, called Bacterial Artificial Chromosome (BAC) mediated transgenics, we have succeeded in creating novel transgenic mouse models of HI) expressing full-length mutant Huntingtin under the endogenous regulation. Some of these full-length transgenic founders have already demonstrated early and severe motor deficits. The specific aims of this proposal are to: 1. Characterize the fulfull-lengthC models of HD and select lines suitable for genetic modifier studies. 2. Apply the newly developed rapid BAC modification system to generate mice over expressing two modifier genes and to test their efficacy in suppressing mHt toxicity in the full-length transgenic models. If proven effective, our BAC transgenic System can readily be scaled up to systematically study a large number of putative HD genetic modifiers in vivo. Identification of effective genetic modifiers in mice may provide novel insights into disease pathogenesis and new targets to develop therapeutics.
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Project Title: HUNTINGTON'S DISEASE AND THE STRIATUM Principal Investigator & Institution: Ehrlich, Michelle E.; Professor of Neurology; Neurology; Thomas Jefferson University 201 South 11Th Street Philadelphia, Pa 191075587 Timing: Fiscal Year 2005; Project Start 15-JUL-2005; Project End 30-JUN-2007 Summary: (provided by applicant): Huntington's disease (HD) is an autosomal dominant disorder caused by a mutation in the IT15 gene encoding the protein huntingtin (htt). The mutation consists of an expanded polyglutamine region characterized by CAG repeats (The Huntington's Disease Collaborative Research Group, 1993), and the protein is expressed throughout the nervous system and periphery. The medium size spiny neuron (MSN) of the striatum is the most vulnerable
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Huntington Disease
cell in this disease. Current areas of research focus include the etiology of neuronal dysfunction, i.e. transcriptional dysregulation, which appears to precede neuronal death, and the determination of whether the pathophysiology is cell-autonomous. Thus, open questions include :) Is expression of mutant huntingtin in striatal neurons sufficient to produce MSN dysfunction and/or death? And 2) Is down-regulation of striatal-enriched proteins in the presence of mutant htt related to a cell-specific transcriptional mechanism? Using a unique reagent, the recently identified fragment of the DARPP-32 promoter (D9) that restricts transgene expression in the forebrain to the MSNs of the striatum. the Aims of the proposed project are: Specific Aim 1: To produce transgenic mouse models of Huntington's disease with striatal-specific expression of mutant htt, either Exon 1, or full-length, and Specific Aim 2: To determine if D9/LacZ is transcriptionally down-regulated in the presence of mutant htt. This will be accomplished by crossing of the already established D9/LacZ mouse with the R6/2 HD mouse model, in which endogenous DARPP-32 is down-regulated. •
Project Title: HUNTINGTON'S DISEASE CENTER WITHOUT WALLS P50 Principal Investigator & Institution: Gusella, James F.; Director of Neurogenetics Laboratory; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2006; Project Start 01-JUL-1997; Project End 31-MAR-2011 Description (provided by applicant): Huntington's disease (HD) is a dominant neurodegenerative disorder due to expanded polyglutamine conferring a novel "gainof-function" on the large huntingtin protein, apparently via an abnormal conformational property. The pathogenic process in HD can be viewed as a cascade triggered by the presence of the polyglutamine tract in full-length huntingtin protein and culminating in the dysfunction and death of medium spiny striatal projection neurons (and some others), with the consequent clinical manifestations of a characteristic, progressive movement disorder, psychiatric abnormalities and cognitive decline. The novel conformational property of mutant huntingtin and its immediate consequences in the cell are therefore targets for potential therapies acting at the level of the pathogenic trigger in HD. However, human genotype-phenotype studies show that while age at onset of neurological symptoms is primarily determined by polyglutamine length, it is also altered by genetic modifiers. Identification and characterization of these modifiers, which could act at any step in the pathogenic cascade, is of critical importance, since their inherent capacity to alter pathogenesis would make them valid targets for development of therapeutics. Consequently, our goal is to use genetic and chemical strategies to understand the pathogenic process in HD and to implicate means of preventing or modifying it, both at its trigger and later in the consequent pathway of pathogenesis. Beyond the advancement of knowledge concerning the pathogenic trigger, the subsequent cascade, and mechanisms for their modification, these studies also have a realistic potential to benefit HD patients, as modulators with therapeutic potential will be investigated in a true drug development paradigm, including LEAD optimization, animal testing and human trials (all outside the scope of this grant) by the non-profit Cure HD Initiative, Inc. which has made a major organizational and financial commitment to capitalize on basic science findings from academic studies such as those of this long-standing HD Center.
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Project Title: HUNTINGTON'S PATHOGENESIS
DISEASE
REPEAT
INSTABILITY
AND
Principal Investigator & Institution: Wheeler, Vanessa C.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114
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Timing: Fiscal Year 2005; Project Start 01-SEP-2005; Project End 31-MAY-2010 Summary: (provided by applicant): Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat tract beyond a threshold of ~ 36 units. The expanded CAG repeat is translated into a polyglutamine stretch at the amino-terminus of the huntingtin protein, triggering cell death in a subset of neurons in the striatum and cortex. The expanded CAG repeat also exhibits dramatic instability in the germline and in somatic tissues. The long-term goals of this research are to elucidate the molecular pathways that underlie the instability of the HD CAG repeat and the specific neurodegeneration triggered by mutant huntingtin. In HD knock-in mice, which accurately recapitulate the human HD mutation, the Msh2 gene is a modifier of repeat instability and an early striatal phenotype. In this study, we will test the hypothesis that Msh2 acts in the mismatch repair pathway to modify CAG repeat instability and early phenotypes in HD knock-in mice. We will perform genetic crosses with mice deficient in specific mismatch repair genes and mouse line carrying a mutation in Msh2's ATPase domain. These experiments will provide mechanistic insight into Msh2's role in CAG repeat instability and phenotypic expression of the mutant HD allele. To determine whether candidate DNA repair genes are modifiers of the age of onset of HD in humans genetic association studies will be performed using 'extreme' individuals with onset ages deviating from values predicted by CAG repeat size. To gain further insight into the mechanism by which Msh2 modifies repeat instability and early striatal disease in the mouse we will generate a conditional knockout of the Msh2 gene using the Cre-loxP system. We will specifically inactivate Msh2 in forebrain neurons using a Camklla-driven Cre transgene to test the hypothesis that Msh2 acts in striatal neurons to modify instability and early phenotypes. Together, these studies will provide insight into mechanisms of repeat instability and pathogenesis, leading to rational therapeutic strategies aimed at slowing or halting this devastating disease. •
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 2006; Project Start 01-APR-1987; Project End 30-NOV-2009 Summary: (provided by applicant): Expansions of CTG/CAG repeats in specific human genes cause numerous neurological diseases, including myotonic dystrophy, Huntington disease, and several spinocerebellar ataxias. These diseases arise when the number of triplet repeats increases beyond a threshold of about 25-35 repeats to a length that has pathologic consequences. This application focuses on the basis for CTG/CAG repeat instability. Studies in model systems have shown that processes that expose single strands of DNA - replication, recombination, repair, transcription - are capable of destabilizing triplet repeats. CTG and CAG repeats in single strands form hairpins and slipped-strand structures, which are the key intermediates in instability. These structures either interfere with normal repair or trigger aberrant repair, which changes the length of the repeat tract. In no case, however, has the mechanism for triplet repeat instability in humans been defined. Using a novel selection assay for CAG repeat contraction, we have identified two processes that greatly destabilize triplet repeats in mammalian cells: genome-wide demethylation and transcription. The two documented periods of repeat instability in development -early embryogenesis and germline differentiation -correspond to the two waves of epigenetic reprogramming that occur in mammals. Thus, demethylation-induced repeat instability is likely to be directly relevant to the germline events that lead to the progressive worsening of the disease phenotype in subsequent generations - the clinical phenomenon of anticipation.
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Huntington Disease
Ongoing, age-dependent repeat instability occurs in affected patient tissues such as neurons, which do not divide, and may exacerbate the disease pathology. Because the disease genes are transcribed in these tissues, transcription-induced instability may be a major contributor to this ongoing, non-replication-dependent instability. We propose to define the specific DNA repair proteins responsible for demethylation- and transcription-induced instability, and in that way define the molecular mechanisms underlying CTG/CAG repeat instability. We will use siRNA knockdowns in selection assays in human cells to identify specific components required for repeat instability. We will extend our studies to mice to examine the effects of altered genomic methylation and transcription on repeat stability in germline and somatic tissues. Finally, we propose to use our selection assay to screen insertion vector libraries, siRNA libraries, and chemical libraries to identify genes that alter repeat stability. Our goal is to delineate those processes that are responsible for both the germline and somatic CTG/CAG repeat instability that characterizes myotonic dystrophy and other neurological diseases. •
Project Title: INTRABODY THERAPY IN DROSOPHILA FOR HUNTINGTON'S DISEASE Principal Investigator & Institution: Wolfgang, William J.; Wadsworth Center Health Research, Inc. Rensselaer, Ny 12144 Timing: Fiscal Year 2005; Project Start 18-MAY-2005; Project End 30-APR-2007 Summary: (provided by applicant): The overall goal of our work is to cure Huntington's Disease (HD). This proposal seeks to evaluate new intracellular antibodies (intrabodies) directed against the Huntingtin (htt) protein using an established Drosophila model for HD. Work in tissue culture cells and brain slice preparations has demonstrated that intrabodies can ameliorate pathology associated with expression of mutant forms of the htt. We have recently demonstrated that our prototypical anti-htt intrabody, C4 scFv, partially suppresses HD pathology in the functioning nervous system of Drosophila. The degree of suppression is quantifiable, allowing the rapid evaluation of new intrabodies for improved efficacy over our existing intrabody. Additionally, through unbiased functional genetic screens available in Drosophila, the cellular processes triggered by the intrabody/target interaction that result in disease correction can be elucidated. Identification of cellular pathways involved in intrabody-dependent correction of pathology will allow us to devise strategies to augment intrabody therapy as well as predict potential deleterious side effects. Finally, we will develop new models for testing intrabodies in flies. Currently, the intrabody and disease-causing htt transgene are co-expressed from early embryonic stages onward. In humans, therapy with intrabodies would likely commence in adults after the onset of diseases. Our new model will allow testing of intrabody efficacy at any time subsequent to the onset of disease. If successful this will provide validation of intrabodies as disease therapeutics and impetus to proceed to preclinical testing in vertebrate models of HD.
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Project Title: ION CHANNEL DYSFUNCTION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Cantrell, Angela R.; Assistant Professor; Anatomy and Neurobiology; University of Tennessee Health Sci Ctr 62 S. Dunlap Memphis, Tn 38163 Timing: Fiscal Year 2005; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): It has recently been suggested that neuronal degeneration may occur as a secondary phenomenon in response to neuronal dysfunction in HD. In support of this idea, recent reports have indicated that
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electrophysiological abnormalities occur in the brains of HD transgenic animals. These abnormalities include altered somatic discharge, broadening of the excitatory postsynaptic potential and failure to induce long term potentiation following high frequency stimulation. These abnormalities precede neurobehavioral and neuropathological alterations suggesting to some researchers that cytoplasmic functions including neurotransmitter regulation of ion channels and regulation of intracellular Ca2+ may play a role in this disease. If this is in fact the case, then understanding neuronal dysfunction in HD may be critical to the development of rational treatment strategies and early intervention programs. An extrinisic mechanism such as glutamate excitotoxicity has been proposed to account for the ultimate degeneration of medium spiny neostriatal neurons, therefore, we hypothesized that changes in the membrane properties of the cortical projection neurons which provide input to the medium spiny neostriatal neurons might be important in HD. This idea, while intriguing, has not been fully investigated using the newly available animal models of HD. We present preliminary data to support this idea and demonstrate that electrophysiological abnormalities occur in the presynaptic corticostriatal projection neurons in HD transgenic mice. Since the electrical activity of a neuron is regulated by its own intrinsic cytoplasmic properties as well as its synaptic inputs, it will be important to conduct a thorough study of these alterations in the electrophysiological properties of the presynaptic cortical projection neurons in HD. These electrophysiological abnormalities in corticostriatal projection neurons may contribute to neuronal dysfunction and the subsequent neuropathology observed in HD. This hypothesis will be tested in acutely isolated, identified cortical projection neurons obtained from HD mouse models in which expression of mutant huntingtin has been induced. Techniques employed include patch-clamp recording methods, single-cell RT-PCR and immunohistochemistry. This proposal has 3 Specific Aims: 1) To define the physiological properties of pharmacologically isolated HVA Ca2+ channels, voltage-gated Na+ channels and voltage-gated K+ channels in acutely isolated corticostriatal projection neurons from HD transgenic mouse models. 2) To determine the molecular mechanisms underlying the observed increase in HVA Ca2+ channel activity in corticostriatal neurons from R6/2 transgenic mice. 3) To expand our studies to include other classes of cortical projection neurons. These studies will provide valuable information for the elucidation and treatment of a variety of motor deficits and neurodegeneration observed in HD and a host of other neurological disorders. •
Project Title: LONGITUDINAL STUDIES AMONG AT-RISK HD GENE CARRIERS Principal Investigator & Institution: Foroud, Tatiana M.; Professor; Medical and Molecular Genetics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2005; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) To identify and quantify changes among presymptomatic Huntington disease gene carriers who had not yet developed definite chorea, we performed the largest, study of individuals at-risk for HD (n=657) Subtle abnormalities in oculomotor, extrapyramidal and pyramidal motor, and cognitive measures were identified. We propose to reexamine this unique sample of at-risk individuals using an expanded test battery that includes more sensitive and specific quantitative measures for each subset of variables for which significant differences between presymptomatic gene carriers and nongene carriers were initially observed. These new measures increase the power of our proposed longitudinal studies of the rate of change among presymptomatic gene carriers as they approach the manifestation of clinically diagnosable HD. These novel studies are designed to: 1) Further delineate the
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Huntington Disease
deficits observed in the subclinical and early symptomatic phase of disease; 2) measure the rate of increasing abnormality among presymptomatic gene carriers; 3) investigate the interrelationships among the variables so as to identify measures with similar rates of deterioration, which might suggest common pathways affected early in the disease process; 4) quantify the relationship of CAG repeat number with disease onset and progression. The results of these studies will improve the understanding of the presymptomatic and early symptomatic phase of HD allowing for earlier diagnosis and identify subclinical biomarkers that can be utilized in clinical trials to evaluate therapeutic agents designed to slow progression and delay the onset of clinical HD. •
Project Title: LOSS-OF-FUNCTION MECHANISMS IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Zeitlin, Scott O.; Aissistant Professor; Neuroscience; University of Virginia Charlottesville Box 400195 Charlottesville, Va 229044195 Timing: Fiscal Year 2005; Project Start 01-MAR-2003; Project End 28-FEB-2008 Summary: (provided by applicant): Huntington's disease (HD) is a dominant hereditary neurodegenerative disease that is caused by the expansion of a stretch of CAG repeats within the HD gene that encodes a large protein (huntingtin; htt) of unknown function. HD is thought to be the consequence of a deleterious gain-of-function that is conferred by the expanded stretch of polyglutamine encoded by the CAG repeats. The role of the normal function of htt in the disease process is unknown, but our recent work and that of others suggests that loss of normal htt function may also contribute to pathogenesis. Our long-term objective is to use genetic approaches to understand the role of htt's normal functions in HD pathogenesis using both cell culture and mouse models. To accomplish this objective, we propose three complementary specific aims that are designed to test the potential contribution of different loss-of-function mechanisms in HD. A fourth aim is designed to test a potential therapeutic strategy based on restoring normal htt function in HD mouse models. (1) To test the hypothesis that loss-of-function in HD may occur through mutant htt's ability to sequester wild-type htt via the polyglutamine stretch, we will generate an epitope-tagged allele of the mouse HD gene homologue (Hdh-deltaQ) that lacks precisely the polyglutamine stretch. The ability of this modified version of htt to resist sequestration by mutant htt will be assessed in cell culture. In addition, in order to test if htt is capable of participating in potential dominant-negative interactions by interacting with itself, an ES cell line with targeted insertion of different epitope tags in each Hdh allele will be generated for use in immunoprecipitation pull-down assays. (2) To test if htt loss-of-function may occur through mutant htt's ability to activate caspase-mediated proteolysis, and if proteolytic cleavage of htt is a rate-limiting step in HD pathogenesis, we will compare the onset and progression of phenotypes exhibited by two knockin HD mouse models: the first expressing a full-length mutant htt, and the second expressing a truncated version of mutant htt. Both mutant proteins are expressed under the control of the endogenous Hdh promoter, enabling a direct comparison between the two models. (3) Htt loss-offunction may also occur via dominant-negative interference of wild-type htt interactions with protein partners. To test this hypothesis in vivo, we will characterize the impact of losing htt interactions with the postsynaptic density 95 protein that could lead to altered N-methyl-D-aspartate (NMDA) receptor function in an Hdh conditional knockout mouse model. (4) Finally, we will attempt to rescue phenotypes in an HD mouse model by over-expressing a temporally regulated dominant-negative resistant form of htt in the forebrain.
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Project Title: MEMBRANE FUSION ATPASES AND THE GOLGI APPARATUS Principal Investigator & Institution: Warren, Graham B.; Professor; Cell Biology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2005; Project Start 01-MAR-2000; Project End 31-MAR-2008 Summary: (provided by applicant): Using a cell-free system than mimics the mitotic cycle of the Golgi apparatus, we have been able to identify many of the proteins involved in the fragmentation and reassembly of this organelle. The last granting period focused on the reassembly of Golgi cisternae that is catalyzed by two ATPases, NSF and p97. NSF was shown to have an activity additional to its well-characterized role in unraveling SNARE complexes. It was found to add the ubiquitin-like protein, GATE-16, to the v-SNARE, GOS-28, a process that prevented the formation of non-productive cis SNARE complexes, and primed the SNARE for its interaction with the cognate tSNARE, syntaxin-5. The p97 ATPase utilizes p47 as an adaptor molecule and this was shown to recognize mono-ubiquitinated proteins as part of the Golgi reassembly process. Other adaptor molecules were identified and characterized, notably the Ufd1p/Np14 complex, and this was shown to mediate p97 action in processes ranging from ER-associated degradation through to nuclear envelope reassembly. The present proposal continues the analysis of these two ATPase-driven pathways focusing on the following aims: 1: Studying the p115 tethering protein to work out precisely how it choreographs the capture and docking of cis-directed COPI transport vesicles. 2: Characterizing a new tethering complex that likely mediates the capture and docking of other COPI vesicles to medial/trans cistemae. The composition and function of these vesicles will also be characterized as will others identified and isolated through capture by different tethers. 3: Determining the role played by ubiquitin in the p97 pathway of Golgi reassembly. Ubiquitinated targets will be identified and characterized. 4: Testing the idea that p97 unravels t-t SNARE complexes just as NSF unravels v-t SNARE complexes. The fusion of ER membranes in budding yeast will be used as the assay. Though the main thrust of this application is the study of fundamental membrane traffic processes, there are medical implications. The tethering proteins were first identified as auto-antigens in patients with Sjogren's syndrome, and in one case as a partner for OCRL1, a PIP2 phosphatase, implicated in oculocerebrorenal syndrome. Ufd1p is mutated in DiGeorge syndrome, a congenital developmental disorder, and the role played by p97 in unraveling protein aggregates has implicated this ATPase in neurodegenerative diseases ranging from Alzheimer's to Huntington disease. Insights into the molecular mechanism of Golgi reassembly may therefore provide insight into these medical conditions.
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Project Title: MODELING HUNTINGTON'S DISEASE IN DROSOPHILA Principal Investigator & Institution: Littleton, J Troy.; Assistant Professor; Biology; Massachusetts Institute of Technology 77 Massachusetts Ave Cambridge, Ma 02139 Timing: Fiscal Year 2005; Project Start 01-JUN-2005; Project End 31-MAY-2010 Summary: (provided by applicant): Huntington's disease is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein that results in intracellular aggregate formation and neurodegeneration. Pathways leading from polyglutamine tract expansion to disease pathogenesis remain obscure. To elucidate how polyglutamine expansion causes neuronal dysfunction, we have generated Drosophila transgenic strains expressing human huntingtin cDNAs encoding pathogenic or nonpathogenic proteins. While expression of nonpathogenic huntingtin has no discernible effect on behavior, lifespan or neuronal morphology, pan-neuronal expression of huntingtin containing a Q128 tract
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Huntington Disease
causes a progressive loss of motor coordination, decreased lifespan and time-dependent formation of huntingtin aggregates specifically in the cytoplasm and neurites. Huntingtin aggregates sequester other expanded polyglutamine proteins in the cytoplasm and lead to synaptic aggregate accumulation and disruption of axonal transport. In contrast, Drosophila expressing an expanded polyglutamine tract alone, or an expanded polyglutamine tract in the context of the spinocerebellar ataxia type 3 protein, display only nuclear aggregates and do not disrupt axonal trafficking. We propose to expand upon these studies to determine how non-nuclear events induced by cytoplasmic huntingtin aggregation may cause the progressive neurodegeneration observed in Huntington's disease. In addition, we will characterize the in vivo role of the native huntingtin protein and screen for direct suppressors of huntingtin aggregation. Together, these approaches should expand our understanding of the normal function of the huntingtin protein, as well as provide novel insights into the pathogenesis of Huntington's Disease. •
Project Title: MODULATION OF CASPASE PATHWAYS IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Friedlander, Robert M.; Associate Director; Brigham and Women's Hospital Research Administration Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 01-JAN-2000; Project End 31-JAN-2010 Summary: (provided by applicant): Recent evidence implicates caspase-mediated cell death pathways in several neurological disorders. In particular, inappropriate activation of caspase-1 and -3 leads to the death of cortical and striatal neurons in Huntington's disease (HD). We contend that understanding the roles of these "Cysteine-dependent, ASPartate-directed proteASES" in HD will suggest therapies for this untreatable and universally fatal syndrome. The following four lines of investigation examine the molecular pathology of HD and ways to restore healthy physiology via genetic and pharmacological therapies. 1) Normal huntingtin protein (htt) as an antagonist to cell death: Htt is both a substrate for and an inhibitor of caspase-3. Therefore, we hypothesize that depletion of huntingtin is both a consequence of HD and a cause of progressive ailment. Expression of excess htt in cultured cells should break this detrimental feedback loop. In addition to that in vitro test of the "runaway caspase" hypothesis, whole animal experiments will be conducted. A transgenic mouse will be constructed to have elevated systemic levels of htt. The animal will be tested for its predicted resistance to HD. 2 and 3) While the first line of research concerns the effects of a caspase pathway, these two sets of experiments investigate signals that initiate one. As discussed within the application, activation of caspase-1 is among the earliest molecular changes associated with HD. Experiments are proposed to investigate the proteins that modulate caspase-1: the activator Rip2 and the inhibitor Cop. CARDmediated interactions among caspase-1 and these antagonistic regulators determine the level of enzyme activity. Furthermore, expression of both Rip2 and Cop is aberrant in the brains of R6/2 mice (animal models of HD) and in post mortem samples from human HD patients. We propose genetic manipulations of cells and of mice with the aim of restoring proper caspase-1 homeostasis, and inhibiting disease progression. 4) Minocycline has been demonstrated to slow disease progression in HD mice. The combined effect of minocycline with creatine and coenzyme Q (two Compounds that other researchers find to slow disease progression in HD mice) shall be evaluated. These compounds have different modes of action, suggesting that their salutary effects will reinforce one-another. Combination therapies will be tested using HD mice.
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Project Title: MUTANT GENE IDENTIFICATION IN THE DYSTONIC RAT Principal Investigator & Institution: Ledoux, Mark S.; Professor, Department of Neurology; Neurology; University of Tennessee Health Sci Ctr 62 S. Dunlap Memphis, Tn 38163 Timing: Fiscal Year 2005; Project Start 05-FEB-2005; Project End 31-JAN-2009 Summary: (provided by applicant): Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Dystonia is a relatively common neurological disease. For example, dystonia is more prevalent than the combination of Huntington disease, amyotrophic lateral sclerosis and Duchenne muscular dystrophy. There are no definitive cures for dystonia and treatments are expensive and often ineffective. Over fourteen chromosomal loci associated with a dystonia phenotype exist in humans. However, only a few genes clearly associated with the development of dystonia have been cloned to date. Identifying other defective genes in either humans or animal models should provide critical insights into the extremely complex molecular and neural network pathophysiology of dystonia. In addition, any effort to understand dystonia will likely contribute in important ways to our understanding of motor systems and neuronal plasticity. The genetically dystonic (dt) rat, an autosomal recessive mutant discovered in the Sprague-Dawley strain, exhibits a movement disorder that closely resembles the generalized dystonia seen in humans. Dystonic rats demonstrate twisting movements and abnormal postures by Postnatal Day 12. The mutation is fully penetrant. Even with supportive measures, "dt" rats die before 40 days of age. However, cerebellectomy can eliminate dystonia in the "dt" rat, extend its life into adulthood, and enable it to bear and rear offspring. Behavioral, biochemical, and electrophysiological studies indicate that olivocerebellar pathway dysfunction is critical to the dt rat motor syndrome. A systematic approach to finding the mutant gene associated with the dt rat phenotype was begun by crossing homozygote male "dt" rats to females of an inbred strain. The heterozygote first-generation offspring were crossbred to produce second-generation offspring. Rats were genotyped using a set of markers spaced across the rat genome and the responsible gene has been narrowed down to a region of less than 0.5 cM. We plan to locate and clone the mutant gene in the "dt" rat and fully characterize the temporal and spatial expression of this gene's transcriptional and translational products. Patients with dystonia will be screened for mutations in the human homologue. These proposed studies will likely increase our understanding of both dystonia and olivocerebellar motor systems.
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Project Title: MUTANT POLYGLUTAMINE HUNTINGTON'S DISEASE
AND
NEUROTOXICITY
IN
Principal Investigator & Institution: Poirier, Michelle A.; Psychiatry and Behavioral Sciences; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2006; Project Start 10-JAN-2006; Project End 31-DEC-2010 Summary: (provided by applicant): Analysis of mutant huntingtin (htt) polyglutamine (polyQ) aggregation has suggested a role for this process in the pathogenesis of Huntington's Disease (HD). Biochemical information on mutant polyglutamine is incomplete, but commonalities with other neurodegenerative protein aggregation diseases suggest common features of neurodegenerative pathogenesis. While inclusion bodies themselves appear not to be the toxic species, aspects of protein conformational change and aggregation appear relevant to pathogenesis. To investigate biochemical features of mutant htt, we prepared a structure-based cell culture model of htt polyQ
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Huntington Disease
aggregation and toxicity by expressing htt exon-1 N-terminal fragment with a modified expanded polyQ region in mammalian cell lines and in cultured murine primary cortical neurons. The data show a correlation between htt polyQ proteins predicted to assume a compact beta-structure and toxicity. We have also developed an in vitro system for the biochemical and biophysical analysis of htt mutant polyQ aggregation, allowing us to probe the htt aggregation pathway. Globular and protofibrillar species were observed at early stages of aggregation, and may represent intermediates in the fibrillization process. In specific aim 1 of this proposal, we will use our cell culture model to characterize the beta-sheet structural organization within htt mutant polyQ aggregates. In aim 2, we will use our in vitro model to investigate the relevance of the putative compact beta-sheet on htt mutant polyQ fibrillization. In aim 3, we will characterize the role of mutant htt intramolecular structure in polyQ-induced toxicity in mammalian cell culture. These studies will elucidate the relationship between mutant htt polyQ structure and neurotoxicity in HD. •
Project Title: NEUROBIOLOGICAL PREDICTORS OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Paulsen, Jane S.; Professor; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2005; Project Start 01-APR-2000; Project End 31-AUG-2008 Summary: (provided by applicant): Although treatments in animal models for HD have proven successful, and several clinical trials are underway in persons with manifest HD, there currently exists no methodology in which to test experimental therapeutics prior to diagnosis of manifest motor disease. The Predict-HD study is designed to provide essential methodology for the initiation of preventive clinical trials in Huntington's disease (HD). Early identification of neurological disease is imperative so that intervention using protective, gene therapy, and regenerative strategies can be initiated at high levels of life quality and prior to the occurence of irreversible cellular injury. The Predict-HD study has successfully recruited nearly 500 healthy participants who had previously undergone genetic testing for the HD expansion. Annual measures of brain imaging and cognitive performance are obtained in concert with other demographic, clinical and genetic information. Findings already suggest a remarkable convergence of the first detectable decline in brain morphology, motor skill, and cognitive ability at about 15 years prior to traditional motor diagnosis. This is notably earlier than had generally suspected and represents a major advance in our understanding of HD. With completion of the requested 3-year continuation of the Predict-HD study we will have longitudinal observations that allow us to: 1) Test and refine the model of early HD changes suggested by our baseline data; 2) Determine which measures of functional decline are concurrent with measureable brain morphology changes; and 3) Better understanding of the relationships among striatal and cortical changes, DNA repeat length, and clinical phenotype in HD. Completion of Predict-HD will result in a methodology and a cohort that can be readily applied to presymptomatic treatments as they become available. In addition to the contribution this will make towards early intervention in HD, our findings are likely to improve our understanding of the functional pathophysiology of other neurodegenerative and genetic illnesses.
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Project Title: NEURODEGENERATION WITH DROSOPHILA Principal Investigator & Institution: Botas, Juan; Assistant Professor; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 01-JUL-2001; Project End 30-JUN-2006
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Summary: (Adapted from applicant's abstract): The ultimate goal of this project is to gain insight into polyglutamine-induced neurodegeneration by identifying genes, pathways and molecular mechanisms involved in the pathogenesis of spinocerebellar ataxia type 1 (SCA1). A Drosophila model of SCA1 was created by generating flies that express either normal or expanded human SCA1 transgenes. This fly model recapitulates the cellular phenotypes observed in SCA1 patients including the formation of nuclear inclusions (NI) and progressive neuronal degeneration. Capitalizing on the power of Drosophila genetics, two large genetic screens were designed to identify genes that modify a SCA1 neurodegenerative phenotype in the eye. The first screen yielded modifiers of the SCA1 phenotype when gene activity was decreased; the second screen yielded SCA1 modifiers when gene activity was increased. Both suppressors and enhancers of the neurodegenerative phenotype were obtained from each screen. The first aim of the proposed work is to identify the genes that modify the SCA1 neurodegenerative phenotype. These modifiers will be further characterized in sensitive viability and locomoter assays that allow the quantification of their modifier effects. The most powerful suppressors will be selected for further studies. To investigate whether different polyglutamine disease share common mechanisms of pathogenesis, the SCA1 modifiers will be tested in fly models of Huntington disease and polyglutamine toxicity. Finally, because the normal function of the SCA1 gene may be relevant to pathogenesis, the function of the Drosophila SCA1 gene will be investigated by generating lack-of-function mutations and transgenes for its over expression. In future studies, the most promising SCA1 suppressors characterized in flies will be investigated in the SCA1 mouse model, and in mouse models of polyglutamine disease. These genes may also be relevant to research aimed at treating other neurodegenerative proteinopathies such as Alzheimer disease and Parkinson disease. They will provide valuable targets for future pharmacological research aimed at developing drugs for therapy. •
Project Title: NEUROPROTECTION HUNTINGTON'S DISEASE
VIA
XIAP
GENE
THERAPY
IN
Principal Investigator & Institution: Kaplitt, Michael G.; Assistant Professor & Director; Neurology and Neuroscience; Weill Medical College of Cornell Univ 1300 York Avenue New York, Ny 10021 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2008 Summary: (provided by applicant): Huntington's disease (HD) is devastating hereditary neurodegenerative disorder characterized by a severe movement disorder, mood and emotional disturbances, and cognitive decline before premature death. It is caused by a CAG repeat expansion in the gene encoding huntingtin (htt), but the mechanism whereby mutant htt (mhtt) ultimately induces selective neurodegeneration is still unknown. There is substantial evidence from multiple HD models that mhtt induces apoptotic cell death processes and mitochondrial dysfunction. XIAP is a potent inhibitor of apoptosis and thus represents an attractive target for neuroprotection in Huntington's disease. The goal of this proposal is to determine the potential therapeutic utility of a novel gene delivery approach, using an AAV-vector approach to deliver the gene encoding XIAP to the major site of neurodegeneration in Huntington's disease, the neostriatum. The proposed experiments in genetic mouse models of Huntington's disease arise from the observations that (i) we have found that XIAP has neuroprotective actions against mhtt- induced toxicity in vitro, (ii) that this effect is potentially mediated by inhibitory actions against Smac/DIABLO or Omi, rather than caspase inhibition, (iii) that our adeno-associated viral (AAV) vector delivery system results in widespread gene expression within the striatum, and (iv) pilot experiments
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suggest that XIAP gene delivery improves phenotype in a mouse model of Huntington's disease. Specifically, we will examine whether an AAV gene therapy approach to deliver the anti-apoptotic agent XIAP to striatal neurons improves outcome and reduces neurodegeneration in animal models of Huntington's disease, by examining AAV-dXIAP's effects in the N171-82Q "fragment" mouse model of Huntington's disease, and in a second "full length" HD model, YAC-128 HD mice. We will also elucidate whether XIAP'S neuroprotective anti-apoptotic actions are due to inhibition of Smac/DIABLO or Omi/HtrA2, rather than direct effects on caspases in HD mice. We will generate AAV vectors carrying dXlAP with point mutations either disabling its ability to bind to Smac/DIABLO-Omi, or caspases, and examine their effects on HD pathobiology in an HD mouse model. The outcomes of these studies will provide a substantial foundation for larger studies to determine cell damage pathways underlying HD pathogenesis, and to develop an effective gene-delivery approach for the treatment of Huntington's disease. •
Project Title: OBSESSIONS/COMPULSIONS IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Anderson, Karen E.; Psychiatry; University of Maryland Balt Prof School Professional School Baltimore, Md 21201 Timing: Fiscal Year 2005; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (provided by applicant) Huntington's disease (HD) is a neurological illness with prominent psychiatric comorbidity. Obsessions and compulsion appear to be highly represented in HD, but have not been studied. There is compelling evidence that obsessive-compulsive disorder (OCD) is related to dysfunctional cortico-striatal networks. Because it is a neurological disorder with well-characterized striatal pathology, and accurate genetic testing, HD provides a unique opportunity for study of these symptoms In this Mentored Clinical Scientist Development Award proposal, a program is outlined that will prepare the candidate to become an independent investigator. The candidate will learn how to evaluate obsessive and compulsive symptoms in HI) patients. HD patients' data will be compared with data from primary OCD patients to examine how obsessions and ompulsions may differ in a neurological illness that primarily affects the striatum. Clinical and neuropsychological correlate of OCD in HD will be explored. Cognitive activation paradigms will be used with neuroimaging studies to engage network implicated in primary OCD. First, task-related cerebral activation changes particular to HD itself will be studied, and these networks will be related to presence or absence of obsessive and compulsive symptoms. Supervision of the candidate during this award will be provided by these mentors: Drs. Yaakov Stern (training coordination, neuropsychology supervision), Karen Marder (neurological expertise, evaluation of HD), Michael Liebowit training in evaluation of obsessive and compulsive symptoms), and Dr. James Haxby (neuro-imaging). Advanced instruction n the neuroanatomy of frontal-striatal circuitry, including handon correlation of brain slices with Magnetic Resonanc mages, is included. The goals of this award are to promote the candidate's training, study psychiatric symptoms in HD, and Ldd to current understanding of neural circuitry implicated in HD. The ultimate goal is to provide the candidate with the skill and knowledge base to become an independent, multidisciplinary investigator of neuropsychiatric illness.
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Project Title: PATHOGENIC HUNTINGTON'S DISEASE
IMPACT
OF
SUMO
MODIFICATION
IN
Principal Investigator & Institution: Thompson, Leslie M.; Associate Professor; Biological Chemistry; University of California Irvine Irvine, Ca 926977600
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Timing: Fiscal Year 2006; Project Start 01-JUN-2006; Project End 31-MAY-2011 Summary: (provided by applicant): Accumulation of pathogenic proteins and peptides with expanded polyglutamine repeats is characteristic of Huntington's disease (HD) and related neurodegenerative diseases. Other than the fact that a polyQ expansion within the disease protein causes disease, the major cellular mechanisms of pathogenesis are not clear. Multiple cellular processes have been implicated, but proximal causative events have proven difficult to distinguish from distal correlative events. As polyQ disease proteins can be modified in ways that change their cellular function or fate, it is likely that Htt protein modifications contribute to pathology. We find that Htt can be SUMO modified and that this modification can affect its biochemical properties and pathogenic potential in a Drosophila model. These observations form the rationale for this proposal. I propose to investigate, in depth, the role of SUMOylation in HD pathogenesis and to investigate the biochemical mechanisms involved in the SUMO-1 modification and de-SUMOylation of mutant Htt using a multidisciplinary approach. Implicit in this research will be an effort to identify potential therapeutic targets and develop strategies for interventions that disrupt or prevent pathology in the biochemical pathways responsible for alteration of mutant Htt. Hypothesis 1: SUMO modification of Htt is involved in HD phenotypes Mutant Htt accumulates in the nuclei of neurons and induces the dysregulation of key cellular processes including transcription. The impact of SUMOylation of mutant Htt upon cellular functions will be tested using in vitro and in vivo systems. Hypothesis 2: Specific E3-SUMO ligases are responsible for SUMO modification of Htt. An overall reduction of SUMOylation suppresses pathogenesis in vivo, therefore the identification of the specific enzymes involved in the attachment of SUMO groups to the Htt protein or in the removal of SUMO from the Htt protein may provide novel therapeutic targets for treatment of HD. Hypothesis 3: SUMO modification of Htt is critical to disease pathogenesis in vivo. Here we will test the physiologic relevance of SUMO modification pathways in Drosophila. •
Project Title: PHASE III TRIAL OF MINOCYCLINE IN ALS:I-CLINICAL CENTER Principal Investigator & Institution: Gordon, Paul H.; Neurology; Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 25-AUG-2003; Project End 31-MAY-2007 Summary: (provided by the applicant): Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to death on average in 3 years (1). There is no cure or known treatment that significantly improves function. Loss of motor neurons in the brain and spinal cord of ALS patients causes the progressive symptoms. Motor nerve degeneration may result from a cascade of events including free radical toxicity, glutamate excitotoxicity and mitochondrial dysfunction (2-4), which lead to the activation of cell death pathways (5-9). Mitogen-Activated Protein (MAP) kinases, including p38, are up-regulated in response to cell stress, and promote pro-apoptotic and inflammatory mediators (10, 11). Caspase enzymes and inflammatory mediators regulate cell death pathways (12-14), and are activated in human and transgenic mousemodel ALS (15,16). Caspase enzyme inhibitors and anti-inflammatory agents have been shown to slow progression in the ALS model (6,7,17,18). Minocycline, FDA approved for treatment of infection, has high central nervous system penetration when taken orally, inhibits p38 MAP kinase, prevents activation of caspase-1, caspase-3 and inflammatory mediators (19,20), and delays disease progression in animal models of neurodegenerative disorders, including Huntington disease (19), Parkinson disease (21) and ALS (22) (Serge Przedborski, personal communication). It is well-tolerated as an oral treatment for outpatients. The objective of this clinical trial is to determine whether
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Minocycline slows disease progression and helps maintain function in patients with ALS. The study design selects patients early in the course of ALS when a neuroprotective therapy may be most beneficial, measures functional improvement from the medication, which patients and physicians consider most important, and minimizes subject drop out. The proposed study will be an IRB-approved, investigatorinitiated, multi-center, randomized, double-blind, placebo-controlled study of Minocycline in 400 subjects with ALS treated for 9 months. The primary outcome measure is the change in slope of the revised ALS Functional Rating Scale (ALSFRS-R). Secondary outcome measures consist of changes in disease progression rate, as measured by Manual Muscle Testing (MMT), forced vital capacity (percent predicted) and survival. Should Minocycline prove effective in slowing the rate of functional decline, it would have an immediate impact both clinically and from the perspective of understanding the underlying pathophysiology of human ALS. This application is the clinical part of a combined proposal to carry out the clinical trial. A Data Center will be established at the California Pacific Medical Center in San Francisco to carry out data management and statistical analyses (see companion grant application Phase III Trial of Minocycline in ALS: II Data Center. P.I. Dr. Robert Miller). •
Project Title: EXPRESSION
POLYGLUTAMINE
EXPANSION
AND
ALTERED
GENE
Principal Investigator & Institution: Li, Shi-Hua; Assistant Professor; Human Genetics; Emory University 1784 North Decatur Road, Suite 510 Atlanta, Ga 30322 Timing: Fiscal Year 2005; Project Start 01-MAR-2004; Project End 28-FEB-2009 Summary: (provided by applicant): Nine inherited neurodegenerative disorders are caused by an expansion of a polyglutamine tract in the associated disease proteins. Increasing evidence indicates that huntingtin containing an expanded polyglutamine tract accumulates in the nucleus and affects gene expression in Huntington disease (HD). Transcriptional dysregulation may also be the major pathological cause in SCA17 in which polyglutamine expansion is present in the TATA binding protein (TBP). HD and SCA17 show similar neurological phenotypes and neuropathology characterized by neurodegeneration in the striatum and cortex, suggesting that both diseases may share a similar pathological mechanism. Although recent studies have shown that mutant huntingtin binds to the transcriptional factors Sp1 and TAF130, the mechanism by which mutant polyglutamine proteins affect gene expression remains to be investigated. Furthermore, it is unclear how the abnormal interactions between mutant polyglutamine proteins and transcription factors contribute to the disease process. We hypothesize that soluble polyglutamine proteins interfere with gene expression by altering the interactions between transcription factors and their DNA targets before the formation of large nuclear inclusions. To test this hypothesis, we will (1) study how mutant N-terminal huntingtin abnormally binds to Sp1 to affect gene expression, (2) investigate whether polyglutamine expansion causes TBP to abnormally bind to the TATA box and its associated factors, and (3) examine whether polyglutamine expansion causes TBP and huntingtin to abnormally bind to the transcriptional factor TAF130, leading to a common transcriptional defect that may contribute to the similar neuropathology in HD and SCA17. These studies aim to provide insights into the mechanism by which polyglutamine expansion affects gene expression. They will also help identify a therapeutic target for the treatment of polyglutamine diseases
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Project Title: PROSPECTIVE NEUROIMAGING IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Rosas, Herminia D.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Huntington's disease (HD) is a devastating autosomal dominant progressive neurodegenerative disorder. New therapies are being developed to slow disease progression or to delay its onset. Testing these compounds clinically is a major challenge because there are limited numbers of potential subjects either genetically at-risk for HD or already symptomatic. Currently, therapeutic trials in HD rely on clinical measures of diagnosis and progression, which are quite variable and also change relatively slowly and thus require large numbers of subjects and long periods of follow-up. There is a critical need to develop surrogate markers, such as neuroanatomic measures, which more precisely correlate with progression than variable clinical measures or which may be predictive of onset. Neuroimaging technology provides a way to prospectively examine the HD brain in vivo. We have developed novel neuro-imaging technologies that enable us to obtain highly accurate, reliable, and rapid morphometric measurements of progressive regional atrophy occurring in the entire brain. We have preliminary evidence that regional brain atrophy occurs in genepositive presymptomatic individuals, permitting its detection and longitudinal assessment even before HD can be diagnosed clinically. By the time of diagnosis, atrophy is apparent in many cortical and subcortical regions and appears to occur in particular patterns, which likely correspond to the appearance of specific clinical features of the disease. Our data challenges the traditional focus on basal ganglia degeneration in HD, provides evidence for earlier and more extensive involvement of many additional brain regions, and greatly enriches the potential for brain imaging to help elucidate the structural basis of symptoms while providing relevant biological markers for response to neuroprotective therapies that can be tested in both symptomatic and presymptomatic patients. We propose to perform a prospective, longitudinal neuro-imaging study of presymptomatic and symptomatic individuals with HD to fully characterize the regional and progressive changes that occur throughout the disease. We will determine the sensitivity and reliability of our morphometric measures as surrogate markers of disease onset and disease progression in comparison to standard clinical measures to determine their potential as surrogate markers.
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Project Title: RAAV-MEDIATED KNOCKDOWN FOR HUNTINGTON'S DISEASE Principal Investigator & Institution: Mandel, Ronald J.; Associate Professor; Neuroscience; University of Florida 219 Grinter Hall Gainesville, Fl 32611 Timing: Fiscal Year 2006; Project Start 01-FEB-2006; Project End 31-JAN-2011 Summary: (provided by applicant): Huntington's disease (HD) is an autosomal dominantly inherited progressive neurological disorder. The neuropathological symptoms appear to be caused by progressive dysfunction and death of neostriatal neurons and/or the cortico-striatal tract. The HD gene was first described in 1993 and the gene defect was identified as an expansion of a series of CAG repeats above a threshold level in exon 1 of a gene encoding a protein called huntingtin. Subsequently, similar repeat expansions have been identified in eight other genes that are known to cause different neurological disorders when the trinucleotide expansions reach thresholds typical for each disease. These different disorders are also conceptually linked because, like HD, symptoms are caused by the dysfunction of specific neurons in the CNS. Moreover, in all CAG expansion mutation-induced disorders, the mutant
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protein seems to induce abnormal nuclear protein aggregations termed neuronal intranuclear inclusions. In HD, the best data seem to indicate that both a toxic gain of function and a loss of some normal function in the mutant form of huntingtin lead to neuropathology. Thus, our proposal aims to use recombinant adeno-associated viral vectors to deliver genes encoding constructs to knock-down huntingtin in striatal neurons. Long-term knock-down of striatal huntingtin will test the hypothesis that reduced huntingtin expression should limit the formation of neuronal Intranuclear inclusions in transduced neurons and thereby slow disease progression in mouse models of HD. We will use both RNA-cleaving enzymes called ribozymes and small interfering RNAs (siRNAs) to knock-down huntingtin in striatal neurons. Moreover, we propose two ways to test the hypothesis that normal huntingtin expression is beneficial. First, we will compare the effects of huntingtin knock-down in both knock-in HD mice and transgenic HD mice. Since transgenic HD mice still express the normal amount of mouse huntingtin, our hypothesis would predict that huntingtin knock-down will be more beneficial in the transgenic mice compared to the knock-in HD mice that have only mutant huntingtin expression. Second, we will simultaneously deliver the vectors that knock-down striatal huntingtin with a vector that expresses a version of huntingtin that is engineered to be resistant to either the ribozymes or the interfering RNA in the knockin animals as a more clinically relevant test of our hypothesis. We will use reduction in the amount of striatal neuronal nuclear inclusions and inhibition of known transcriptional changes as our initial screen for beneficial effects followed by detailed functional analysis of motor behavior as metric of success of this strategy. •
Project Title: RECEPTOR GENE TRANSCRIPTION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Cha, Jang-Ho J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 12-AUG-1999; Project End 30-APR-2009 Summary: (provided by applicant): Huntington's disease is a progressive neurodegenerative disease for which no effective treatment exists. Transcriptional dysregulation is now considered to be an important mechanism in the pathogenesis of Huntington's disease (HD) and other polyglutamine diseases. Alteration of mRNA populations, including those encoding for neurotransmitter receptors, is a hallmark of murine and cellular models of HD as well as human HD. Although numerous studies have confirmed that mRNA populations are altered in HD models, the mechanism underlying such changes remains unknown. Transcription factors, including specificity protein 1 (Sp1), have been implicated in HD pathogenesis, but the role of altered Sp1 function in producing mRNA alterations has not been answered. In this application, we take advantage of a well-described set of gene alterations--those occurring in neurotransmitter receptors--as a starting point for determining the molecular mechanisms of transcriptional dysregulation. We propose a series of hypotheses that will yield critical mechanistic insight into the processes that alter mRNA populations and cause disease pathogenesis. Specific Aim 1 will test the hypothesis that mutant huntingtin selectively alters the association of Sp1 with the promoters of genes that are downregulated in HD. Chromatin Immunoprecipitation (CHIP) assays will assess the degree of Sp1-gene binding in cellular, murine and human HD tissues. Specific Aim 2 will test the hypothesis that decreased Sp1 binding to selected gene promoters causes HD phenotypes. Sp1 levels will be manipulated through RNA interference, dominant negative constructs and overexpression, and the effects of these manipulations on mRNA and cellular toxicity will be assessed. Specific Aim 3 tests the hypothesis that interference in Sp 1 function by huntingtin causes abnormal histone modification. Histone modifications will be examined in mouse and cell models of HD. Taken
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together, these proposed experiments will systematically address several key molecular loci of potential damage by mutant huntingtin. Such fundamental mechanistic information is critical to the eventual development of effective therapy for HD. •
Project Title: REGULATION OF POLYGLUTAMINE AGGREGATION AND TOXICITY Principal Investigator & Institution: Diamond, Marc I.; Assistant Professor; Cellular & Molecular Pharmacology; University of California San Francisco 3333 California St., Ste. 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2006; Project Start 15-JAN-2006; Project End 31-DEC-2009 Summary: (provided by applicant): Polyglutamine neurodegenerative diseases are a devastating family of inherited disorders that include Huntington Disease and spinobulbar muscular atrophy (SBMA). Long-term goals of this project are to identify molecular mechanisms of polyglutamine neurodegenerative disease, to determine specific therapeutic targets, and to develop mechanism-based therapies. Previous work demonstrated that Y-27632, an inhibitor of the rho-associated kinase p160ROCK, reduced polyglutamine aggregation and toxicity in cell and Drosophila models. Aim 1: Identify and characterize novel regulatory pathways and target molecules. We will complete a screen of a library of biologically active small molecules. We will also analyze hits from two prior screens of biologically active compounds. Results will be analyzed in a systematic fashion using a combination of genetic and pharmacologic approaches to determine new pathways of potential significance. Aim 2: Determine the molecular mechanism by which p160ROCK signaling influences polyglutamine aggregation and toxicity. The role of specific components of the p160ROCK signaling pathway will be tested in Drosophila. The molecular basis of polyglutamine protein association with actin will be tested, and its role in modulating polyglutamine aggregation determined. Aim 3: Test the activity of Y-27632 in preventing neurodegeneration in vivo. Bioactivity of Y-27632 in brain, and systemic toxicity shall be determined in order to plan an appropriate dosing regimen. Y-27632 inhibition of polyglutamine-dependent pathology in vivo shall be tested using a variety of behavior, rotarod, pathological and biochemical analyses in the R6/2 mouse model of Huntington's disease.
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Project Title: RNAI FOR HUNTINGTON'S DISEASE Principal Investigator & Institution: Davidson, Beverly L.; Roy J. Carver Professor in Internal Medi; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2005; Project Start 01-DEC-2004; Project End 30-NOV-2009 Summary: This project is focused on the development of RNAi as therapy for HD. We previously demonstrated the ability of RNAi to silence a disease allele in an animal model of a related neurogenetic disease, Spinocerebellar ataxia type 1, resulting in improved behavior and neuropathology. We will now test several specific hypotheses regarding inhibition of mutant htt expression by RNAi: 1) RNAi can protect, and/or reverse, the neuropathology in mouse models of human Huntington's disease. Earlier studies in an HD mouse model with an inducible mutant allele demonstrate that if expression of the disease allele is abrogated, behavior and pathology improve. RNAi for silencing could yield a similar, promising benefit. 2) RNAi targeted to htt cDNA polymorphisms can be utilized for allele-specific silencing of mutant htt. One published disease-linked polymorphism and several novel ones will be tested for their utility to specifically silence the disease allele in cell culture studies. 3) Regulated RNAi can be achieved in vivo, and can be used to address duration of efficacy. HD usually takes
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decades to develop. If RNAi is beneficial it is unlikely that lifelong suppression of expression is required for sustained benefit. Thus we will take advantage of our recently developed regulated RNAi vectors to determine how long RNAi-induced improvements last and whether any problems from expressing RNAi in HD brain resolve once vector-expressed RNAi is reduced. 4) The off target effects of RNAi are minimal and can be resolved by cessation of RNAi. Earlier microarray analyses on HD mice brain from various models have shown that transcriptional changes induced by mutant htt are confined to a circumscribed set of genes. Regulatable vectors allow us to test if off-target effects resolve when shRNAs are no longer expressed. •
Project Title: SNRP PROGRAM AT UCC Principal Investigator & Institution: Eterovic, Vesna A.; Professor of Biochemistry; Biochemistry; Universidad Central Del Caribe Bayamon, Pr 009606032 Timing: Fiscal Year 2005; Project Start 30-SEP-1999; Project End 31-AUG-2010 Summary: (provided by applicant): The SNRP-1 Program at UCC is centered around three research topics: norepinephrine modulation of sensitization to cocaine, neuroprotection by nicotine and tobacco cembranoids, and cembranoid mechanism of action on nicotinic receptors. A Natural Products Core provides tobacco and marine cembranoids, both known and new. Each project is performed in collaboration with a collaborator from a research-intensive institution: UCLA, Cornell U. (Ithaca) and the Vollum Institute (OHSU). SNRP-1 was funded since October 1999. Four RO1 proposals were presented to the NIH during the third year, three of which are now in the process of re-submission. Thirty nine manuscripts were published in peer-reviewed journals. Among the scientific discoveries reported, we would like to mention the following: 1) Noradrenergic transmission through alpha-2 receptors mediates some of the inhibitory effects of cocaine in the prefrontal cortex. 2) Both nicotine and tobacco cembranoids protect the hippocampal slice from NMDA-induced excitotoxicity, but the signal transduction pathways are different. 3) Cembranoids are nicotinic antagonists whose inhibitory action can be released by certain cocaine derivatives. We now propose to continue this successful program for a second cycle of five years. Three new scientists will address the issues of oxidative damage in Huntington disease, direct effects of thyroid hormones on the nAChR and on synapse remodelling, and modulation of potassium channels by spermine. Collaborators are from Washington University and UCLA. Program activities include seminars, courses, travel, etc. A transition plan from SNRP-1 to RO1 funding, is proposed for the present investigators. A plan to attract Puerto Rican Ph.Ds to postdoctoral positions with SNRP scientists at UCC is also presented.
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Project Title: SYNAPTIC TOXICITY OF HUNTINGTON DISEASE PROTEIN Principal Investigator & Institution: Li, Xiao-Jiang; Professor; Human Genetics; Emory University 1784 North Decatur Road, Suite 510 Atlanta, Ga 30322 Timing: Fiscal Year 2007; Project Start 01-MAY-2001; Project End 28-FEB-2012 Summary: (provided by applicant): Polyglutamine (polyQ) expansion causes selective neurodegeneration in nine inherited neurological disorders despite the widespread expression of the disease proteins. The unique neuronal structure, which is characterized by numerous neuronal processes that interact with each other at their terminals, may confer the preferential vulnerability to expanded polyQ proteins. In Huntington disease mice that precisely and genetically mimic the expression of fulllength mutant huntingtin (htt) in HD patients, degraded N- terminal fragments of htt preferentially form aggregates in striatal neurons that are most affected in Huntington's
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disease. Interestingly, these aggregates are predominantly present in the nuclei and neuronal processes and reside in presynaptic and postsynaptic terminals, consistent with the idea that the nucleus and nerve terminals are primary sites to be affected by the disease. This application will focus on mutant htt in axons and nerve terminals and aims to provide mechanistic insight into why mutant htt preferentially accumulates in nerve terminals and how it affects neuronal function. We hypothesize that the intracellular capacity of nerve terminals to clear misfolded polyQ proteins is more likely to decrease with age, leading to the accumulation of mutant htt in axons and their terminals. The increased accumulation of mutant htt then leads to abnormal protein interactions and neuronal dysfunction by affecting vesicular or protein trafficking. Since polyQ proteins are found to impair the proteasomal activity, it is also possible that mutant htt in nerve terminals affects the proteasome to mediate synaptic toxicity. We propose three Aims to test these hypotheses. In Aim-1, we will generate the proteasomal activity reporters that are specifically targeted to presynaptic and postsynaptic terminals for examining whether the activity of presynaptic and postsynaptic proteasome is lower than that in the cell body and is preferentially reduced by aging. In Aim-2, we will examine whether mutant htt affects proteasomal activity in nerve terminals of cultured neurons and in HD mouse brains. In Aim-3, we will investigate whether mutant htt affects actindependent vesicular secretion and neurotransmitter release, which are important for synaptic vesicular exocytosis and transmission. These studies will help understand the mechanism for the selective neurodegeneration in Huntington's disease and find the strategy to treat the early and specific neuropathology in Huntington's disease. •
Project Title: THE ROLE OF NFKB IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Patterson, Paul H.; None; California Institute of Technology Office of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125 Timing: Fiscal Year 2005; Project Start 01-JUN-2003; Project End 30-NOV-2006 Summary: (provided by applicant): Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. Mutant Htt forms intracellular aggregates and is cytotoxic to specific neurons in the striatum and cortex. Causes of cell death in HD include the activation of cell death genes and/or alteration of normal transcription. The objective of this proposal is to investigate how mutant Htt interacts with NF-kappaB signaling pathway. This pathway regulates expression of pro-survival genes, is central to the function of neurotrophic factors and cytokines, and is activated during excitotoxic cell death mediated by NMDA receptors. We are investigating the interaction of mutant Htt with the IkappaB kinase (IKK) complex that regulates NF-kappaB, and how this affects neuronal responses to extracellular signals. We will focus on the mechanism of how the direct interaction between mutant Htt and IKKgamma, a regulatory component of IKK, influences neurodegeneration in HD. Molecular, cell culture, brain slice and animal model approaches will help to explore the nature and consequence of this interaction. We have preliminary evidence that IKKgamma influences NF- kappaB-regulated neuronal gene expression, as well as mutant Htt-induced cell death and aggregation. (i) Using in vitro and cellular assays, we are mapping the domains in mutant Htt and IKKgamma that mediate their binding. (ii) The functional consequences of Htt-IKKgamma interaction are assessed by isolating IKK complex from mutant and normal Htt-expressing cultured cells and HD transgenic mouse brain. Its kinase activity and ability to regulated NFkappaB mediated gene expression is then tested using in vitro kinase and gene reporter assays. (iii) Downstream genes influenced by the Htt-IKKgamma interaction will be identified by cDNA mini-arrays. mRNA will be isolated from several brain regions from HD and normal mice. (iv) The influence of IKKgamma on mutant Htt-induced cell death
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and aggregation is being examined in HD transgenic mice and in PC12 cells that inducibly express Htt and/or IKKgamma. We have constructed lentiviral vectors expressing a dominant negative form of IKKgamma as well as cell permeable peptides that block IKKgamma activity in cells. These reagents will be injected into the brains of HD mice in tests of their efficacy in inhibiting mutant Htt toxicity and aggregation. They will also be tested on brain slices from HD mice, in the presence and absence of NMDA. •
Project Title: TRANSGENIC MOUSE MODELS OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Levine, Michael S.; Professor; Mental Retardation Res Center; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2005; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): This proposal will examine cellular mechanisms underlying the dysfunctions detected in Huntington's disease (HD) using four different murine models. The lethal mutation in HD produces an expanded trinucleotide (GAG) repeat within the protein huntingtin. It causes selective neurodegeneration especially in the striatum and cortex, by an unidentified mechanism. Each of the HD models we will examine exhibits a different phenotype produced by unique transgene constructs or 'knocked-in" GAG repeat lengths. By evaluating multiple models we will be able to examine the dysfunctions in more detail and understand the specificity and sequence of physiological changes common to HD and the models. Based on our preliminary studies, we have uncovered several common cellular deficits in two models. These are enhanced responsiveness of N-methyl-D-aspartate (NMDA) receptors in the striatum associated with increased Ca2+ flux, a marked decrease in K+ conductances and a change in the corticostriatal synaptic response. A third model also displays the enhanced response to NMDA. Some of these changes potentially predispose striatal medium-sized spiny neurons to excitotoxic damage. Using a physiological approach, we will examine four hypotheses concerning the cellular mechanisms of dysfunction in HD: 1) alterations in ionotropic glutamate receptor function and changes in evoked and spontaneous excitatory synaptic inputs to striatal neurons 2) alterations in metabotropic glutamate and dopaminergic receptor modulation of ionotropic glutamate receptor function, 3) alterations in K+ conductances and 4) alterations in Ca2+ conductances. The precise onset of changes will be investigated in relationship to the expression of behavioral deficits by using animals that are presymptomatic or after development of overt motor signs. We will examine striatal and corticostriatal neurons, visualized in the slice preparation or acutely dissociated cells, to characterize basic functions by currentand voltage-clamp analyses. Because HD destroys so many different capabilities intellectual, physical and emotional - the insights gained from this research elucidating the cellular malfunctions in HD are relevant to understanding other GAG repeat disorders and neurological diseases associated with protein aggregate pathologies like Alzheimer's and Parkinson's disease.
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Project Title: YEAST MODEL FOR TWO NEURODEGENERATION-LINKED PROTEINS Principal Investigator & Institution: Debburman, Shubhik Kumar.; Biology; Lake Forest College 555 N Sheridan Rd Lake Forest, Il 60045 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 30-APR-2007 Summary: (provided by applicant): Budding Yeast (S. cerevisiae) has emerged as a powerful model system for understanding molecular aspects of many human diseases. Protein misfolding linked to certain neurodegenerative diseases (NDDs) like
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Huntington Disease, Lou Gehrig's disease, and prion diseases have been successfully recapitulated in S. cerevisiae and led to identification of therapeutically relevant regulators of misfolding. No S. cerevisiae models for Parkinson's Disease (PD) or dentatorubral pallidoluysian atrophy (DRPLA) have been reported. PD is one of the most common NDDs, while DRPLA is a rare inherited NDD of the triplet repeat disease family. In both diseases, misfolding of a specific protein (alpha-synuclein for PD and atrophin for DRPLA) is thought to cause selective neuronal death. Unlike the wellcharacterized huntingtin protein in Huntington Disease (which shares many similarities to DRPLA), less is known about the misfolding of mutant atrophin in DRPLA. A S. cerevisiae expression system for studying alpha-synuclein has recently been developed in our lab. Preliminary evidence supports that both wildtype and disease-associated mutants are aggregating within yeast cells and upon purification. A similar effort to establish atrophin-1 expression in yeast is underway. To extend initial observations with alpha-synuclein in yeast and fully develop a yeast model for atrophin, three goals are proposed. 1) Misfolding properties between wildtype and mutant versions of both proteins will be investigated in vivo (immunofluorescence and GFPbased localization and assessment of protein half-life) and in vitro (by measuring protease sensitivity and differential solubility). 2) Influences of chaperones and ubiquitin-proteasomal pathway proteins on folding and degradation of these proteins will be assessed in strains compromised for chaperone/proteasomal function, or those that overexpress chaperones, and by co-immunoprecipitation assessment. 3) A fission yeast (S. pombe) expression model for alpha-synuclein and atrophin properties (as in Aim 1) will be developed and compared with the S. cerevisiae model; NDD models have not been reported in S. pombe. These studies may further clarify the molecular bases for misfolding and degradation of PD- and DRPLA-linked proteins and extend the usefulness of yeast models. Importantly, the scientific training of many undergraduates will be supported, strengthening their cell biology and molecular genetics skills and appreciation for model organisms. NTIS (National Technical Information Service) The NTIS (www.ntis.gov), a service of the U.S. Department of Commerce, has published the following information on sponsored studies related to Huntington disease: •
"Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders. - Annual rept. 1 May 2001-30 Apr 2002," published in May 2002. Sponsored by: Cornell Univ. Medical Coll., New York. Written by: S. E. Brown. Abstract: This project aimed to determine the contributions of bioenergetic dysfunction and oxidative stress to neurodegeneration in Huntington's Disease (HE) and amyotrophic lateral sclerosis (ALS). We found elevations in cerebral glucose utilization in two distinctly different mutant mouse models of HD: Hdh(Q92) and N171-82Q. Hypermetabolism preceded pathologic changes and symptoms, but was not accompanied by alterations in oxidative phosphorylation enzyme activities. We also found late increases in oxidative damage to DNA -and lipids in R6/2 and N171-82Q HD mice. Another approach to model HD is to inhibit mitochondrial complex II using the neurotoxin 3-nitropropionic acid (3-NP). In contrast to genetic models, reductions in glucose use following 3- NP coincided with neuronal loss, suggesting a different sequence of pathologic events in this model. In a model of ALS, G93A mice, we also
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found early metabolic changes preceding neuronal pathology and symptom onset. Reduced glucose utilization in brain and spinal cord at 60 days of age was concomitant with increased mitochondrial complex I activity and depletions in ATP levels. Elevated free radical generation was evident by 90 days. Results clearly demonstrate the early involvement of metabolic changes in the pathologic events initiated by expression of the mutant disease gene in ALS and HD models. •
"New imaging systems in nuclear medicine. Technical progress report," published in 1991. Abstract: We continue to use and maintain PCR-I, the single-slice high- resolution highsensitivity positron emission tomograph, while development proceeds on PCR-II, a three-dimensional PET system. A two-dimensional BGO scintillation detector has been designed and we are nearing completion of the detector, including the light guide, crystals and phototube assembly, and the gantry electronics. We are currently exploring techniques for a very high resolution (sub-mm) PET imaging system. We are using the current PCR-I system to assess changes in presynaptic dopamine receptors and glucose utilization in current biological models of Huntington's Disease. Our preliminary studies support the use of the primate (Cynomolgus monkey) model of Huntington's Disease to monitor in vivo functional changes. We are planning to extend this study to examine the MPTP model of Parkinson disease, and to assess the therapeutic value of D(sub 1) dopamine receptor agonists for treatment of MPTP-induced neurological defects. 13 refs., 5 figs.
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"Protective Mechanisms Against Apoptic Neurodegeneration in the Substantia Nigra. - Annual rept. 1 Sep 2000-31 Aug 2001," published in September 2001. Sponsored by: Massachusetts Univ. Medical Center, Worcester. Written by: N. Aronin. Abstract: The goal in this proposal is to understand mechanisms by which neurotoxicity destroys cells in the substantia nigra Our hypothesis is that c- JUN kinases (JNK), which is a set of enzymes known to participate in death of neurons, mediates neurodegeneration in the substantia nigra after exposure to MPTP or glutamate excitotoxicity. Spurred by the DoD meeting in Potomac, 2001, I have extended our research in Parkinson's disease to include new strategies to improve survival of stem cells in mammalian brain. We also modified our protocol for MPTP neurotoxicity after ad hoc reviews of our data at the DoD meeting. Results in year 3 of our proposal indicated that mice lacking JNK 1 or JNK 3 lack neuroprotection against MPTP neurotoxicity, as measured by loss of tyrosine hydroxylase labeled neurons. The changes in protocol made our results more robust and reproducible, compared to the former protocol. Results favored an apoptotic pathway where JNK activity is proximal to mitochondrial initiation of apoptosis. Our group reported a role for p38 and not JNK as a target of MAP kinase apoptosis after nerve growth factor withdrawal. Mutant Huntington gene causes striatal neurons to have increased responsiveness to NMDA receptor activation. Caspase 3, a key enzyme for transducing apoptotic signals, cleaves mutant Huntington in cells transfected with Huntington cDNA and in Huntington's Disease brain. Pilot results show that intravenously injected, bone-marrow derived stem cells form neuron-like cells in mice genetically engineered to accept transplanted tissues. In year 4, we will submit manuscripts on neuroprotection of JNK knockout mice for MPTP, the role of AP-1 transcription in this paradigm, and neurotoxicity of quinolinic acid in JNK knockout and Huntington's Disease mouse models. We will initiate studies to improve stem cell transplantation in mouse brains after neurotoxic lesions.
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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.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with Huntington disease, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type Huntington disease (or synonyms) into the search box, and click Go. The following is the type of output you can expect from PubMed for Huntington disease (hyperlinks lead to article summaries): •
A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. Author(s): Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, Dode C, Morrison PJ, Suchowersky O, Ross CA, Margolis RL, Rosenblatt A, Gomez-Tortosa E, Cabrero DM, Novelletto A, Frontali M, Nance M, Trent RJ, McCusker E, Jones R, Paulsen JS, Harrison M, Zanko A, Abramson RK, Russ AL, Knowlton B, Djousse L, Mysore JS, Tariot S, Gusella MF, Wheeler VC, Atwood LD, Cupples LA, Saint-Hilaire M, Cha JH, Hersch SM, Koroshetz WJ, Gusella JF, MacDonald ME, Myers RH. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12900792&query_hl=8&itool=pubmed_docsum
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A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Author(s): Giorgini F, Guidetti P, Nguyen Q, Bennett SC, Muchowski PJ. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15806102&query_hl=8&itool=pubmed_docsum
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A hereditary disorder in the family and the family life cycle: Huntington disease as a paradigm. Author(s): Brouwer-Dudokdewit AC, Savenije A, Zoeteweij MW, Maat-Kievit A, Tibben A. Source: Family Process. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12613124&query_hl=8&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 Huntington disease-like neurodegenerative disorder maps to chromosome 20p. Author(s): Xiang F, Almqvist EW, Huq M, Lundin A, Hayden MR, Edstrom L, Anvret M, Zhang Z. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9792871&query_hl=8&itool=pubmed_docsum
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A novel PCR-based approach for the detection of the Huntington disease associated trinucleotide repeat expansion. Author(s): Panagopoulos I, Lassen C, Kristoffersson U, Aman P. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10090478&query_hl=8&itool=pubmed_docsum
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A randomized trial of amantadine in Huntington disease. Author(s): O'Suilleabhain P, Dewey RB Jr. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12873857&query_hl=8&itool=pubmed_docsum
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A recurrent expansion of a maternal allele with 36 CAG repeats causes Huntington disease in two sisters. Author(s): Laccone F, Christian W. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10712225&query_hl=8&itool=pubmed_docsum
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A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Author(s): Holmes SE, O'Hearn E, Rosenblatt A, Callahan C, Hwang HS, IngersollAshworth RG, Fleisher A, Stevanin G, Brice A, Potter NT, Ross CA, Margolis RL. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11694876&query_hl=8&itool=pubmed_docsum
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A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease. Author(s): Almqvist EW, Bloch M, Brinkman R, Craufurd D, Hayden MR. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10205260&query_hl=8&itool=pubmed_docsum
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Accurate determination of the number of CAG repeats in the Huntington disease gene using a sequence-specific internal DNA standard. Author(s): Bruland O, Almqvist EW, Goldberg YP, Boman H, Hayden MR, Knappskog PM. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10334474&query_hl=8&itool=pubmed_docsum
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Accurate sizing of (CAG)n repeats causing Huntington disease by fluorescent PCR. Author(s): Toth T, Findlay I, Nagy B, Papp Z. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9439466&query_hl=8&itool=pubmed_docsum
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Adults seeking presymptomatic gene testing for Huntington disease. Author(s): Williams JK, Schutte DL, Evers CA, Forcucci C. Source: Image--The Journal of Nursing Scholarship. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10380384&query_hl=8&itool=pubmed_docsum
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Adverse effects of predictive testing for Huntington disease underestimated: longterm effects 7-10 years after the test. Author(s): Timman R, Roos R, Maat-Kievit A, Tibben A. Source: Health Psychology : Official Journal of the Division of Health Psychology, American Psychological Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15008664&query_hl=8&itool=pubmed_docsum
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Age at onset of Huntington disease is not modulated by the R72P variation in TP53 and the R196K variation in the gene coding for the human caspase activated DNase (hCAD). Author(s): Arning L, Kraus PH, Saft C, Andrich J, Epplen JT. Source: Bmc Medical Genetics [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16202123&query_hl=8&itool=pubmed_docsum
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Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. Author(s): Kehoe P, Krawczak M, Harper PS, Owen MJ, Jones AL. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10051007&query_hl=8&itool=pubmed_docsum
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Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington disease gene. Author(s): Cha JH, Kosinski CM, Kerner JA, Alsdorf SA, Mangiarini L, Davies SW, Penney JB, Bates GP, Young AB. 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=9600992&query_hl=8&itool=pubmed_docsum
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Americo Negrette (1924 to 2003): diagnosing Huntington disease in Venezuela. Author(s): Okun MS, Thommi N. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15277631&query_hl=8&itool=pubmed_docsum
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An electrophysiological analysis of altered cognitive functions in Huntington disease. Author(s): Munte TF, Ridao-Alonso ME, Preinfalk J, Jung A, Wieringa BM, Matzke M, Dengler R, Johannes S. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9311352&query_hl=8&itool=pubmed_docsum
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Analysis of gait abnormalities in Huntington disease. Author(s): Reynolds NC Jr, Myklebust JB, Prieto TE, Myklebust BM. 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=9915373&query_hl=8&itool=pubmed_docsum
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Ancient origin of the CAG expansion causing Huntington disease in a Spanish population. Author(s): Garcia-Planells J, Burguera JA, Solis P, Millan JM, Ginestar D, Palau F, Espinos C. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15832309&query_hl=8&itool=pubmed_docsum
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Assessing genetic effects in survival data by correlating martingale residuals with an application to age at onset of Huntington disease. Author(s): Wintrebert CM, Zwinderman AH, Maat-Kievit A, Roos RA, van Houwelingen HC. Source: Statistics in Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16416406&query_hl=8&itool=pubmed_docsum
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Association between BDNF Val66Met polymorphism and age at onset in Huntington disease. Author(s): Alberch J, Lopez M, Badenas C, Carrasco JL, Mila M, Munoz E, Canals JM. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16186551&query_hl=8&itool=pubmed_docsum
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At risk for Huntington disease: The PHAROS (Prospective Huntington At Risk Observational Study) cohort enrolled. Author(s): Huntington Study Group PHAROS Investigators. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16831969&query_hl=8&itool=pubmed_docsum
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Awareness of involuntary movements in Huntington disease. Author(s): Snowden JS, Craufurd D, Griffiths HL, Neary D. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9626771&query_hl=8&itool=pubmed_docsum
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Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. Author(s): Sapp E, Penney J, Young A, Aronin N, Vonsattel JP, DiFiglia M. Source: Journal of Neuropathology and Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10029099&query_hl=8&itool=pubmed_docsum
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Basal ganglia volume and proximity to onset in presymptomatic Huntington disease. Author(s): Aylward EH, Codori AM, Barta PE, Pearlson GD, Harris GJ, Brandt J. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8970459&query_hl=8&itool=pubmed_docsum
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Behavioral changes in Huntington Disease. Author(s): Craufurd D, Thompson JC, Snowden JS. Source: Neuropsychiatry, Neuropsychology, and Behavioral Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11725215&query_hl=8&itool=pubmed_docsum
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Bicaudate index in computerized tomography of Huntington disease and cerebral atrophy. Author(s): Barr AN, Heinze WJ, Dobben GD, Valvassori GE, Sugar O. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=152416&query_hl=8&itool=pubmed_docsum
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Brain-derived neurotrophic factor in Huntington disease. Author(s): Ferrer I, Goutan E, Marin C, Rey MJ, Ribalta T. Source: Brain Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10825501&query_hl=8&itool=pubmed_docsum
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Bromocriptine and dopaminergic function in Huntington disease. Author(s): Loeb C, Roccatagliata G, Albano C, Besio G. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=155784&query_hl=8&itool=pubmed_docsum
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Canadian experience with predictive testing for Huntington disease: lessons for genetic testing centers and policy makers. Author(s): Chapman MA. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1535176&query_hl=8&itool=pubmed_docsum
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Capucin: a novel striatal marker down-regulated in rodent models of Huntington disease. Author(s): de Chaldee M, Brochier C, Van de Vel A, Caudy N, Luthi-Carter R, Gaillard MC, Elalouf JM. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16359841&query_hl=8&itool=pubmed_docsum
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Cerebrospinal fluid levels of orexin-A are not a clinically useful biomarker for Huntington disease. Author(s): Bjorkqvist M, Petersen A, Nielsen J, Ecker D, Mulder H, Hayden MR, Landwehrmeyer B, Brundin P, Leavitt BR. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16813610&query_hl=8&itool=pubmed_docsum
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Characteristics of individuals with Huntington disease in long-term care. Author(s): Nance MA, Sanders G. Source: Movement Disorders : Official Journal of the Movement Disorder Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8866495&query_hl=8&itool=pubmed_docsum
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Characterization and localization of the Huntington disease gene product. Author(s): Hoogeveen AT, Willemsen R, Meyer N, de Rooij KE, Roos RA, van Ommen GJ, Galjaard H. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8111375&query_hl=8&itool=pubmed_docsum
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Chromosome mapping of the rod photoreceptor cGMP phosphodiesterase betasubunit gene in mouse and human: tight linkage to the Huntington disease region (4p16.3). Author(s): Altherr MR, Wasmuth JJ, Seldin MF, Nadeau JH, Baehr W, Pittler SJ. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1315306&query_hl=8&itool=pubmed_docsum
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Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease. Author(s): Anderson KD, Panayotatos N, Corcoran TL, Lindsay RM, Wiegand SJ. 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=8692996&query_hl=8&itool=pubmed_docsum
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Clinical characteristics of childhood-onset (juvenile) Huntington disease: report of 12 patients and review of the literature. Author(s): Gonzalez-Alegre P, Afifi AK. Source: Journal of Child Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16901424&query_hl=8&itool=pubmed_docsum
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Clinical deficits in Huntington disease correlate with reduced striatal uptake on iodine-123 epidepride single-photon emission tomography. Author(s): Leslie WD, Greenberg CR, Abrams DN, Hobson D. Source: European Journal of Nuclear Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10552088&query_hl=8&itool=pubmed_docsum
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Cloning and mapping of the alpha-adducin gene close to D4S95 and assessment of its relationship to Huntington disease. Author(s): Goldberg YP, Lin BY, Andrew SE, Nasir J, Graham R, Glaves ML, Hutchinson G, Theilmann J, Ginzinger DG, Schappert K, et al. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1284592&query_hl=8&itool=pubmed_docsum
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Cloning of the Huntington disease region in yeast artificial chromosomes. Author(s): Zuo J, Robbins C, Taillon-Miller P, Cox DR, Myers RM. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1303170&query_hl=8&itool=pubmed_docsum
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Cognitive and psychiatric aspects of Huntington disease contribute to functional capacity. Author(s): Nehl C, Paulsen JS; Huntington Study Group. 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=14718780&query_hl=8&itool=pubmed_docsum
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Cognitive manifestations of Huntington disease in relation to genetic structure and clinical onset. Author(s): Jason GW, Suchowersky O, Pajurkova EM, Graham L, Klimek ML, Garber AT, Poirier-Heine D. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9311351&query_hl=8&itool=pubmed_docsum
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Comparative semi-automated analysis of (CAG) repeats in the Huntington disease gene: use of internal standards. Author(s): Williams LC, Hegde MR, Herrera G, Stapleton PM, Love DR. Source: Molecular and Cellular Probes. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10441201&query_hl=8&itool=pubmed_docsum
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Confirmation of subtle motor changes among presymptomatic carriers of the Huntington disease gene. Author(s): Kirkwood SC, Siemers E, Bond C, Conneally PM, Christian JC, Foroud T. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10891987&query_hl=8&itool=pubmed_docsum
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Construction of cosmid contigs and high-resolution restriction mapping of the Huntington disease region of human chromosome 4. Author(s): Zuo J, Robbins C, Baharloo S, Cox DR, Myers RM. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8364572&query_hl=8&itool=pubmed_docsum
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Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses. Author(s): Chong SS, Almqvist E, Telenius H, LaTray L, Nichol K, Bourdelat-Parks B, Goldberg YP, Haddad BR, Richards F, Sillence D, Greenberg CR, Ives E, Van den Engh G, Hughes MR, Hayden MR. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9063751&query_hl=8&itool=pubmed_docsum
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Couples' experiences of predictive testing and living with the risk or reality of Huntington disease: a qualitative study. Author(s): Richards F. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15057982&query_hl=8&itool=pubmed_docsum
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Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. Author(s): Borrell-Pages M, Canals JM, Cordelieres FP, Parker JA, Pineda JR, Grange G, Bryson EA, Guillermier M, Hirsch E, Hantraye P, Cheetham ME, Neri C, Alberch J, Brouillet E, Saudou F, Humbert S. Source: The Journal of Clinical Investigation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16604191&query_hl=8&itool=pubmed_docsum
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Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates. Author(s): Kotliarova S, Jana NR, Sakamoto N, Kurosawa M, Miyazaki H, Nekooki M, Doi H, Machida Y, Wong HK, Suzuki T, Uchikawa C, Kotliarov Y, Uchida K, Nagao Y, Nagaoka U, Tamaoka A, Oyanagi K, Oyama F, Nukina N. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15836623&query_hl=8&itool=pubmed_docsum
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Decreased striatal monoaminergic terminals in Huntington disease. Author(s): Bohnen NI, Koeppe RA, Meyer P, Ficaro E, Wernette K, Kilbourn MR, Kuhl DE, Frey KA, Albin RL. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10802780&query_hl=8&itool=pubmed_docsum
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Delayed amnesic syndrome after riluzole autointoxication in Huntington disease. Author(s): Haaxma CA, Kremer HP, van de Warrenburg BP. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16606937&query_hl=8&itool=pubmed_docsum
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Deranged neuronal calcium signaling and Huntington disease. Author(s): Bezprozvanny I, Hayden MR. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15336977&query_hl=8&itool=pubmed_docsum
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Detection of CAG repeats using silver staining in patients with Huntington disease in Hungary. Author(s): Toth T, Nemeti M, Papp Z. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9182790&query_hl=8&itool=pubmed_docsum
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Diagnosis in Huntington disease. Author(s): Gruenthal M, Olson WL. Source: J Ky Med Assoc. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8064201&query_hl=8&itool=pubmed_docsum
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Diagnosis of Huntington disease. Author(s): Margolis RL, Ross CA. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14500613&query_hl=8&itool=pubmed_docsum
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Diagnosis of Huntington disease: model for a predictive testing program based on understanding the stages of psychological response. Author(s): Nance MA, Ludowese CJ. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7977455&query_hl=8&itool=pubmed_docsum
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Diagnosis of patients presenting to a Huntington disease (HD) clinic without a family history of HD. Author(s): Nance MA, Westphal B, Nugent S. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8960750&query_hl=8&itool=pubmed_docsum
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Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer. Author(s): Goellner GM, Tester D, Thibodeau S, Almqvist E, Goldberg YP, Hayden MR, McMurray CT. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9106534&query_hl=8&itool=pubmed_docsum
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Different phenotypic expression in monozygotic twins with Huntington disease. Author(s): Anca MH, Gazit E, Loewenthal R, Ostrovsky O, Frydman M, Giladi N. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14679593&query_hl=8&itool=pubmed_docsum
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Differential 3' polyadenylation of the Huntington disease gene results in two mRNA species with variable tissue expression. Author(s): Lin B, Rommens JM, Graham RK, Kalchman M, MacDonald H, Nasir J, Delaney A, Goldberg YP, Hayden MR. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7903579&query_hl=8&itool=pubmed_docsum
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Dilemmas of anonymous predictive testing for Huntington disease: privacy vs. optimal care. Author(s): Burgess MM, Adam S, Bloch M, Hayden MR. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9217222&query_hl=8&itool=pubmed_docsum
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Discovering the family history of Huntington disease (HD). Author(s): Etchegary H. Source: Journal of Genetic Counseling. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16541330&query_hl=8&itool=pubmed_docsum
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Distribution of inclusions in neuronal nuclei and dystrophic neurites in Huntington disease brain. Author(s): Maat-Schieman ML, Dorsman JC, Smoor MA, Siesling S, Van Duinen SG, Verschuuren JJ, den Dunnen JT, Van Ommen GJ, Roos RA. Source: Journal of Neuropathology and Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10029096&query_hl=8&itool=pubmed_docsum
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DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Author(s): Squitieri F, Andrew SE, Goldberg YP, Kremer B, Spence N, Zeisler J, Nichol K, Theilmann J, Greenberg J, Goto J, et al. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7881406&query_hl=8&itool=pubmed_docsum
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DNA testing for Huntington disease in the Turkish population. Author(s): Akbas F, Erginel-Unaltuna N. Source: European Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12824708&query_hl=8&itool=pubmed_docsum
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Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Author(s): Kennedy L, Evans E, Chen CM, Craven L, Detloff PJ, Ennis M, Shelbourne PF. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14570710&query_hl=8&itool=pubmed_docsum
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Dysfunction of wild-type huntingtin in Huntington disease. Author(s): Cattaneo E. Source: News in Physiological Sciences : an International Journal of Physiology Produced Jointly by the International Union of Physiological Sciences and the American Physiological Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12531930&query_hl=8&itool=pubmed_docsum
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Dystonia-predominant adult-onset Huntington disease: association between motor phenotype and age of onset in adults. Author(s): Louis ED, Anderson KE, Moskowitz C, Thorne DZ, Marder K. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10987900&query_hl=8&itool=pubmed_docsum
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Early and progressive accumulation of reactive microglia in the Huntington disease brain. Author(s): Sapp E, Kegel KB, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, Bhide PG, Vonsattel JP, DiFiglia M. Source: Journal of Neuropathology and Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11273004&query_hl=8&itool=pubmed_docsum
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Early cognitive and motor symptoms in identified carriers of the gene for Huntington disease. Author(s): de Boo GM, Tibben A, Lanser JB, Jennekens-Schinkel A, Hermans J, MaatKievit A, Roos RA. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9362982&query_hl=8&itool=pubmed_docsum
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Early Huntington disease prenatal diagnosis by maternal semiquantitative fluorescent-PCR. Author(s): Gonzalez-Gonzalez MC, Trujillo MJ, Rodriguez de Alba M, Ramos C. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12682342&query_hl=8&itool=pubmed_docsum
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Early onset Huntington disease: a neuronal degeneration syndrome. Author(s): Seneca S, Fagnart D, Keymolen K, Lissens W, Hasaerts D, Debulpaep S, Desprechins B, Liebaers I, De Meirleir L. Source: European Journal of Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15338298&query_hl=8&itool=pubmed_docsum
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Effect of donepezil on motor and cognitive function in Huntington disease. Author(s): Cubo E, Shannon KM, Tracy D, Jaglin JA, Bernard BA, Wuu J, Leurgans SE. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17030764&query_hl=8&itool=pubmed_docsum
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Effect of laboratory or clerical error on presymptomatic risk calculations for Huntington disease: a simulation study. Author(s): King TM, Brandt J, Meyers DA. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8484402&query_hl=8&itool=pubmed_docsum
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Efficacy of levetiracetam in Huntington disease. Author(s): de Tommaso M, Di Fruscolo O, Sciruicchio V, Specchio N, Cormio C, De Caro MF, Livrea P. Source: Clinical Neuropharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16340384&query_hl=8&itool=pubmed_docsum
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Efficiency of carbamazepine in the treatment of micturitional disturbances in Huntington disease. Author(s): Cochen V, Degos JD, Bachoud-Levi AC. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11134405&query_hl=8&itool=pubmed_docsum
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Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Author(s): Guidetti P, Bates GP, Graham RK, Hayden MR, Leavitt BR, MacDonald ME, Slow EJ, Wheeler VC, Woodman B, Schwarcz R. Source: Neurobiology of Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16697652&query_hl=8&itool=pubmed_docsum
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Energy balance in early-stage Huntington disease. Author(s): Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer CN. 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=15941884&query_hl=8&itool=pubmed_docsum
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Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents in a mouse model of Huntington disease. Author(s): Li L, Murphy TH, Hayden MR, Raymond LA. Source: Journal of Neurophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15240759&query_hl=8&itool=pubmed_docsum
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Errors in Huntington disease diagnostic test caused by trinucleotide deletion in the IT15 gene. Author(s): Gellera C, Meoni C, Castellotti B, Zappacosta B, Girotti F, Taroni F, DiDonato S. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8755937&query_hl=8&itool=pubmed_docsum
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Ethical, social and legal issues in Huntington disease: the nurse's role. Author(s): Rohs G, Klimek ML. Source: Axone. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8715551&query_hl=8&itool=pubmed_docsum
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Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Author(s): Djousse L, Knowlton B, Hayden MR, Almqvist EW, Brinkman RR, Ross CA, Margolis RL, Rosenblatt A, Durr A, Dode C, Morrison PJ, Novelletto A, Frontali M, Trent RJ, McCusker E, Gomez-Tortosa E, Mayo Cabrero D, Jones R, Zanko A, Nance M, Abramson RK, Suchowersky O, Paulsen JS, Harrison MB, Yang Q, Cupples LA, Mysore J, Gusella JF, MacDonald ME, Myers RH. Source: Neurogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15029481&query_hl=8&itool=pubmed_docsum
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Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. Author(s): Portera-Cailliau C, Hedreen JC, Price DL, Koliatsos VE. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7751945&query_hl=8&itool=pubmed_docsum
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Evidence from antibody studies that the CAG repeat in the Huntington disease gene is expressed in the protein. Author(s): Jou YS, Myers RM. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7795604&query_hl=8&itool=pubmed_docsum
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Expansion of a 27 CAG repeat allele into a symptomatic Huntington diseaseproducing allele. Author(s): Kelly TE, Allinson P, McGlennen RC, Baker J, Bao Y. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10528258&query_hl=8&itool=pubmed_docsum
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Exploration of the effects of predictive testing for Huntington disease on intimate relationships. Author(s): Quaid KA, Wesson MK. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7645597&query_hl=8&itool=pubmed_docsum
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Expression of the Huntington disease gene in rodents: cloning the rat homologue and evidence for downregulation in non-neuronal tissues during development. Author(s): Schmitt I, Bachner D, Megow D, Henklein P, Hameister H, Epplen JT, Riess O. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8528205&query_hl=8&itool=pubmed_docsum
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Factors related to onset age of Huntington disease. Author(s): Myers RH, Madden JJ, Teague JL, Falek A. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6211092&query_hl=8&itool=pubmed_docsum
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Failure of aminooxyacetic acid therapy in Huntington disease. Author(s): Perry TL, Wright JM, Hansen S, Allan BM, Baird PA, MacLeod PM. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6446691&query_hl=8&itool=pubmed_docsum
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Failure of isoniazid therapy in Huntington disease. Author(s): McLean DR. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6214730&query_hl=8&itool=pubmed_docsum
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Familial influence on age of onset among siblings with Huntington disease. Author(s): Rosenblatt A, Brinkman RR, Liang KY, Almqvist EW, Margolis RL, Huang CY, Sherr M, Franz ML, Abbott MH, Hayden MR, Ross CA. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11449389&query_hl=8&itool=pubmed_docsum
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Family and molecular data for a fine analysis of age at onset in Huntington disease. Author(s): Squitieri F, Sabbadini G, Mandich P, Gellera C, Di Maria E, Bellone E, Castellotti B, Nargi E, de Grazia U, Frontali M, Novelletto A. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11186892&query_hl=8&itool=pubmed_docsum
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Family intervention in rehabilitation of patient with Huntington disease. Author(s): Power PW. 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=6214236&query_hl=8&itool=pubmed_docsum
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Favourable mutation test outcomes for individuals at risk for Huntington disease change the perspectives of first-degree relatives. Author(s): Bonke B, Tibben A, Lindhout D, Stijnen T. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12215844&query_hl=8&itool=pubmed_docsum
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Few psychological consequences of presymptomatic testing for Huntington disease. Author(s): Bundey S. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8988110&query_hl=8&itool=pubmed_docsum
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Fifteen years of experience in predictive testing for Huntington disease at a single testing center in Victoria, Australia. Author(s): Trembath MK, Tassicker RJ, Collins VR, Mansie S, Sheffield LJ, Delatycki MB. 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=17108758&query_hl=8&itool=pubmed_docsum
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Fine mapping of the Huntington disease linked D4S10 locus by non-radioactive in situ hybridization. Author(s): Landegent JE, Jansen in de Wal N, Fisser-Groen YM, Bakker E, van der Ploeg M, Pearson PL. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2943662&query_hl=8&itool=pubmed_docsum
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Forgotten person in the Huntington disease family. Author(s): Kessler S. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8291568&query_hl=8&itool=pubmed_docsum
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gamma-Aminobutyric acid receptors in normal human brain and Huntington disease. Author(s): Van Ness PC, Watkins AE, Bergman MO, Tourtellotte WW, Olsen RW. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6275305&query_hl=8&itool=pubmed_docsum
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Genetic analysis of Huntington disease in Italy. Author(s): Ajmar F, Mandich P, Bellone E, Abbruzzese G. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1829583&query_hl=8&itool=pubmed_docsum
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Genetic analysis workshop IV: Huntington disease linkage analysis summary. Author(s): Pericak-Vance MA, Meyers DA. Source: Genet Epidemiol Suppl. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2952549&query_hl=8&itool=pubmed_docsum
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Genetic analysis workshop IV: Huntington disease linkage analysis, data description. Author(s): Pericak-Vance MA, Meyers DA, Gusella JF, Folstein SE, Conneally PM. Source: Genet Epidemiol Suppl. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2952548&query_hl=8&itool=pubmed_docsum
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Genetic background of Huntington disease in Croatia: Molecular analysis of CAG, CCG, and Delta2642 (E2642del) polymorphisms. Author(s): Hecimovic S, Klepac N, Vlasic J, Vojta A, Janko D, Skarpa-Prpic I, CankiKlain N, Markovic D, Bozikov J, Relja M, Pavelic K. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12204002&query_hl=8&itool=pubmed_docsum
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Genetic landmarks through philately: Woodrow Wilson 'Woody' Guthrie and Huntington disease. Author(s): Innes AM, Chudley AE. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12030890&query_hl=8&itool=pubmed_docsum
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Genetic linkage between Huntington disease and the D4S10 locus in South African families: further evidence against non-allelic heterogeneity. Author(s): Greenberg LJ, Martell RW, Theilman J, Hayden MR, Joubert J. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1834541&query_hl=8&itool=pubmed_docsum
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Genetic linkage studies in Huntington disease. Author(s): Pericak-Vance MA, Conneally PM, Merritt AD, Roos R, Norton JA Jr, Vance JM. Source: Cytogenetics and Cell Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=156628&query_hl=8&itool=pubmed_docsum
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Genetic testing and mental health: the model of Huntington disease. Author(s): Williams JK, Schutte DL. Source: Online Journal of Issues in Nursing [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11380269&query_hl=8&itool=pubmed_docsum
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Genetic testing of children at risk for Huntington's disease. US Huntington Disease Genetic Testing Group. Author(s): Nance MA. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9339688&query_hl=8&itool=pubmed_docsum
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Genetics of childhood disorders: X. Huntington disease. Author(s): DiFiglia M. Source: Journal of the American Academy of Child and Adolescent Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10638076&query_hl=8&itool=pubmed_docsum
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Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Author(s): Rubinsztein DC, Leggo J, Chiano M, Dodge A, Norbury G, Rosser E, Craufurd D. 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=9108071&query_hl=8&itool=pubmed_docsum
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Glyceraldehyde 3-phosphate dehydrogenase abnormality in metabolically stressed Huntington disease fibroblasts. Author(s): Cooper AJ, Sheu KF, Burke JR, Strittmatter WJ, Blass JP. Source: Developmental Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9778585&query_hl=8&itool=pubmed_docsum
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High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Author(s): Almqvist EW, Elterman DS, MacLeod PM, Hayden MR. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11595021&query_hl=8&itool=pubmed_docsum
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High-dose creatine therapy for Huntington disease: a 2-year clinical and MRS study. Author(s): Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15883340&query_hl=8&itool=pubmed_docsum
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Highly disabling cerebellar presentation in Huntington disease. Author(s): Squitieri F, Pustorino G, Cannella M, Toscano A, Maglione V, Morgante L, Tortorella 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=12823498&query_hl=8&itool=pubmed_docsum
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History of genetic disease: the molecular genetics of Huntington disease - a history. Author(s): Bates GP. Source: Nature Reviews. Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16136077&query_hl=8&itool=pubmed_docsum
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Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Author(s): Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Levi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12615650&query_hl=8&itool=pubmed_docsum
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Huntingtin processing in pathogenesis of Huntington disease. Author(s): Qin ZH, Gu ZL. Source: Acta Pharmacologica Sinica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15456523&query_hl=8&itool=pubmed_docsum
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Huntington disease expansion mutations in humans can occur before meiosis is completed. Author(s): Yoon SR, Dubeau L, de Young M, Wexler NS, Arnheim N. 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=12857955&query_hl=8&itool=pubmed_docsum
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Huntington disease in children: genotype-phenotype correlation. Author(s): Rasmussen A, Macias R, Yescas P, Ochoa A, Davila G, Alonso E. Source: Neuropediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11071143&query_hl=8&itool=pubmed_docsum
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Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles. Author(s): Underwood BR, Broadhurst D, Dunn WB, Ellis DI, Michell AW, Vacher C, Mosedale DE, Kell DB, Barker RA, Grainger DJ, Rubinsztein DC. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16464959&query_hl=8&itool=pubmed_docsum
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Huntington disease phenocopy is a familial prion disease. Author(s): Moore RC, Xiang F, Monaghan J, Han D, Zhang Z, Edstrom L, Anvret M, Prusiner SB. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11593450&query_hl=8&itool=pubmed_docsum
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Huntington disease. Author(s): Wexler A. Source: Journal of the Royal Society of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16449768&query_hl=8&itool=pubmed_docsum
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Huntington disease. Author(s): Harper B. 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=16319434&query_hl=8&itool=pubmed_docsum
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Huntington disease. Author(s): Siemers E. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11176971&query_hl=8&itool=pubmed_docsum
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Huntington disease: a case study of early onset presenting as depression. Author(s): Duesterhus P, Schimmelmann BG, Wittkugel O, Schulte-Markwort M. Source: Journal of the American Academy of Child and Adolescent Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15381897&query_hl=8&itool=pubmed_docsum
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Huntington disease: a nursing perspective. Author(s): Skirton H. Source: Medsurg Nursing : Official Journal of the Academy of Medical-Surgical Nurses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16035633&query_hl=8&itool=pubmed_docsum
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Huntington disease: clinical, genetic, and social aspects. Author(s): Nance MA. Source: Journal of Geriatric Psychiatry and Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9877527&query_hl=8&itool=pubmed_docsum
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Huntington disease: DNA analysis in Brazilian population. Author(s): Raskin S, Allan N, Teive HA, Cardoso F, Haddad MS, Levi G, Boy R, Lerena Junior J, Sotomaior VS, Janzen-Duck M, Jardim LB, Fellander FR, Andrade LA. Source: Arquivos De Neuro-Psiquiatria. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11105061&query_hl=8&itool=pubmed_docsum
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Huntington disease: new insights on the role of huntingtin cleavage. Author(s): Wellington CL, Leavitt BR, Hayden MR. Source: Journal of Neural Transmission. Supplementum. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11128600&query_hl=8&itool=pubmed_docsum
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Huntington disease: volumetric, diffusion-weighted, and magnetization transfer MR imaging of brain. Author(s): Mascalchi M, Lolli F, Della Nave R, Tessa C, Petralli R, Gavazzi C, Politi LS, Macucci M, Filippi M, Piacentini S. Source: Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15215553&query_hl=8&itool=pubmed_docsum
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Huntington disease-unaffected fetus diagnosed from maternal plasma using QF-PCR. Author(s): Gonzalez-Gonzalez MC, Trujillo MJ, Rodriguez de Alba M, Garcia-Hoyos M, Lorda-Sanchez I, Diaz-Recasens J, Ayuso C, Ramos C. Source: Prenatal Diagnosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12627425&query_hl=8&itool=pubmed_docsum
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Identification of an oculomotor biomarker of preclinical Huntington disease. Author(s): Golding CV, Danchaivijitr C, Hodgson TL, Tabrizi SJ, Kennard C. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16625001&query_hl=8&itool=pubmed_docsum
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Impact of genetic testing for Huntington disease on the family system. Author(s): Sobel SK, Cowan DB. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10602118&query_hl=8&itool=pubmed_docsum
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Impact on couple relationships of predictive testing for Huntington disease: a longitudinal study. Author(s): Richards F, Williams K. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15057981&query_hl=8&itool=pubmed_docsum
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Impairment of energy metabolism and excitotoxic cell death in Huntington disease. Author(s): Young AB. Source: Revue Neurologique. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9683998&query_hl=8&itool=pubmed_docsum
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Improved polymerase chain reaction conditions for quick diagnostics of Huntington disease. Author(s): Culjkovic B, Ruzdijic S, Rakic L, Romac S. Source: Brain Research. Brain Research Protocols. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9438070&query_hl=8&itool=pubmed_docsum
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In our parents' shadow. Huntington disease. Author(s): Gelbart M. Source: Nurs Times. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9625960&query_hl=8&itool=pubmed_docsum
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In vitro and in vivo models for Huntington disease: lessons for the polyglutamine expansion disorders. Author(s): Hayden MR. Source: Pathologie-Biologie. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9885820&query_hl=8&itool=pubmed_docsum
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In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease. Author(s): Fennema-Notestine C, Archibald SL, Jacobson MW, Corey-Bloom J, Paulsen JS, Peavy GM, Gamst AC, Hamilton JM, Salmon DP, Jernigan TL. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15452288&query_hl=8&itool=pubmed_docsum
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Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Author(s): Sawa A, Wiegand GW, Cooper J, Margolis RL, Sharp AH, Lawler JF Jr, Greenamyre JT, Snyder SH, Ross CA. Source: Nature Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10502825&query_hl=8&itool=pubmed_docsum
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Increased basal ganglia iron levels in Huntington disease. Author(s): Bartzokis G, Cummings J, Perlman S, Hance DB, Mintz J. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10328252&query_hl=8&itool=pubmed_docsum
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Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population. Author(s): Goldberg YP, McMurray CT, Zeisler J, Almqvist E, Sillence D, Richards F, Gacy AM, Buchanan J, Telenius H, Hayden MR. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8595415&query_hl=8&itool=pubmed_docsum
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Increased rate of whole-brain atrophy over 6 months in early Huntington disease. Author(s): Henley SM, Frost C, MacManus DG, Warner TT, Fox NC, Tabrizi SJ. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16924028&query_hl=8&itool=pubmed_docsum
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Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial. Author(s): Kremer B, Clark CM, Almqvist EW, Raymond LA, Graf P, Jacova C, Mezei M, Hardy MA, Snow B, Martin W, Hayden MR. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10496259&query_hl=8&itool=pubmed_docsum
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Informed consent and Huntington disease: a model for communication. Author(s): Sharpe NF. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8042667&query_hl=8&itool=pubmed_docsum
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Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Author(s): Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15146184&query_hl=8&itool=pubmed_docsum
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Interaction of Huntington disease protein with transcriptional activator Sp1. Author(s): Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ. Source: Molecular and Cellular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11839795&query_hl=8&itool=pubmed_docsum
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Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. Author(s): Djousse L, Knowlton B, Hayden M, Almqvist EW, Brinkman R, Ross C, Margolis R, Rosenblatt A, Durr A, Dode C, Morrison PJ, Novelletto A, Frontali M, Trent RJ, McCusker E, Gomez-Tortosa E, Mayo D, Jones R, Zanko A, Nance M, Abramson R, Suchowersky O, Paulsen J, Harrison M, Yang Q, Cupples LA, Gusella JF, MacDonald ME, Myers RH. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12784292&query_hl=8&itool=pubmed_docsum
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Inverse relationship between age at onset of Huntington disease and paternal age suggests involvement of genetic imprinting. Author(s): Farrer LA, Cupples LA, Kiely DK, Conneally PM, Myers RH. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1531729&query_hl=8&itool=pubmed_docsum
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Is the retina affected in Huntington disease? Author(s): Petrasch-Parwez E, Saft C, Schlichting A, Andrich J, Napirei M, Arning L, Wieczorek S, Dermietzel R, Epplen JT. Source: Acta Neuropathologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16222522&query_hl=8&itool=pubmed_docsum
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Italian Huntington disease patients--data and tissue bank. Author(s): Squitieri F, Cannella M, Gaudio L, Martino T, Maglione V, Giallonardo P, Simonelli M, Simonelli G, Mangeruga D, Ciarmiello A, Pierelli F. 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=14598094&query_hl=8&itool=pubmed_docsum
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Joseph disease and Huntington disease: protein patterns in fibroblasts and brain. Author(s): Rosenberg RN, Ivy N, Kirkpatrick J, Bay C, Nyhan WL, Baskin F. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6455606&query_hl=8&itool=pubmed_docsum
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Juvenile Huntington disease in the Netherlands. Author(s): Siesling S, Vegter-van der Vlis M, Roos RA. Source: Pediatric Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9308974&query_hl=8&itool=pubmed_docsum
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Juvenile Huntington disease. Author(s): Geevasinga N, Richards FH, Jones KJ, Ryan MM. 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=16925544&query_hl=8&itool=pubmed_docsum
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Juvenile Huntington disease. Author(s): van Dijk JG, van der Velde EA, Roos RA, Bruyn GW. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2942452&query_hl=8&itool=pubmed_docsum
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Juvenile Huntington disease: CT and MR features. Author(s): Ho VB, Chuang HS, Rovira MJ, Koo B. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7484624&query_hl=8&itool=pubmed_docsum
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Juvenile onset Huntington disease resulting from a very large maternal expansion. Author(s): Nahhas FA, Garbern J, Krajewski KM, Roa BB, Feldman GL. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16096998&query_hl=8&itool=pubmed_docsum
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Larger CAG expansions in skeletal muscle compared with lymphocytes in Kennedy disease but not in Huntington disease. Author(s): Ansved T, Lundin A, Anvret M. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9818876&query_hl=8&itool=pubmed_docsum
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Late-onset and typical Huntington disease families from Crete have distinct genetic origins. Author(s): Kartsaki E, Spanaki C, Tzagournissakis M, Petsakou A, Moschonas N, Macdonald M, Plaitakis A. Source: International Journal of Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16391835&query_hl=8&itool=pubmed_docsum
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Leber hereditary optic neuropathy with chorea and dementia resembling Huntington disease. Author(s): Morimoto N, Nagano I, Deguchi K, Murakami T, Fushimi S, Shoji M, Abe K. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15623735&query_hl=8&itool=pubmed_docsum
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Letter: Asphyxiation, bulimia, and insulin levels in Huntington disease (chorea). Author(s): Whittier JR. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=130504&query_hl=8&itool=pubmed_docsum
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Levetiracetam-induced Parkinsonism in a Huntington disease patient. Author(s): Gatto EM, Roca CU, Etcheverry JL, Fadel D. Source: Clinical Neuropharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17095892&query_hl=8&itool=pubmed_docsum
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Levetiracetam-induced parkinsonism in a Huntington disease patient. Author(s): Zesiewicz TA, Sanchez-Ramos J, Sullivan KL, Hauser RA. Source: Clinical Neuropharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16062099&query_hl=8&itool=pubmed_docsum
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Linkage analysis between Huntington disease and the G8 marker locus. Author(s): Badner JA, Chakravarti A, Buetow KH. Source: Genet Epidemiol Suppl. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2883077&query_hl=8&itool=pubmed_docsum
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Linkage disequilibrium and modification of risk for Huntington disease. Author(s): Adam S, Theilmann J, Buetow K, Hedrick A, Collins C, Weber B, Huggins M, Hayden M. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1671809&query_hl=8&itool=pubmed_docsum
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Linkage studies and prediction of risks for Huntington disease. Author(s): Maestri NE, Beaty TH, Meyers DA. Source: Genet Epidemiol Suppl. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2883082&query_hl=8&itool=pubmed_docsum
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Linkage, but not gene order, of homologous loci, including alpha-L-iduronidase (Idua), is conserved in the Huntington disease region of the mouse and human genomes. Author(s): Koizumi T, MacDonald M, Bucan M, Hopwood JJ, Morris CP, Scott HS, Gusella JF, Nadeau JH. Source: Mammalian Genome : Official Journal of the International Mammalian Genome Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1533802&query_hl=8&itool=pubmed_docsum
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Long term treatment of Huntington disease with L-glutamate and pyridoxine. Author(s): Barr AN, Heinze W, Mendoza JE, Perlik S. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=153484&query_hl=8&itool=pubmed_docsum
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Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers. Author(s): Kirkwood SC, Siemers E, Stout JC, Hodes ME, Conneally PM, Christian JC, Foroud T. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10328251&query_hl=8&itool=pubmed_docsum
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Longitudinal personality changes among presymptomatic Huntington disease gene carriers. Author(s): Kirkwood SC, Siemers E, Viken R, Hodes ME, Conneally PM, Christian JC, Foroud T. Source: Neuropsychiatry, Neuropsychology, and Behavioral Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12218712&query_hl=8&itool=pubmed_docsum
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Loss of cortical and thalamic neuronal tenascin-C expression in a transgenic mouse expressing exon 1 of the human Huntington disease gene. Author(s): Kusakabe M, Mangiarini L, Laywell ED, Bates GP, Yoshiki A, Hiraiwa N, Inoue J, Steindler DA. Source: The Journal of Comparative Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11169482&query_hl=8&itool=pubmed_docsum
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Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases. Author(s): Falush D, Almqvist EW, Brinkmann RR, Iwasa Y, Hayden MR. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11225602&query_hl=8&itool=pubmed_docsum
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Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Author(s): Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, Brooks DJ, Piccini P. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16769933&query_hl=8&itool=pubmed_docsum
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Minocycline safety and tolerability in Huntington disease. Author(s): Huntington Study Group. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15304592&query_hl=8&itool=pubmed_docsum
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Mitochondrial aconitase is a transglutaminase 2 substrate: transglutamination is a probable mechanism contributing to high-molecular-weight aggregates of aconitase and loss of aconitase activity in Huntington disease brain. Author(s): Kim SY, Marekov L, Bubber P, Browne SE, Stavrovskaya I, Lee J, Steinert PM, Blass JP, Beal MF, Gibson GE, Cooper AJ. Source: Neurochemical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16341586&query_hl=8&itool=pubmed_docsum
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Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene. Author(s): Zuhlke C, Riess O, Bockel B, Lange H, Thies U. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8111374&query_hl=8&itool=pubmed_docsum
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Modulation of age at onset of Huntington disease patients by variations in TP53 and human caspase activated DNase (hCAD) genes. Author(s): Chattopadhyay B, Baksi K, Mukhopadhyay S, Bhattacharyya NP. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15644269&query_hl=8&itool=pubmed_docsum
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Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Author(s): Telenius H, Kremer HP, Theilmann J, Andrew SE, Almqvist E, Anvret M, Greenberg C, Greenberg J, Lucotte G, Squitieri F, et al. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8268906&query_hl=8&itool=pubmed_docsum
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Molecular detection of new mutations, resolution of ambiguous results and complex genetic counseling issues in Huntington disease. Author(s): Alford RL, Ashizawa T, Jankovic J, Caskey CT, Richards CS. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8985488&query_hl=8&itool=pubmed_docsum
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Molecular diagnosis of Huntington disease in Brazilian patients. Author(s): Lima E Silva TC, Serra HG, Bertuzzo CS, Lopes-Cendes I. Source: Arquivos De Neuro-Psiquiatria. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10770860&query_hl=8&itool=pubmed_docsum
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Molecular diagnosis of Huntington disease in Portugal: implications for genetic counselling and clinical practice. Author(s): Costa Mdo C, Magalhaes P, Ferreirinha F, Guimaraes L, Januario C, Gaspar I, Loureiro L, Vale J, Garrett C, Regateiro F, Magalhaes M, Sousa A, Maciel P, Sequeiros J. 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=14571273&query_hl=8&itool=pubmed_docsum
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Monozygotic twins discordant for Huntington disease after 7 years. Author(s): Friedman JH, Trieschmann ME, Myers RH, Fernandez HH. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15956172&query_hl=8&itool=pubmed_docsum
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Mosaicism of the CAG repeat sequence in the Huntington disease gene in a pair of monozygotic twins. Author(s): Norremolle A, Hasholt L, Petersen CB, Eiberg H, Hasselbalch SG, Gideon P, Nielsen JE, Sorensen SA. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15372528&query_hl=8&itool=pubmed_docsum
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Motor changes in presymptomatic Huntington disease gene carriers. Author(s): Siemers E, Foroud T, Bill DJ, Sorbel J, Norton JA Jr, Hodes ME, Niebler G, Conneally PM, Christian JC. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8660148&query_hl=8&itool=pubmed_docsum
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MR imaging and spectroscopy in juvenile Huntington disease. Author(s): Schapiro M, Cecil KM, Doescher J, Kiefer AM, Jones BV. Source: Pediatric Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15042332&query_hl=8&itool=pubmed_docsum
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MR of human postmortem brain tissue: correlative study between T2 and assays of iron and ferritin in Parkinson and Huntington disease. Author(s): Chen JC, Hardy PA, Kucharczyk W, Clauberg M, Joshi JG, Vourlas A, Dhar M, Henkelman RM. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8456699&query_hl=8&itool=pubmed_docsum
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Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Author(s): Manley K, Shirley TL, Flaherty L, Messer A. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10581038&query_hl=8&itool=pubmed_docsum
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MSJAMA. The dilemma of confidentiality in Huntington disease. Author(s): Wusthoff C. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12953009&query_hl=8&itool=pubmed_docsum
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Multidisciplinary approach to management of a hereditary neurodegenerative disorder: Huntington disease. Author(s): Klimek ML, Rohs G, Young L, Suchowersky O, Trew M. Source: Axone. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9481240&query_hl=8&itool=pubmed_docsum
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Mutant protein in Huntington disease is resistant to proteolysis in affected brain. Author(s): Dyer RB, McMurray CT. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11600884&query_hl=8&itool=pubmed_docsum
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Nature and development of Huntington disease in a nursing home population: The Behavior Observation Scale Huntington (BOSH). Author(s): Timman R, Claus H, Slingerland H, van der Schalk M, Demeulenaere S, Roos RA, Tibben A. Source: Cognitive and Behavioral Neurology : Official Journal of the Society for Behavioral and Cognitive Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16340395&query_hl=8&itool=pubmed_docsum
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Negotiating responsibility: case studies of reproductive decision-making and prenatal genetic testing in families facing Huntington disease. Author(s): Downing C. Source: Journal of Genetic Counseling. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15959653&query_hl=8&itool=pubmed_docsum
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Neuroleptic malignant syndrome caused by dopamine-depleting drugs in a patient with Huntington disease. Author(s): Burke RE, Fahn S, Mayeux R, Weinberg H, Louis K, Willner JH. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6115336&query_hl=8&itool=pubmed_docsum
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Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Author(s): Rajkowska G, Selemon LD, Goldman-Rakic PS. Source: Archives of General Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9510215&query_hl=8&itool=pubmed_docsum
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New Huntington disease mutation arising from a paternal CAG34 allele showing somatic length variation in serially passaged lymphoblasts. Author(s): Cannella M, Maglione V, Martino T, Simonelli M, Ragona G, Squitieri F. Source: Am J Med Genet B Neuropsychiatr Genet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15546151&query_hl=8&itool=pubmed_docsum
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New insights into the clinical features, pathogenesis and molecular genetics of Huntington disease. Author(s): Kremer B, Weber B, Hayden MR. Source: Brain Pathology (Zurich, Switzerland). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1341966&query_hl=8&itool=pubmed_docsum
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N-myc and c-myc expression in Alzheimer disease, Huntington disease and Parkinson disease. Author(s): Ferrer I, Blanco R. Source: Brain Research. Molecular Brain Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10837922&query_hl=8&itool=pubmed_docsum
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No association between polymorphisms in the BDNF gene and age at onset in Huntington disease. Author(s): Mai M, Akkad AD, Wieczorek S, Saft C, Andrich J, Kraus PH, Epplen JT, Arning L. Source: Bmc Medical Genetics [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17096834&query_hl=8&itool=pubmed_docsum
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Non-disclosing preimplantation genetic diagnosis for Huntington disease. Author(s): Stern HJ, Harton GL, Sisson ME, Jones SL, Fallon LA, Thorsell LP, Getlinger ME, Black SH, Schulman JD. Source: Prenatal Diagnosis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12116316&query_hl=8&itool=pubmed_docsum
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Nonisotopic method for accurate detection of (CAG)n repeats causing Huntington disease. Author(s): Muglia M, Leone O, Annesi G, Gabriele AL, Imbrogno E, Grandinetti C, Conforti FL, Naso F, Brancati C. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8855141&query_hl=8&itool=pubmed_docsum
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Nonlinear effects in behavioral changes in Huntington disease. Author(s): Timman R, Tibben A, Roos RA. Source: Cognitive and Behavioral Neurology : Official Journal of the Society for Behavioral and Cognitive Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14765005&query_hl=8&itool=pubmed_docsum
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Non-random association between DNA markers and Huntington disease locus in the Italian population. Author(s): Novelletto A, Mandich P, Bellone E, Malaspina P, Vivona G, Ajmar F, Frontali M. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1683157&query_hl=8&itool=pubmed_docsum
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Nonrandom association between Huntington disease and two loci separated by about 3 Mb on 4p16.3. Author(s): Andrew S, Theilmann J, Hedrick A, Mah D, Weber B, Hayden MR. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1351866&query_hl=8&itool=pubmed_docsum
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NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Author(s): Arning L, Kraus PH, Valentin S, Saft C, Andrich J, Epplen JT. Source: Neurogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15742215&query_hl=8&itool=pubmed_docsum
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Nucleotide sequence and PCR-amplification of a polymorphic MboI site in human DNA marker D4S95 linked to the Huntington disease locus. Author(s): Norremolle A, Sorensen SA, Arctander P. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1358489&query_hl=8&itool=pubmed_docsum
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Null alleles at the Huntington disease locus: implications for diagnostics and CAG repeat instability. Author(s): Williams LC, Hegde MR, Nagappan R, Faull RL, Giles J, Winship I, Snow K, Love DR. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10794362&query_hl=8&itool=pubmed_docsum
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Nutritional evaluation of Huntington disease patients. Author(s): Morales LM, Estevez J, Suarez H, Villalobos R, Chacin de Bonilla L, Bonilla E. 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=2526577&query_hl=8&itool=pubmed_docsum
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Obsessive compulsive disorder in Huntington disease: a case of isolated obsessions successfully treated with sertraline. Author(s): Patzold T, Brune M. Source: Neuropsychiatry, Neuropsychology, and Behavioral Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12218715&query_hl=8&itool=pubmed_docsum
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Olfactory functions in asymptomatic carriers of the Huntington disease mutation. Author(s): Larsson M, Lundin A, Robins Wahlin TB. Source: J Clin Exp Neuropsychol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17050264&query_hl=8&itool=pubmed_docsum
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On attitudes and appreciation 6 months after predictive DNA testing for Huntington disease in the Dutch program. Author(s): Tibben A, Frets PG, van de Kamp JJ, Niermeijer MF, Vegtervan der Vlis M, Roos RA, Rooymans HG, van Ommen GJ, Verhage F. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8362926&query_hl=8&itool=pubmed_docsum
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On planting alfalfa and growing orchids: the cloning of the gene causing Huntington disease. Author(s): Hayden MR. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8375101&query_hl=8&itool=pubmed_docsum
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Onset and rate of striatal atrophy in preclinical Huntington disease. Author(s): Aylward EH, Sparks BF, Field KM, Yallapragada V, Shpritz BD, Rosenblatt A, Brandt J, Gourley LM, Liang K, Zhou H, Margolis RL, Ross CA. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15249612&query_hl=8&itool=pubmed_docsum
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Opinion: predictive testing for Huntington disease in childhood: challenges and implications. Author(s): Bloch M, Hayden MR. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2136787&query_hl=8&itool=pubmed_docsum
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Oral motor dysfunction in individuals at risk of Huntington disease. Author(s): Coleman R, Anderson D, Lovrien E. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2146877&query_hl=8&itool=pubmed_docsum
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Origins and evolution of Huntington disease chromosomes. Author(s): Andrew SE, Hayden MR. Source: Neurodegeneration : a Journal for Neurodegenerative Disorders, Neuroprotection, and Neuroregeneration. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8581556&query_hl=8&itool=pubmed_docsum
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Outrageous fortune: the risk of suicide in genetic testing for Huntington disease. Author(s): Bird TD. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10205259&query_hl=8&itool=pubmed_docsum
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Patterns of meiotic variability of the (CAG)n repeat in the Huntington disease gene. Author(s): Lucotte G, Gerard N, Aouizerate A, Loirat F, Hazout S. Source: Genet Couns. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9219003&query_hl=8&itool=pubmed_docsum
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PCR reagents for detection of (CAG)n repeats in Huntington disease. Author(s): Toth T, Nagy B, Papp Z. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9267332&query_hl=8&itool=pubmed_docsum
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Perspectives towards predictive testing in Huntington disease. Author(s): Nagaraja SM, Jain S, Muthane UB. Source: Neurology India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17114842&query_hl=8&itool=pubmed_docsum
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Phenotypic homogeneity of the Huntington disease-like presentation in a SCA17 family. Author(s): Schneider SA, van de Warrenburg BP, Hughes TD, Davis M, Sweeney M, Wood N, Quinn NP, Bhatia KP. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17101913&query_hl=8&itool=pubmed_docsum
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Phosphorus 31 magnetic resonance spectroscopy in patients with Huntington disease. Author(s): Williamson PC, Malla A, Cortese L, Stoessl AJ, Drost D, Stanley JA. Source: Archives of General Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9040287&query_hl=8&itool=pubmed_docsum
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Polymorphisms in the CAG repeat--a source of error in Huntington disease DNA testing. Author(s): Yu S, Fimmel A, Fung D, Trent RJ. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11149616&query_hl=8&itool=pubmed_docsum
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Predictability of age at onset in Huntington disease in the Dutch population. Author(s): Maat-Kievit A, Losekoot M, Zwinderman K, Vegter-van der Vlis M, Belfroid R, Lopez F, Van Ommen GJ, Breuning M, Roos R. Source: Medicine; Analytical Reviews of General Medicine, Neurology, Psychiatry, Dermatology, and Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12169880&query_hl=8&itool=pubmed_docsum
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Predictive and pre-natal testing for Huntington Disease in Australia: results and challenges encountered during a 10-year period (1994-2003). Author(s): Tassicker RJ, Marshall PK, Liebeck TA, Keville MA, Singaram BM, Richards FH. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17100992&query_hl=8&itool=pubmed_docsum
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Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Author(s): Semaka A, Creighton S, Warby S, Hayden MR. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16965319&query_hl=8&itool=pubmed_docsum
Studies
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Predictive testing for persons at risk for homozygosity for CAG expansion in the Huntington disease gene. Author(s): Squitieri F, Almqvist EW, Cannella M, Cislaghi G, Hayden MR. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14986835&query_hl=8&itool=pubmed_docsum
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Predictive testing of 25 percent at-risk individuals for Huntington disease (1987-1997). Author(s): Maat-Kievit A, Vegter-Van Der Vlis M, Zoeteweij M, Losekoot M, van Haeringen A, Roos RA. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10581487&query_hl=8&itool=pubmed_docsum
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Predictors of nursing home placement in Huntington disease. Author(s): Wheelock VL, Tempkin T, Marder K, Nance M, Myers RH, Zhao H, Kayson E, Orme C, Shoulson I; Huntington Study Group. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12654967&query_hl=8&itool=pubmed_docsum
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Prevalence of Huntington disease in New South Wales in 1996. Author(s): McCusker EA, Casse RF, Graham SJ, Williams DB, Lazarus R. Source: The Medical Journal of Australia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11008591&query_hl=8&itool=pubmed_docsum
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Proactive transplantation of human neural stem cells prevents degeneration of striatal neurons in a rat model of Huntington disease. Author(s): Ryu JK, Kim J, Cho SJ, Hatori K, Nagai A, Choi HB, Lee MC, McLarnon JG, Kim SU. Source: Neurobiology of Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15207263&query_hl=8&itool=pubmed_docsum
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Progression of symptoms in the early and middle stages of Huntington disease. Author(s): Kirkwood SC, Su JL, Conneally P, Foroud T. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11176966&query_hl=8&itool=pubmed_docsum
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Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Author(s): Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, Mitchell D, Steinman L. Source: Nature Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11821898&query_hl=8&itool=pubmed_docsum
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Propofol and remifentanil total intravenous anesthesia for a patient with Huntington disease. Author(s): MacPherson P, Harper I, MacDonald I. Source: Journal of Clinical Anesthesia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15590259&query_hl=8&itool=pubmed_docsum
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Proteomic analysis of protein expression and oxidative modification in r6/2 transgenic mice: a model of Huntington disease. Author(s): Perluigi M, Poon HF, Maragos W, Pierce WM, Klein JB, Calabrese V, Cini C, De Marco C, Butterfield DA. Source: Molecular & Cellular Proteomics : Mcp. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15968004&query_hl=8&itool=pubmed_docsum
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Psychological impact of news of genetic risk for Huntington disease. Author(s): Horowitz MJ, Field NP, Zanko A, Donnelly EF, Epstein C, Longo F. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11745989&query_hl=8&itool=pubmed_docsum
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Psychosocial impact of predictive testing for Huntington disease on support persons. Author(s): Williams JK, Schutte DL, Holkup PA, Evers C, Muilenburg A. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10898914&query_hl=8&itool=pubmed_docsum
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Quantitative autoradiography of neurotransmitter receptors in Huntington disease. Author(s): Penney JB Jr, Young AB. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6292789&query_hl=8&itool=pubmed_docsum
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R.H.I.S.A. -- cysternography study in sporadic choreo-athetotic syndrome accompanied with dementia (sporadic Huntington disease). Author(s): Vardi J, Flechter S, Rabi JM, Streifler M. Source: Riv Patol Nerv Ment. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=162355&query_hl=8&itool=pubmed_docsum
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Radiation hybrid map spanning the Huntington disease gene region of chromosome 4. Author(s): Altherr MR, Plummer S, Bates G, MacDonald M, Taylor S, Lehrach H, Frischauf AM, Gusella JF, Boehnke M, Wasmuth JJ. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1387106&query_hl=8&itool=pubmed_docsum
Studies
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Rapid onset of tardive dyskinesia in Huntington disease with olanzapine. Author(s): Benazzi F. Source: Journal of Clinical Psychopharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12172349&query_hl=8&itool=pubmed_docsum
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Reactions to predictive testing in Huntington disease: case reports of coping with a new genetic status. Author(s): Wahlin TB, Lundin A, Backman L, Almqvist E, Haegermark A, Winblad B, Anvret M. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9415699&query_hl=8&itool=pubmed_docsum
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Recent insights into the molecular pathogenesis of Huntington disease. Author(s): Leavitt BR, Wellington CL, Hayden MR. Source: Seminars in Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10716661&query_hl=8&itool=pubmed_docsum
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Recombination of 4p16 DNA markers in an unusual family with Huntington disease. Author(s): Pritchard C, Zhu N, Zuo J, Bull L, Pericak-Vance MA, Vance JM, Roses AD, Milatovich A, Francke U, Cox DR, et al. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1350884&query_hl=8&itool=pubmed_docsum
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Regional cerebral glucose metabolism differs in adult and rigid juvenile forms of Huntington disease. Author(s): Matthews PM, Evans AC, Andermann F, Hakim AM. Source: Pediatric Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2532511&query_hl=8&itool=pubmed_docsum
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Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Author(s): Rosas HD, Hevelone ND, Zaleta AK, Greve DN, Salat DH, Fischl B. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16157910&query_hl=8&itool=pubmed_docsum
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Reluctance to undergo predictive testing: the case of Huntington disease. Author(s): Quaid KA, Morris M. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11657397&query_hl=8&itool=pubmed_docsum
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Reorientation of attention in Huntington disease. Author(s): Georgiou-Karistianis N, Churchyard A, Chiu E, Bradshaw JL. Source: Neuropsychiatry, Neuropsychology, and Behavioral Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12464749&query_hl=8&itool=pubmed_docsum
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Response to Hayden, Bloch, Fox and Crauford: presymptomatic and prenatal testing in Huntington disease. Author(s): Shaw MW. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2962496&query_hl=8&itool=pubmed_docsum
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Risk reversals in predictive testing for Huntington disease. Author(s): Almqvist E, Adam S, Bloch M, Fuller A, Welch P, Eisenberg D, Whelan D, Macgregor D, Meschino W, Hayden MR. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9382108&query_hl=8&itool=pubmed_docsum
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Saccades in presymptomatic and early stages of Huntington disease. Author(s): Blekher T, Johnson SA, Marshall J, White K, Hui S, Weaver M, Gray J, Yee R, Stout JC, Beristain X, Wojcieszek J, Foroud T. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16855205&query_hl=8&itool=pubmed_docsum
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Scientists scope out Huntington disease. Author(s): Hampton T. Source: Jama : the Journal of the American Medical Association. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15632323&query_hl=8&itool=pubmed_docsum
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Screening for Huntington disease and certain other dominantly inherited disorders: a case for preimplantation genetic testing. Author(s): Schulman JD, Black SH. Source: Journal of Medical Screening. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9275265&query_hl=8&itool=pubmed_docsum
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Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease. Author(s): Van Raamsdonk JM, Murphy Z, Slow EJ, Leavitt BR, Hayden MR. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16278236&query_hl=8&itool=pubmed_docsum
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Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Author(s): Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Bissada N, Hossain SM, Yang YZ, Li XJ, Simpson EM, Gutekunst CA, Leavitt BR, Hayden MR. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12812983&query_hl=8&itool=pubmed_docsum
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Sequence analysis of the CAG triplet repeats region in the Huntington disease gene (IT15) in several mammalian species. Author(s): Pecheux C, Gall AL, Kaplan JC, Dode C. Source: Annales De Genetique. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8766138&query_hl=8&itool=pubmed_docsum
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Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation. Author(s): Squitieri F, Cannella M, Sgarbi G, Maglione V, Falleni A, Lenzi P, Baracca A, Cislaghi G, Saft C, Ragona G, Russo MA, Thompson LM, Solaini G, Fornai F. Source: Mechanisms of Ageing and Development. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16289240&query_hl=8&itool=pubmed_docsum
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Severity of cognitive impairment in juvenile and late-onset Huntington disease. Author(s): Gomez-Tortosa E, del Barrio A, Garcia Ruiz PJ, Pernaute RS, Benitez J, Barroso A, Jimenez FJ, Garcia Yebenes J. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9626775&query_hl=8&itool=pubmed_docsum
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Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes. Author(s): Kremer B, Almqvist E, Theilmann J, Spence N, Telenius H, Goldberg YP, Hayden MR. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7668260&query_hl=8&itool=pubmed_docsum
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Short-term effects of olanzapine in Huntington disease. Author(s): Squitieri F, Cannella M, Piorcellini A, Brusa L, Simonelli M, Ruggieri S. Source: Neuropsychiatry, Neuropsychology, and Behavioral Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11234911&query_hl=8&itool=pubmed_docsum
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Significantly lower incidence of cancer among patients with Huntington disease: An apoptotic effect of an expanded polyglutamine tract? Author(s): Sorensen SA, Fenger K, Olsen JH. Source: Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10506723&query_hl=8&itool=pubmed_docsum
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Somatic expansion of the (CAG)n repeat in Huntington disease brains. Author(s): De Rooij KE, De Koning Gans PA, Roos RA, Van Ommen GJ, Den Dunnen JT. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7868117&query_hl=8&itool=pubmed_docsum
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Southern transfer protocol for confirmation of Huntington disease. Author(s): Guida M, Fenwick RG, Papp AC, Snyder PJ, Sedra M, Prior TW. Source: Clinical Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8855159&query_hl=8&itool=pubmed_docsum
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Speech and language delay are early manifestations of juvenile-onset Huntington disease. Author(s): Yoon G, Kramer J, Zanko A, Guzijan M, Lin S, Foster-Barber A, Boxer AL. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17030763&query_hl=8&itool=pubmed_docsum
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Stability of the Huntington disease (CAG)n repeat in a late onset form occuring on the Island of Crete. Author(s): Tzagournissakis M, Fesdjian CO, Shashidharan P, Plaitakis A. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8634693&query_hl=8&itool=pubmed_docsum
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Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease. Author(s): van Oostrom JC, Maguire RP, Verschuuren-Bemelmans CC, Veenma-van der Duin L, Pruim J, Roos RA, Leenders KL. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16186542&query_hl=8&itool=pubmed_docsum
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Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease. Author(s): Shehadeh J, Fernandes HB, Zeron Mullins MM, Graham RK, Leavitt BR, Hayden MR, Raymond LA. Source: Neurobiology of Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16165367&query_hl=8&itool=pubmed_docsum
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Structural analysis of the 5' region of mouse and human Huntington disease genes reveals conservation of putative promoter region and di- and trinucleotide polymorphisms. Author(s): Lin B, Nasir J, Kalchman MA, McDonald H, Zeisler J, Goldberg YP, Hayden MR. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7759106&query_hl=8&itool=pubmed_docsum
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Sweet relief for Huntington disease. Author(s): Katsuno M, Adachi H, Sobue G. Source: Nature Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14760414&query_hl=8&itool=pubmed_docsum
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Sympathetic skin response and heart rate variability in patients with Huntington disease. Author(s): Sharma KR, Romano JG, Ayyar DR, Rotta FT, Facca A, Sanchez-Ramos J. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10520941&query_hl=8&itool=pubmed_docsum
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Technical standards and guidelines for Huntington disease testing. Author(s): Potter NT, Spector EB, Prior TW. 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=14726813&query_hl=8&itool=pubmed_docsum
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Testing the test--why pursue a better test for Huntington disease? Author(s): Timman R, Maat-Kievit A, Brouwer-DudokdeWit C, Zoeteweij M, Breuning MH, Tibben A. Source: Am J Med Genet B Neuropsychiatr Genet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12555240&query_hl=8&itool=pubmed_docsum
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Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Author(s): Huntington Study Group. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16476934&query_hl=8&itool=pubmed_docsum
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The "flap" endonuclease gene FEN1 is excluded as a candidate gene implicated in the CAG repeat expansion underlying Huntington disease. Author(s): Otto CJ, Almqvist E, Hayden MR, Andrew SE. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11260214&query_hl=8&itool=pubmed_docsum
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The association of CAG repeat length with clinical progression in Huntington disease. Author(s): Rosenblatt A, Liang KY, Zhou H, Abbott MH, Gourley LM, Margolis RL, Brandt J, Ross CA. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16606912&query_hl=8&itool=pubmed_docsum
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The CAG repeat at the Huntington disease gene in the Portuguese population: insights into its dynamics and to the origin of the mutation. Author(s): Costa Mdo C, Magalhaes P, Guimaraes L, Maciel P, Sequeiros J, Sousa A. Source: Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16372132&query_hl=8&itool=pubmed_docsum
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The detection of a VNTR at the Huntington disease genetic marker D4S10. Author(s): Carlock L, Vo T. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8364554&query_hl=8&itool=pubmed_docsum
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The expanded CAG repeat associated with juvenile Huntington disease shows a common origin of most or all neurons and glia in human cerebrum. Author(s): Kahlem P, Djian P. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10832020&query_hl=8&itool=pubmed_docsum
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The gender effect in juvenile Huntington disease patients of Italian origin. Author(s): Cannella M, Gellera C, Maglione V, Giallonardo P, Cislaghi G, Muglia M, Quattrone A, Pierelli F, Di Donato S, Squitieri F. Source: Am J Med Genet B Neuropsychiatr Genet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14755452&query_hl=8&itool=pubmed_docsum
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The identification of a functional nuclear localization signal in the Huntington disease protein. Author(s): Bessert DA, Gutridge KL, Dunbar JC, Carlock LR. Source: Brain Research. Molecular Brain Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8774958&query_hl=8&itool=pubmed_docsum
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The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Author(s): Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9150168&query_hl=8&itool=pubmed_docsum
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The murine homologues of the Huntington disease gene (Hdh) and the alphaadducin gene (Add1) map to mouse chromosome 5 within a region of conserved synteny with human chromosome 4p16.3. Author(s): Nasir J, Lin B, Bucan M, Koizumi T, Nadeau JH, Hayden MR. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7959767&query_hl=8&itool=pubmed_docsum
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The status of SCA1, MJD/SCA3, FRDA, DRPLA and MD triplet containing genes in patients with Huntington disease and healthy controls. Author(s): Keckarevic D, Culjkovic B, Savic D, Stojkovic O, Kostic V, Vukosavic S, Romac S. Source: Journal of Neurogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11342385&query_hl=8&itool=pubmed_docsum
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Transcriptional abnormalities in Huntington disease. Author(s): Sugars KL, Rubinsztein DC. Source: Trends in Genetics : Tig. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12711212&query_hl=8&itool=pubmed_docsum
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Transglutaminase cross-links in intranuclear inclusions in Huntington disease. Author(s): Zainelli GM, Ross CA, Troncoso JC, Muma NA. Source: Journal of Neuropathology and Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12528814&query_hl=8&itool=pubmed_docsum
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Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Author(s): Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M, Nukina N. Source: Nature Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14730359&query_hl=8&itool=pubmed_docsum
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Trinucleotide repeat elongation in the Huntingtin gene in Huntington disease patients from 71 Danish families. Author(s): Norremolle A, Riess O, Epplen JT, Fenger K, Hasholt L, Sorensen SA. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8242074&query_hl=8&itool=pubmed_docsum
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Trinucleotide repeats in the human genome: size distributions for all possible triplets and detection of expanded disease alleles in a group of Huntington disease individuals by the repeat expansion detection method. Author(s): Hofferbert S, Schanen NC, Chehab F, Francke U. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9002673&query_hl=8&itool=pubmed_docsum
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Two centuries of mortality in ten large families with Huntington disease: a rising impact of gene carriership. Author(s): Hille ET, Siesling S, Vegter-van der Vlis M, Vandenbroucke JP, Roos RA, Rosendaal FR. Source: Epidemiology (Cambridge, Mass.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10535784&query_hl=8&itool=pubmed_docsum
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Two novel single-base-pair substitutions adjacent to the CAG repeat in the Huntington disease gene (IT15): implications for diagnostic testing. Author(s): Margolis RL, Stine OC, Callahan C, Rosenblatt A, Abbott MH, Sherr M, Ross CA. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9915978&query_hl=8&itool=pubmed_docsum
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Understanding the decision to take the predictive test for Huntington disease. Author(s): Meissen GJ, Mastromauro CA, Kiely DK, McNamara DS, Myers RH. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1678928&query_hl=8&itool=pubmed_docsum
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Use of the G8 probe in predicting risk of Huntington disease. Author(s): Maestri NE, Beaty TH, Folstein SE, Meyers DA. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2961260&query_hl=8&itool=pubmed_docsum
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Using a roster and haplotyping is useful in risk assessment for persons with intermediate and reduced penetrance alleles in Huntington disease. Author(s): Maat-Kievit A, Helderman-van den Enden P, Losekoot M, de Knijff P, Belfroid R, Vegter-van der Vlis M, Roos R, Breuning M. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11803522&query_hl=8&itool=pubmed_docsum
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Using survival methods to estimate age-at-onset distributions for genetic diseases with an application to Huntington disease. Author(s): Cupples LA, Terrin NC, Myers RH, D'Agostino RB. Source: Genetic Epidemiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2524419&query_hl=8&itool=pubmed_docsum
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Viral susceptibility of skin fibroblasts from patients with Huntington disease. Author(s): Miller CA, Rasheed S. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=6259937&query_hl=8&itool=pubmed_docsum
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Visually guided exploration in Huntington disease. Author(s): Lang CJ, Reischies FM, Majer M, Daum RF. Source: Cortex. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10574083&query_hl=8&itool=pubmed_docsum
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Years of life lost due to Huntington disease. Author(s): Jones MB. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=160199&query_hl=8&itool=pubmed_docsum
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CHAPTER 2. ALTERNATIVE MEDICINE AND HUNTINGTON DISEASE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to Huntington disease. 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 Huntington disease 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 Huntington disease (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 Huntington disease: •
Abnormalities of prepulse inhibition do not depend on blink reflex excitability: a study in Parkinson's disease and Huntington's disease. Author(s): Valls-Sole J, Munoz JE, Valldeoriola F. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15203054&query_hl=1&itool=pubmed_docsum
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Anti-inflammatory treatment with acetylsalicylate or rofecoxib is not neuroprotective in Huntington's disease transgenic mice. Author(s): Norflus F, Nanje A, Gutekunst CA, Shi G, Cohen J, Bejarano M, Fox J, Ferrante RJ, Hersch SM.
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Source: Neurobiology of Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15474369&query_hl=1&itool=pubmed_docsum •
Attitudes of Dutch general practitioners towards presymptomatic DNA-testing for Huntington disease. Author(s): Thomassen R, Tibben A, Niermeijer MF, van der Does E, van de Kamp JJ, Verhage F. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8448902&query_hl=1&itool=pubmed_docsum
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Cell therapy for Huntington's disease, the next step forward. Author(s): Peschanski M, Dunnett SB. Source: Lancet. Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12849508&query_hl=1&itool=pubmed_docsum
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Cell therapy in Huntington's disease. Author(s): Dunnett SB, Rosser AE. Source: Neurorx. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15717043&query_hl=1&itool=pubmed_docsum
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Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington's disease. Author(s): Ferrante RJ, Ryu H, Kubilus JK, D'Mello S, Sugars KL, Lee J, Lu P, Smith K, Browne S, Beal MF, Kristal BS, Stavrovskaya IG, Hewett S, Rubinsztein DC, Langley B, Ratan RR. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15548647&query_hl=1&itool=pubmed_docsum
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Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice. Author(s): Stack EC, Kubilus JK, Smith K, Cormier K, Del Signore SJ, Guelin E, Ryu H, Hersch SM, Ferrante RJ. Source: The Journal of Comparative Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16127709&query_hl=1&itool=pubmed_docsum
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Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease. Author(s): Van Raamsdonk JM, Pearson J, Slow EJ, Hossain SM, Leavitt BR, Hayden MR.
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Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15843620&query_hl=1&itool=pubmed_docsum •
Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Author(s): Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16434666&query_hl=1&itool=pubmed_docsum
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Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial. Author(s): Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Van Leemputte M, Hespel P, Dom R. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14557561&query_hl=1&itool=pubmed_docsum
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Creatine supplementation lowers brain glutamate levels in Huntington's disease. Author(s): Bender A, Auer DP, Merl T, Reilmann R, Saemann P, Yassouridis A, Bender J, Weindl A, Dose M, Gasser T, Klopstock T. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15672208&query_hl=1&itool=pubmed_docsum
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Creatine therapy for Huntington's disease: clinical and MRS findings in a 1-year pilot study. Author(s): Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12847181&query_hl=1&itool=pubmed_docsum
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Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. Author(s): Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, Ferrante RJ. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12787055&query_hl=1&itool=pubmed_docsum
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Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation. Author(s): Fox JH, Barber DS, Singh B, Zucker B, Swindell MK, Norflus F, Buzescu R, Chopra R, Ferrante RJ, Kazantsev A, Hersch SM.
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Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15447674&query_hl=1&itool=pubmed_docsum •
Deficits in experience-dependent cortical plasticity and sensory-discrimination learning in presymptomatic Huntington's disease mice. Author(s): Mazarakis NK, Cybulska-Klosowicz A, Grote H, Pang T, Van Dellen A, Kossut M, Blakemore C, Hannan AJ. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15788762&query_hl=1&itool=pubmed_docsum
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Development of novel therapies for Huntington's disease: hope and challenge. Author(s): Qin ZH, Wang J, Gu ZL. Source: Acta Pharmacologica Sinica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15663888&query_hl=1&itool=pubmed_docsum
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Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures. Author(s): Rosas HD, Tuch DS, Hevelone ND, Zaleta AK, Vangel M, Hersch SM, Salat DH. Source: Movement Disorders : Official Journal of the Movement Disorder Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16755582&query_hl=1&itool=pubmed_docsum
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Effects of multisensory stimulation in people with Huntington's disease: a randomized controlled pilot study. Author(s): Leng TR, Woodward MJ, Stokes MJ, Swan AV, Wareing LA, Baker R. Source: Clinical Rehabilitation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12617377&query_hl=1&itool=pubmed_docsum
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Electrophysiological deterioration over time in patients with Huntington's disease. Author(s): Lefaucheur JP, Menard-Lefaucheur I, Maison P, Baudic S, Cesaro P, Peschanski M, Bachoud-Levi AC. Source: Movement Disorders : Official Journal of the Movement Disorder Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16721731&query_hl=1&itool=pubmed_docsum
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Emerging chemotherapeutic strategies for Huntington's disease. Author(s): Ryu H, Ferrante RJ. Source: Expert Opinion on Emerging Drugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15934871&query_hl=1&itool=pubmed_docsum
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Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial. Author(s): Puri BK, Leavitt BR, Hayden MR, Ross CA, Rosenblatt A, Greenamyre JT, Hersch S, Vaddadi KS, Sword A, Horrobin DF, Manku M, Murck H. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16043801&query_hl=1&itool=pubmed_docsum
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Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease. Author(s): Van Raamsdonk JM, Pearson J, Rogers DA, Lu G, Barakauskas VE, Barr AM, Honer WG, Hayden MR, Leavitt BR. Source: Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16129433&query_hl=1&itool=pubmed_docsum
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Evidence for a disorder of locomotor timing in Huntington's disease. Author(s): Bilney B, Morris ME, Churchyard A, Chiu E, Georgiou-Karistianis N. Source: Movement Disorders : Official Journal of the Movement Disorder Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15390128&query_hl=1&itool=pubmed_docsum
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Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Author(s): Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16893904&query_hl=1&itool=pubmed_docsum
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High-resolution magnetic resonance imaging sinc-interpolation-based subvoxel registration and semi-automated quantitative lateral ventricular morphology employing threshold computation and binary image creation in the study of fatty acid interventions in schizophrenia, depression, chronic fatigue syndrome and Huntington's disease. Author(s): Puri BK. Source: International Review of Psychiatry (Abingdon, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16777669&query_hl=1&itool=pubmed_docsum
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Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. Author(s): Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B, Smith K, Kowall NW, Ratan RR, Luthi-Carter R, Hersch SM. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14561870&query_hl=1&itool=pubmed_docsum
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Huntington's disease. Unorthodox clinical trials meld science and care. Author(s): Couzin J. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15131283&query_hl=1&itool=pubmed_docsum
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Huntington's disease: new frontiers for molecular and cell therapy. Author(s): Melone MA, Jori FP, Peluso G. Source: Current Drug Targets. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15720212&query_hl=1&itool=pubmed_docsum
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Huntington's disease: prospects for neuroprotective therapy 10 years after the discovery of the causative genetic mutation. Author(s): Hersch SM. Source: Current Opinion in Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12869810&query_hl=1&itool=pubmed_docsum
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Improvement of choreic movements by 1 Hz repetitive transcranial magnetic stimulation in Huntington's disease patients. Author(s): Brusa L, Versace V, Koch G, Bernardi G, Iani C, Stanzione P, Centonze D. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16178020&query_hl=1&itool=pubmed_docsum
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Long-term impact of Huntington disease linkage testing. Author(s): Taylor CA, Myers RH. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9182776&query_hl=1&itool=pubmed_docsum
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Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease. Author(s): Trushina E, Heldebrant MP, Perez-Terzic CM, Bortolon R, Kovtun IV, Badger JD 2nd, Terzic A, Estevez A, Windebank AJ, Dyer RB, Yao J, McMurray CT. 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=14527999&query_hl=1&itool=pubmed_docsum
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Motor cortical excitability studied with repetitive transcranial magnetic stimulation in patients with Huntington's disease. Author(s): Lorenzano C, Dinapoli L, Gilio F, Suppa A, Bagnato S, Curra A, Inghilleri M, Berardelli A.
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Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16793338&query_hl=1&itool=pubmed_docsum •
MRI and neuropsychological improvement in Huntington disease following ethylEPA treatment. Author(s): Puri BK, Bydder GM, Counsell SJ, Corridan BJ, Richardson AJ, Hajnal JV, Appel C, Mckee HM, Vaddadi KS, Horrobin DF. Source: Neuroreport. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11924873&query_hl=1&itool=pubmed_docsum
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Neurophysiological study of facial chorea in patients with Huntington's disease. Author(s): Munoz E, Cervera A, Valls-Sole J. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12842721&query_hl=1&itool=pubmed_docsum
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Olfactory and auditory event-related potentials in Huntington's disease. Author(s): Wetter S, Peavy G, Jacobson M, Hamilton J, Salmon D, Murphy C. Source: Neuropsychology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16060817&query_hl=1&itool=pubmed_docsum
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Predictive genetic test decisions for Huntington's disease: context, appraisal and new moral imperatives. Author(s): Taylor SD. Source: Social Science & Medicine (1982). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14572927&query_hl=1&itool=pubmed_docsum
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Sensorimotor mapping affects movement correction deficits in early Huntington's disease. Author(s): Lemay M, Fimbel E, Beuter A, Chouinard S, Richer F. Source: Experimental Brain Research. Experimentelle Hirnforschung. Experimentation Cerebrale. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15875168&query_hl=1&itool=pubmed_docsum
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Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective. Author(s): Qiu Z, Norflus F, Singh B, Swindell MK, Buzescu R, Bejarano M, Chopra R, Zucker B, Benn CL, DiRocco DP, Cha JH, Ferrante RJ, Hersch SM. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16595660&query_hl=1&itool=pubmed_docsum
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The midlatency auditory evoked potential P50 is abnormal in Huntington's disease. Author(s): Uc EY, Skinner RD, Rodnitzky RL, Garcia-Rill E. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12809992&query_hl=1&itool=pubmed_docsum
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The therapeutic role of creatine in Huntington's disease. Author(s): Ryu H, Rosas HD, Hersch SM, Ferrante RJ. Source: Pharmacology & Therapeutics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16055197&query_hl=1&itool=pubmed_docsum
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The use of the R6 transgenic mouse models of Huntington's disease in attempts to develop novel therapeutic strategies. Author(s): Li JY, Popovic N, Brundin P. Source: Neurorx. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16389308&query_hl=1&itool=pubmed_docsum
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Transcranial magnetic stimulation attenuates cell loss and oxidative damage in the striatum induced in the 3-nitropropionic model of Huntington's disease. Author(s): Tunez I, Drucker-Colin R, Jimena I, Medina FJ, Munoz Mdel C, Pena J, Montilla P. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16524377&query_hl=1&itool=pubmed_docsum
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Translating therapies for Huntington's disease from genetic animal models to clinical trials. Author(s): Hersch SM, Ferrante RJ. Source: Neurorx. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15717031&query_hl=1&itool=pubmed_docsum
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Use of oral nutritional supplements in patients with Huntington's disease. Author(s): Trejo A, Boll MC, Alonso ME, Ochoa A, Velasquez L. Source: Nutrition (Burbank, Los Angeles County, Calif.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16087319&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 Huntington disease; 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 Parkinson's Disease Source: Integrative Medicine Communications; www.drkoop.com Tardive Dyskinesia Source: Healthnotes, Inc.; www.healthnotes.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 3. PATENTS ON HUNTINGTON DISEASE Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.7 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “Huntington disease“ (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on Huntington disease, we have not necessarily excluded non-medical patents in this bibliography.
Patent Applications on Huntington Disease As of December 2000, U.S. patent applications are open to public viewing.8 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to Huntington disease:
7Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm. 8 This has been a common practice outside the United States prior to December 2000.
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Treatment of Huntington's disease by brain stimulation Inventor(s): Pianca, Anne M.; (Valencia, CA), Whitehurst, Todd K.; (Santa Clarita, CA) Correspondence: Advanced Bionics Corporation; 25129 Rye Canyon Road; Valencia; CA; 91355; US Patent Application Number: 20040225335 Date filed: May 5, 2004 Abstract: Introducing one or more stimulating drugs to the brain and/or applying electrical stimulation to the brain is used to treat Huntington's disease. At least one implantable system control unit (SCU) produces electrical pulses delivered via electrodes implanted in the brain and/or drug infusion pulses delivered via a catheter implanted in the brain. The stimulation is delivered to targeted brain structures to adjust the activity of those structures. In some embodiments, one or more sensed conditions are used to adjust stimulation parameters. Excerpt(s): The present application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/469,080, filed 08 May 2003, which application is incorporated herein by reference. The present invention generally relates to implantable drug delivery and electrical stimulation systems and methods, and more particularly relates to utilizing one or more implantable devices to deliver electrical stimulation and/or one or more stimulating drugs to certain areas of the brain as a treatment for Huntington's disease. Huntington's disease (HD) is an inherited disorder characterized by abnormalities in motor function, personality, thinking, and memory. While the typical age of onset is approximately 40-45, onset may be much earlier. HD is a progressive disorder that leads to death approximately 17 years after onset. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with Huntington disease, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under Issued Patents, click Quick Search. Then, type Huntington disease (or a synonym) into the Term 1 box. After clicking on the search button, scroll down to see the various patents which have been granted to date on Huntington disease. You can also use this procedure to view pending patent applications concerning Huntington disease. Simply go back to http://www.uspto.gov/patft/index.html. Select Quick Search under Published Applications. Then proceed with the steps listed above.
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CHAPTER 4. BOOKS ON HUNTINGTON DISEASE Overview This chapter provides bibliographic book references relating to Huntington disease. 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 Huntington disease. 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 Huntington disease at online booksellers’ Web sites, you may discover non-medical books that use the generic term “Huntington disease” (or a synonym) in their titles. The following is indicative of the results you might find when searching for Huntington disease (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
A description of selected speech characteristics in Huntington's disease Douglas J Anderson (1988); ISBN: B00071MGW2; http://www.amazon.com/exec/obidos/ASIN/B00071MGW2/icongroupinterna
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A family member speaks about Huntington's disease Marjorie Guthrie (1979); ISBN: B00072XQOS; http://www.amazon.com/exec/obidos/ASIN/B00072XQOS/icongroupinterna
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A genetic checkup: Lessons from Huntington disease and cystic fibrosis: An article from: The Scientist Ricki Lewis (2005); ISBN: B000BEFB2C; http://www.amazon.com/exec/obidos/ASIN/B000BEFB2C/icongroupinterna
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A physician's guide to the management of Huntington's disease (1999); ISBN: 096377302X; http://www.amazon.com/exec/obidos/ASIN/096377302X/icongroupinterna
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Afraid: A book for children "at risk" for Huntington's disease Michelle Hardt Thompson (2002); ISBN: B0006SBKBE; http://www.amazon.com/exec/obidos/ASIN/B0006SBKBE/icongroupinterna
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Care of the patient and family with Huntington's disease: A guide for clinicians Ira Shoulson (1989); ISBN: B00072MUPE; http://www.amazon.com/exec/obidos/ASIN/B00072MUPE/icongroupinterna
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Case studies: the price of silence. (Huntington's disease and ethics; includes commentaries): An article from: The Hastings Center Report John C. Fletcher, Dorothy Wertz, Abbyann Lynch, and Andrew Czeizel (2005); ISBN: B0008MH224; http://www.amazon.com/exec/obidos/ASIN/B0008MH224/icongroupinterna
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Cell Transplantation for Huntington's Disease (Medical Intelligence Unit) Paul R. Sanberg, Klas Wictorin, and Ole Isacson (1994); ISBN: 1570590796; http://www.amazon.com/exec/obidos/ASIN/1570590796/icongroupinterna
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Clinical care of the patient and family with Huntington's disease Ira Shoulson (1978); ISBN: B000738F0C; http://www.amazon.com/exec/obidos/ASIN/B000738F0C/icongroupinterna
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Early Huntington's disease affects movements in transformed sensorimotor mappings C. Boulet, M. Lemay, M.A. Bedard, and M.J. Chouinard (2005); ISBN: B000M7EMMS; http://www.amazon.com/exec/obidos/ASIN/B000M7EMMS/icongroupinterna
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Episodic memory impairment in Huntington's disease: A meta-analysis A. Montoya, M. Pelletier, M. Menear, and E. Duplessis (2006); ISBN: B000HD1TYQ; http://www.amazon.com/exec/obidos/ASIN/B000HD1TYQ/icongroupinterna
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Expression of mutant huntingtin in glial cells contributes to the neuropathology of Huntington's disease: (Dissertation) Ji-Yeon Shin (2006); ISBN: B000JU9X72; http://www.amazon.com/exec/obidos/ASIN/B000JU9X72/icongroupinterna
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Fetal nerve cells transplanted into brain of Huntington's disease patient appear to have survived.(Brief Article): An article from: Transplant News (2005); ISBN: B0008HJX0S; http://www.amazon.com/exec/obidos/ASIN/B0008HJX0S/icongroupinterna
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Fetal striatal cell transplants feasible for Huntington's disease but may not be helpful.(Brief Article): An article from: Transplant News (2005); ISBN: B0009FAEA2; http://www.amazon.com/exec/obidos/ASIN/B0009FAEA2/icongroupinterna
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Gale Encyclopedia of Medicine: Huntington disease Laith Farid Gulli M.D. (2004); ISBN: B00075UZ1C; http://www.amazon.com/exec/obidos/ASIN/B00075UZ1C/icongroupinterna
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Grafting fetal neuroblast cells into the brains of Huntington's disease patients improves motor-function-French study.(INSERM study in Cretail)(Brief Article): An article from: Transplant News (2005); ISBN: B0008J85HS; http://www.amazon.com/exec/obidos/ASIN/B0008J85HS/icongroupinterna
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Hanging in the Balance: In Search of My Inner Soul, Living with Huntington's Disease Arva D. Brackins (1998); ISBN: B000M773HY; http://www.amazon.com/exec/obidos/ASIN/B000M773HY/icongroupinterna
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Heading for Better Care: Commissioning and Providing Mental Health Services for People with Huntington's Disease, Acquired Brain Injury and Early Onset. NHS Health Advisory Service Thematic Review) Richard Williams, Ken Barrett, and Zena
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Muth (1997); ISBN: 0113219377; http://www.amazon.com/exec/obidos/ASIN/0113219377/icongroupinterna •
Huntington Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References ICON Health Publications (2004); ISBN: 0597844550; http://www.amazon.com/exec/obidos/ASIN/0597844550/icongroupinterna
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Huntington disease pathology unfolds: An article from: The Scientist Ricki Lewis (2005); ISBN: B000BEARTE; http://www.amazon.com/exec/obidos/ASIN/B000BEARTE/icongroupinterna
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Huntington's disease (Advances in neurology) (1979); ISBN: 0890043744; http://www.amazon.com/exec/obidos/ASIN/0890043744/icongroupinterna
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Huntington's Disease (Genetic Diseases) Johanna Knowles (2006); ISBN: 1404206949; http://www.amazon.com/exec/obidos/ASIN/1404206949/icongroupinterna
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Huntington's Disease (Oxford Monographs on Medical Genetics, 45) Gillian Bates (1980); ISBN: B000MU6RH8; http://www.amazon.com/exec/obidos/ASIN/B000MU6RH8/icongroupinterna
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Huntington's Disease (The Infinite Mind, vol. 106) The Infinite Mind (2000); ISBN: 1932479570; http://www.amazon.com/exec/obidos/ASIN/1932479570/icongroupinterna
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Huntington's disease : hope through research (SuDoc HE 20.3502:H 92/998) Stephanie E. Clipper (1998); ISBN: B00010WRK0; http://www.amazon.com/exec/obidos/ASIN/B00010WRK0/icongroupinterna
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Imaging gene expression in the brain in vivo in a transgenic mouse model of Huntington's disease with an antisense radiopharmaceutical and drug-targeting. from: The Journal of Nuclear Medicine Hwa Jeong Lee, Ruben J Boado, Dwaine A Braasch, and David R Corey (2005); ISBN: B000BE2616; http://www.amazon.com/exec/obidos/ASIN/B000BE2616/icongroupinterna
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Joint Resolution to Designate the Month of May 1991, as "National Huntington's Disease Awareness Month." United States (1991); ISBN: 0160331323; http://www.amazon.com/exec/obidos/ASIN/0160331323/icongroupinterna
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Learning to Live With Huntington's Disease: One Family's Story Sandy Sulaiman (2007); ISBN: 1843104873; http://www.amazon.com/exec/obidos/ASIN/1843104873/icongroupinterna
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Living with Huntington's Disease: A Book for Patients and Families Dennis Phillips (1982); ISBN: 0299086747; http://www.amazon.com/exec/obidos/ASIN/0299086747/icongroupinterna
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Metabolic network abnormalities in early Huntington's disease: An [(18)F]FDG PET study: An article from: The Journal of Nuclear Medicine Andrew Feigin, Klaus L Leenders, James R Moeller, and John Missimer (2005); ISBN: B000BCVNGC; http://www.amazon.com/exec/obidos/ASIN/B000BCVNGC/icongroupinterna
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Metabolon collaborates on biomarker study for Huntington's Disease.(High Q Foundation): An article from: BIOTECH Patent News (2006); ISBN: B000973GDC; http://www.amazon.com/exec/obidos/ASIN/B000973GDC/icongroupinterna
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Nutrition and Huntington's Disease, A practical guide--A multidisciplinary approach. (Book Reviews).(Book Review): An article from: Nutrition & Dietetics:. of the Dieticians Association of Australia Beth Rohrlach (2005); ISBN: B0008FZ67O; http://www.amazon.com/exec/obidos/ASIN/B0008FZ67O/icongroupinterna
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Reliability of speech intelligibility ratings using the unified Huntington Disease Rating Scale.: An article from: Journal of Medical Speech - Language Pathology Richard I. Zraick, Dena J. Davenport, Samer D. Tabbal, and Terri J. Hutton (2005); ISBN: B000827MV0; http://www.amazon.com/exec/obidos/ASIN/B000827MV0/icongroupinterna
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Remotivation Therapy and Huntington's Disease.: An article from: Journal of Neuroscience Nursing Florinda R. Sullivan, Edward D. Bird, Menekse Alpay, and JangHo J. Cha (2005); ISBN: B0008I04EQ; http://www.amazon.com/exec/obidos/ASIN/B0008I04EQ/icongroupinterna
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Report: Commission for the Control of Huntington's Disease and Its Consequences. Volume I: Overview, Volume II: Technical Report Volume III Part 1: Work Group Reports- Research, Volume III Part 2: Work Group Reports- Social Management [Huntington's Disease]. (1977); ISBN: B000L02RRI; http://www.amazon.com/exec/obidos/ASIN/B000L02RRI/icongroupinterna
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Role ofp53 in Huntington's disease: (Dissertation) Byoung-Il Bae (2006); ISBN: B000GQM1FA; http://www.amazon.com/exec/obidos/ASIN/B000GQM1FA/icongroupinterna
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Sirna granted patent covering siRNAs targeting Huntington's Disease.: An article from: BIOTECH Patent News (2005); ISBN: B000BYKE6A; http://www.amazon.com/exec/obidos/ASIN/B000BYKE6A/icongroupinterna
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Sirna's collaborator publishes breakthrough research on Huntington's Disease.: An article from: BIOTECH Patent News (2006); ISBN: B000ALQ6WK; http://www.amazon.com/exec/obidos/ASIN/B000ALQ6WK/icongroupinterna
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Speech disorders in mild and moderate Huntington disease: results of dysarthria assessments of 19 individuals.: An article from: Journal of Medical Speech - Language Pathology Lena Hartelius, Anna Carlstedt, Monica Ytterberg, and Malin Lillvik (2005); ISBN: B0009FYJ5S; http://www.amazon.com/exec/obidos/ASIN/B0009FYJ5S/icongroupinterna
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The Neurobiology of Huntington's Disease (Frontiers in Neuroscience) Donald C. Lo and Robert E. Hughes (2008); ISBN: 0849390001; http://www.amazon.com/exec/obidos/ASIN/0849390001/icongroupinterna
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The Official Patient's Sourcebook on Huntington's Disease: A Revised and Updated Directory for the Internet Age Icon Health Publications (2002); ISBN: 0597830487; http://www.amazon.com/exec/obidos/ASIN/0597830487/icongroupinterna
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The Test: Living in the Shadow of Huntington's Disease Jean Barema (2005); ISBN: 1879957574; http://www.amazon.com/exec/obidos/ASIN/1879957574/icongroupinterna
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Toward a fuller life: A guide to everyday living with Huntington's disease Eileen Werbel (1990); ISBN: B0006EW7Z6; http://www.amazon.com/exec/obidos/ASIN/B0006EW7Z6/icongroupinterna
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Understanding behavior in Huntington's disease: A practical guide for individuals, families, and professionals coping with HD Jane S Paulsen (1999); ISBN: 0963773046; http://www.amazon.com/exec/obidos/ASIN/0963773046/icongroupinterna
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Understanding the Neuropsychiatric Symptoms of Huntington's Disease.: An article from: Journal of Neuroscience Nursing Nancy Hofmann (2005); ISBN: B00099KFES; http://www.amazon.com/exec/obidos/ASIN/B00099KFES/icongroupinterna
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Use of relaxation training to reduce choreiform movements in a 17-year-old male with Huntington's disease Ora L Smith (1978); ISBN: B0007AO1SK; http://www.amazon.com/exec/obidos/ASIN/B0007AO1SK/icongroupinterna
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Walking the tightrope: Living at risk for Huntington's Disease Randi Jones (1996); ISBN: B0006RZHV4; http://www.amazon.com/exec/obidos/ASIN/B0006RZHV4/icongroupinterna
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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.
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Endoplasmic reticulum (ER): This organelle helps process molecules created by the cell and transport them to their specific destinations either inside or outside the cell.
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Golgi apparatus: The golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.
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Lysosomes and peroxisomes: These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.
9
This appendix is an excerpt from the National Library of Medicine’s handbook, Help Me Understand Genetics. For the full text of the Help Me Understand Genetics handbook, see http://ghr.nlm.nih.gov/handbook.
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Mitochondria: Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.
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Nucleus: The nucleus serves as the cell’s command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.
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Plasma membrane: The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.
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Ribosomes: Ribosomes are organelles that process the cell’s genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum. What Is DNA?
DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.
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DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone. What Is Mitochondrial DNA? Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of
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DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins. What Is a Gene? A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.
Genes are made up of DNA. Each chromosome contains many genes. What Is a Chromosome? In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are not visible in the cell’s nucleus—not even under a microscope—when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know about chromosomes was learned by observing chromosomes during cell division. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.
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DNA and histone proteins are packaged into structures called chromosomes. How Many Chromosomes Do People Have? In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twentytwo of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.
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The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype. How Do Geneticists Indicate the Location of a Gene? Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene’s position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome. Cytogenetic Location Geneticists use a standardized way of describing a gene’s cytogenetic location. In most cases, the location describes the position of a particular band on a stained chromosome: 17q12 It can also be written as a range of bands, if less is known about the exact location: 17q12-q21 The combination of numbers and letters provide a gene’s “address” on a chromosome. This address is made up of several parts: •
The chromosome on which the gene can be found. The first number or letter used to describe a gene’s location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.
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•
The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene’s address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.
•
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.
•
Insertion: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.
•
Deletion: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).
•
Duplication: A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.
•
Frameshift mutation: This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.
•
Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly. Can Changes in Chromosomes Affect Health and Development?
Changes that affect entire chromosomes or segments of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and alter the proteins made by those genes. Conditions caused by a change in the number or structure of chromosomes are known as chromosomal disorders. Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes leads to a chromosomal disorder. These 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.
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The most common form of aneuploidy is trisomy, or the presence of an extra chromosome in each cell. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in each cell instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy—people with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell. Monosomy, or the loss of one chromosome from each cell, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in each cell instead of the normal two copies. Turner syndrome is a condition caused by monosomy. Women with Turner syndrome are often missing one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell. Chromosomal disorders can also be caused by changes in chromosome structure. These changes are caused by the breakage and reunion of chromosome segments when an egg or sperm cell is formed or in early fetal development. Pieces of DNA can be rearranged within one chromosome, or transferred between two or more chromosomes. The effects of structural changes depend on their size and location. Many different structural changes are possible; some cause medical problems, while others may have no effect on a person’s health. Many cancer cells also have changes in their chromosome number or structure. These changes most often occur in somatic cells (cells other than eggs and sperm) during a person’s lifetime. Can Changes in Mitochondrial DNA Affect Health and Development? Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision. Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.
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What Are Complex or Multifactorial Disorders? Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. By 2010, however, researchers predict they will have found the major contributing genes for many common complex disorders. What Information about a Genetic Condition Can Statistics Provide? Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person’s family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient. Common Statistical Terms Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include: Statistical Term Incidence
Description The incidence of a gene mutation or a genetic disorder is the number of people who are born with the mutation or disorder in a specified group per year. Incidence is often written in the form “1 in [a number]” or as a total number of live births.
Examples About 1 in 200,000 people in the United States are born with syndrome A each year. An estimated 15,000 infants with syndrome B were born last year worldwide.
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Prevalence
The prevalence of a gene mutation or a genetic disorder is the total number of people in a specified group at a given time who have the mutation or disorder. This term includes both newly diagnosed and preexisting cases in people of any age. Prevalence is often written in the form “1 in [a number]” or as a total number of people who have a condition.
Approximately 1 in 100,000 people in the United States have syndrome A at the present time. About 100,000 children worldwide currently have syndrome B.
Mortality
Mortality is the number of deaths from a particular disorder occurring in a specified group per year. Mortality is usually expressed as a total number of deaths.
An estimated 12,000 people worldwide died from syndrome C in 2002.
Lifetime risk
Lifetime risk is the average risk of developing a particular disorder at some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a number].” It is important to remember that the risk per year or per decade is much lower than the lifetime risk. In addition, other factors may increase or decrease a person’s risk as compared with the average.
Approximately 1 percent of people in the United States develop disorder D during their lifetimes. The lifetime risk of developing disorder D is 1 in 100.
Naming Genetic Conditions Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment. Disorder names are often derived from one or a combination of sources: •
The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency)
•
One or more major signs or symptoms of the disorder (for example, sickle cell anemia)
•
The parts of the body affected by the condition (for example, retinoblastoma)
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•
The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan)
•
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
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such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders. 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,
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including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins. 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.
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X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50 percent chance of having sons who are affected and a 50 percent chance of having daughters who carry one copy of the mutated gene.
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Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child.
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Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial
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disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected. Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health. Factors that Influence the Effects of Particular Genetic Changes Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern. Reduced Penetrance Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations. Variable Expressivity Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and
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symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience lifethreatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose. What Do Geneticists Mean by Anticipation? The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation. Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation. What Is Genomic Imprinting? Genomic imprinting is a factor that influences how some genetic conditions are inherited. People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited
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from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13). What Is Uniparental Disomy? Uniparental disomy is a factor that influences how some genetic conditions are inherited. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems. Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11. Are Chromosomal Disorders Inherited? Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next. Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.
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Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional. Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next. Why Are Some Genetic Conditions More Common in Particular Ethnic Groups? Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.
Genetic Consultation This section presents information on finding and visiting a genetic counselor or other genetics professional. What Is a Genetic Consultation? A genetic consultation is a health service that provides information and support to people who have, or may be at risk for, genetic disorders. During a consultation, a genetics professional meets with an individual or family to discuss genetic risks or to diagnose, confirm, or rule out a genetic condition. Genetics professionals include medical geneticists (doctors who specialize in genetics) and genetic counselors (certified healthcare workers with experience in medical genetics and counseling). Other healthcare professionals such as nurses, psychologists, and social workers trained in genetics can also provide genetic consultations. Consultations usually take place in a doctor’s office, hospital, genetics center, or other type of medical center. These meetings are most often in-person visits with individuals or families, but they are occasionally conducted in a group or over the telephone.
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Why Might Someone Have a Genetic Consultation? Individuals or families who are concerned about an inherited condition may benefit from a genetic consultation. The reasons that a person might be referred to a genetic counselor, medical geneticist, or other genetics professional include: •
A personal or family history of a genetic condition, birth defect, chromosomal disorder, or hereditary cancer.
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Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.
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A child with a known inherited disorder, a birth defect, mental retardation, or developmental delay.
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A woman who is pregnant or plans to become pregnant at or after age 35. (Some chromosomal disorders occur more frequently in children born to older women.)
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Abnormal test results that suggest a genetic or chromosomal condition.
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An increased risk of developing or passing on a particular genetic disorder on the basis of a person’s ethnic background.
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People related by blood (for example, cousins) who plan to have children together. (A child whose parents are related may be at an increased risk of inheriting certain genetic disorders.)
A genetic consultation is also an important part of the decision-making process for genetic testing. A visit with a genetics professional may be helpful even if testing is not available for a specific condition, however. What Happens during a Genetic Consultation? A genetic consultation provides information, offers support, and addresses a patient’s specific questions and concerns. To help determine whether a condition has a genetic component, a genetics professional asks about a person’s medical history and takes a detailed family history (a record of health information about a person’s immediate and extended family). The genetics professional may also perform a physical examination and recommend appropriate tests. If a person is diagnosed with a genetic condition, the genetics professional provides information about the diagnosis, how the condition is inherited, the chance of passing the condition to future generations, and the options for testing and treatment. During a consultation, a genetics professional will: •
Interpret and communicate complex medical information.
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Help each person make informed, independent decisions about their health care and reproductive options.
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Respect each person’s individual beliefs, traditions, and feelings.
A genetics professional will NOT: •
Tell a person which decision to make.
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Advise a couple not to have children.
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Recommend that a woman continue or end a pregnancy.
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Tell someone whether to undergo testing for a genetic disorder. 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. What Are the Types of Genetic Tests? Genetic testing can provide information about a person’s genes and chromosomes. Available types of testing include:
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•
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 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.
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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 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
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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.
•
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/
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/Publications/FactSheets.htm
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancertopics/pdq
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/health/
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/HealthInformation/Publications/
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/Publications/
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/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidcr.nih.gov/HealthInformation/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/healthinformation/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.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
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/index.html
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Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
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 Huntington disease (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 6512 166 66 6 2 6752
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 Huntington disease (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/.
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Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
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 Huntington disease can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internetbased 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 Huntington disease. 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 Huntington disease. 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 Huntington disease:
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Alzheimer's Disease http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html Behcet's Syndrome http://www.nlm.nih.gov/medlineplus/behcetssyndrome.html Dementia http://www.nlm.nih.gov/medlineplus/dementia.html Genetic Disorders http://www.nlm.nih.gov/medlineplus/geneticdisorders.html Huntington's Disease http://www.nlm.nih.gov/medlineplus/huntingtonsdisease.html Movement Disorders http://www.nlm.nih.gov/medlineplus/movementdisorders.html Neuromuscular Disorders http://www.nlm.nih.gov/medlineplus/neuromusculardisorders.html Paget's Disease of Bone http://www.nlm.nih.gov/medlineplus/pagetsdiseaseofbone.html Parkinson's Disease http://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html Peripheral Nerve Disorders http://www.nlm.nih.gov/medlineplus/peripheralnervedisorders.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: •
Brain Resources for Seniors Source: www.dana.org http://www.dana.org/seniors/browse.cfm?category=1&level=2&sub=76
Patient Resources
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Chorea Information Page: National Institute of Neurological Disorders and Stroke (NINDS) Summary: Chorea is a primary feature of Huntington's disease, a progressive, hereditary movementdisorder that appears in adults. Source: www.ninds.nih.gov http://www.ninds.nih.gov/disorders/chorea/chorea.htm
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DANA BrainWeb & Brain Information: Information on Brain Disorders. Source: www.dana.org http://www.dana.org/brainweb/brainweb.cfm?CategoryID=32
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HONselect - Huntington Disease Source: www.hon.ch http://www.hon.ch/HONselect/RareDiseases/C10.228.140.079.545.html
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Huntington's Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS) Summary: Huntington's Disease information sheet compiled by the National Institute of Neurological Disorders and Stroke (NINDS). What is Huntington's Disease? Source: www.ninds.nih.gov http://www.ninds.nih.gov/disorders/huntington/huntington.htm
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Huntington's Disease Press Releases: National Institute of Neurological Disorders and Stroke (NINDS) Source: www.ninds.nih.gov http://www.ninds.nih.gov/disorders/huntington/press_huntington.htm
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Huntington's Disease Society of America: FAQ's Summary: Huntington's Disease: a devastating, hereditary, degenerative brain disorderfor which there is, at present, no effective treatment or cure. Source: www.hdsa.org http://www.hdsa.org/site/PageServer?pagename=help_info_ed_faq
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Kennedy's Disease Press Releases: National Institute of Neurological Disorders and Stroke (NINDS) Source: www.ninds.nih.gov http://www.ninds.nih.gov/disorders/kennedys/press_kennedys.htm
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MedlinePlus Go Local - Find Huntington's Disease Services Source: www.nlm.nih.gov http://www.nlm.nih.gov/medlineplus/golocal/topicmap_1218.html
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MedlinePlus: Brain and Nerves Topics Source: www.nlm.nih.gov http://www.nlm.nih.gov/medlineplus/brainandnerves.html
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MedlinePlus: Huntington's Disease Source: www.nlm.nih.gov http://www.nlm.nih.gov/medlineplus/huntingtonsdisease.html 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 Huntington disease. 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 Huntington disease (or synonyms) into the search box, and click Search. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMD®Health: http://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 Huntington disease. By consulting all of associations
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listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with Huntington disease. 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 Huntington disease. 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 Huntington disease (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://healthhotlines.nlm.nih.gov/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type Huntington disease (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
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Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html
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Madisons Foundation: http://www.madisonsfoundation.org/
22
Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.
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•
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
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A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html
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Genetic Mapping: http://www.genome.gov/10000715
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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
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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
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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
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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/archive//20040831/nichsr/ta101/ta10108.html
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on Huntington disease: •
Basic Guidelines for Huntington Disease Huntington's disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000770.htm
•
Signs & Symptoms for Huntington Disease Anxiety, stress, and tension Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Behavior changes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003255.htm Change in mental status Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Chorea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003196.htm
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Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Depression Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Difficulty swallowing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003115.htm Hallucinations Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003258.htm Loss of memory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003257.htm Movement, uncontrolled - slow Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003197.htm Movement, unpredictable - jerky Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003196.htm Restless Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003212.htm Speech impairment Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003204.htm Unsteady gait Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003199.htm Wasting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003188.htm •
Diagnostics and Tests for Huntington Disease Dopamine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003561.htm Head CT scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003786.htm Head MRI scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003791.htm PET (isotope) scan of the brain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003827.htm
•
Background Topics for Huntington Disease Symptomatic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002293.htm
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Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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HUNTINGTON DISEASE 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Actin: Essential component of the cell skeleton. [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] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH]
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Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] 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] Alfalfa: A deep-rooted European leguminous plant (Medicago sativa) widely grown for hay and forage. [NIH] 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] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] 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] Amantadine: An antiviral that is used in the prophylactic or symptomatic treatment of Influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. [NIH] Ambulatory Care: Health care services provided to patients on an ambulatory basis, rather than by admission to a hospital or other health care facility. The services may be a part of a hospital, augmenting its inpatient services, or may be provided at a free-standing facility.
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[NIH]
Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminooxyacetic Acid: A compound that inhibits aminobutyrate aminotransferase activity in vivo, thereby raising the level of gamma-aminobutyric acid in tissues. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]
Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]
Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] 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]
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Anisotropy: A physical property showing different values in relation to the direction in or along which the measurement is made. The physical property may be with regard to thermal or electric conductivity or light refraction. In crystallography, it describes crystals whose index of refraction varies with the direction of the incident light. It is also called acolotropy and colotropy. The opposite of anisotropy is isotropy wherein the same values characterize the object when measured along axes in all directions. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
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] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] 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]
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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] Articulation: The relationship of two bodies by means of a moveable joint. [NIH] Aspartate: A synthetic amino acid. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] 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
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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] Behavioral Symptoms: Observable manifestions of impaired psychological functioning. [NIH]
Bewilderment: Impairment or loss of will power. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] 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
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heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Fluids: Liquid components of living organisms. [NIH] 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] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Signaling: Signal transduction mechanisms whereby calcium mobilization (from outside the cell or from intracellular storage pools) to the cytoplasm is triggered by external stimuli. Calcium signals are often seen to propagate as waves, oscillations, spikes or puffs. The calcium acts as an intracellular messenger by activating calcium-responsive proteins. [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] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [NIH] 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] 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] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH]
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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] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] 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] 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 proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] 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] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [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
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the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Chaperonins: A class of sequence-related molecular chaperones found in bacteria, mitochondria, and plastids. Chaperonins are abundant constitutive proteins that increase in amount after stresses such as heat shock, bacterial infection of macrophages, and an increase in the cellular content of unfolded proteins. Bacterial chaperonins are major immunogens in human bacterial infections because of their accumulation during the stress of infection. Two members of this class of chaperones are chaperonin 10 and chaperonin 60. [NIH] 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] Checkup: A general physical examination. [NIH] 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] 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] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Cholinesterase Inhibitors: Drugs that inhibit cholinesterases. The neurotransmitter acetylcholine is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. [NIH] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Choreatic Disorders: Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for
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the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] 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] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [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
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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] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compulsion: In psychology, an irresistible urge, sometimes amounting to obsession to perform a particular act which usually is carried out against the performer's will or better judgment. [NIH] Computational Biology: A field of biology concerned with the development of techniques
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for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [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] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] 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
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results. [NIH] Corpus: The body of the uterus. [NIH] Corpus Striatum: Striped gray and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]
Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] 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] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cystamine: A radiation-protective agent that interferes with sulfhydryl enzymes. It may also protect against carbon tetrachloride liver damage. [NIH] Cysteamine: A radiation-protective agent that oxidizes in air to form cystamine. It can be given intravenously or orally to treat radiation sickness. The bitartrate has been used for the oral treatment of nephropathic cystinosis. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokines: Non-antibody proteins secreted by inflammatory leukocytes and some nonleukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. [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
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(phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytotoxic: Cell-killing. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [NIH]
Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [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] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Discrimination Learning: Learning that is manifested in the ability to respond differentially to various stimuli. [NIH]
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Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] 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] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Donepezil: A drug used in the treatment of Alzheimer's disease. It belongs to the family of drugs called cholinesterase inhibitors. It is being studied as a treatment for side effects caused by radiation therapy to the brain. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drug Combinations: Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. It is differentiated from combination drug therapy in which two or more drugs are administered separately for a combined effect. [NIH] Dwarfism: The condition of being undersized as a result of premature arrest of skeletal growth. It may be caused by insufficient secretion of growth hormone (pituitary dwarfism). [NIH]
Dysarthria: Imperfect articulation of speech due to disturbances of muscular control which result from damage to the central or peripheral nervous system. [EU] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dystonia: Disordered tonicity of muscle. [EU] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electric Conductivity: The ability of a substrate to allow the passage of electrons. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in
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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] 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] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endonucleases: Enzymes that catalyze the hydrolysis of the internal bonds and thereby the formation of polynucleotides or oligonucleotides from ribo- or deoxyribonucleotide chains. EC 3.1.-. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Enhancers: Transcriptional element in the virus genome. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner
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as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [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] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] 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] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excitatory Amino Acids: Endogenous amino acids released by neurons as excitatory neurotransmitters. Glutamic acid is the most common excitatory neurotransmitter in the brain. Aspartic acid has been regarded as an excitatory transmitter for many years, but the extent of its role as a transmitter is unclear. [NIH] Excitotoxicity: Excessive exposure to glutamate or related compounds can kill brain neurons, presumably by overstimulating them. [NIH] Excrete: To get rid of waste from the body. [NIH] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] 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] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and
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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] 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] Facial: Of or pertaining to the face. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] 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]
Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Forearm: The part between the elbow and the wrist. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the
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reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]
Gait: Manner or style of walking. [NIH] Gallate: Antioxidant present in tea. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Order: The sequential location of genes on a chromosome. [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 Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] General practitioner: A medical practitioner who does not specialize in a particular branch of medicine or limit his practice to a specific class of diseases. [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 Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus,
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transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] 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] 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] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] 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] Glycoproteins: Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] 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] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Hair Color: Color of hair or fur. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of
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health. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heat-Shock Proteins: Proteins which are synthesized in eukaryotic organisms and bacteria in response to hyperthermia and other environmental stresses. They increase thermal tolerance and perform functions essential to cell survival under these conditions. [NIH] Heat-Shock Proteins 90: A class of molecular chaperones whose members act in the mechanism of signal transduction by steroid receptors. [NIH] 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] 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] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH]
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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] Homozygote: An individual in which both alleles at a given locus are identical. [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] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] 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 conditions. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] 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] Iduronidase: An enzyme that hydrolyzes iduronosidic linkages in desulfated dermatan. Deficiency of this enzyme produces Hurler's syndrome. EC 3.2.1.76. [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] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] 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] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [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
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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] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] 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] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] 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] 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] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU]
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Intracellular: Inside a cell. [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] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoniazid: Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. [NIH] Kainate: Glutamate receptor. [NIH] 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] Kinetic: Pertaining to or producing motion. [EU] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large
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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] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
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] Ligases: A class of enzymes that catalyze the formation of a bond between two substrate molecules, coupled with the hydrolysis of a pyrophosphate bond in ATP or a similar energy donor. (Dorland, 28th ed) EC 6. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [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] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large
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numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [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 diameter) and used in transferring microorganisms. [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] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macroglia: A type of neuroglia composed of astrocytes. [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] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [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] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment.
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Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] 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 Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]
Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metabotropic: A glutamate receptor which triggers an increase in production of 2 intracellular messengers: diacylglycerol and inositol 1, 4, 5-triphosphate. [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] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [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] Minocycline: A semisynthetic staphylococcus infections. [NIH]
antibiotic
effective
against
tetracycline-resistant
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]
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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] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] 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] Molecular Chaperones: A family of cellular proteins that mediate the correct assembly or disassembly of other polypeptides, and in some cases their assembly into oligomeric structures, but which are not components of those final structures. It is believed that chaperone proteins assist polypeptides to self-assemble by inhibiting alternative assembly pathways that produce nonfunctional structures. Some classes of molecular chaperones are the nucleoplasmins, the chaperonins, the heat-shock proteins 70, and the heat-shock proteins 90. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [NIH]
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] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness,
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malnutrition, and particularly in denervation. [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] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] 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] Neostriatum: The phylogenetically newer part of the corpus striatum consisting of the caudate nucleus and putamen. It is often called simply the striatum. [NIH] Nerve Degeneration: Loss of functional activity and trophic degeneration of nerve axons and their terminal arborizations following the destruction of their cells of origin or interruption of their continuity with these cells. The pathology is characteristic of neurodegenerative diseases. Often the process of nerve degeneration is studied in research on neuroanatomical localization and correlation of the neurophysiology of neural pathways. [NIH]
Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural Pathways: Neural tracts connecting one part of the nervous system with another. [NIH]
Neurites: In tissue culture, hairlike projections of neurons stimulated by growth factors and other molecules. These projections may go on to form a branched tree of dendrites or a single axon or they may be reabsorbed at a later stage of development. "Neurite" may refer to any filamentous or pointed outgrowth of an embryonal or tissue-culture neural cell. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [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] Neurologic: Having to do with nerves or the nervous system. [NIH]
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Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuronal atrophy: Nerve cell death and functional loss. [NIH] Neuronal Plasticity: The capacity of the nervous system to change its reactivity as the result of successive activations. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neuroprotective Agents: Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. [NIH] Neuropsychology: A branch of psychology which investigates the correlation between experience or behavior and the basic neurophysiological processes. The term neuropsychology stresses the dominant role of the nervous system. It is a more narrowly defined field than physiological psychology or psychophysiology. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotoxin: A substance that is poisonous to nerve tissue. [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] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nicotinic Antagonists: Drugs that bind to nicotinic cholinergic receptors (receptors, nicotinic) and block the actions of acetylcholine or cholinergic agonists. Nicotinic antagonists block synaptic transmission at autonomic ganglia, the skeletal neuromuscular junction, and at central nervous system nicotinic synapses. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by
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volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] 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 Localization Signal: Short, predominantly basic amino acid sequences identified as nuclear import signals for some proteins. These sequences are believed to interact with specific receptors at nuclear pores. [NIH] Nuclear Medicine: A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds in a pharmaceutical form. [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Obsession: A recurrent, persistent thought, image, or impulse that is unwanted and distressing (ego-dystonic) and comes involuntarily to mind despite attempts to ignore or suppress it. Common obsessions involve thoughts of violence, contamination, and selfdoubt. [EU] Obsessive-Compulsive Disorder: An anxiety disorder characterized by recurrent, persistent obsessions or compulsions. Obsessions are the intrusive ideas, thoughts, or images that are experienced as senseless or repugnant. Compulsions are repetitive and seemingly purposeful behavior which the individual generally recognizes as senseless and from which the individual does not derive pleasure although it may provide a release from tension. [NIH] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [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
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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] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [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] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternal Age: Age of the father. [NIH] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH]
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PDQ: Physician Data Query. PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information is available on the CancerNet Web site, and more specific information about PDQ can be found at http://cancernet.nci.nih.gov/pdq.html. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Perivascular: Situated around a vessel. [EU] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an antiarrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [NIH] Philately: Study of stamps or postal markings. It usually refers to the design and commemorative aspects of the stamp. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] 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]
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Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of the eye. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] 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] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] 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] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different
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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] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [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] Postherpetic Neuralgia: Variety of neuralgia associated with migraine in which pain is felt in or behind the eye. [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prefrontal Cortex: The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Diagnosis: Determination of the nature of a pathological condition or disease in the postimplantation embryo, fetus, or pregnant female before birth. [NIH] 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] Prion: Small proteinaceous infectious particles that resist inactivation by procedures modifying nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. [NIH]
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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] 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] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] 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]
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Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychophysiology: The study of the physiological basis of human and animal behavior. [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] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Putamen: The largest and most lateral of the basal ganglia lying between the lateral medullary lamina of the globus pallidus and the external capsule. It is part of the neostriatum and forms part of the lentiform nucleus along with the globus pallidus. [NIH] Pyramidal Tracts: Fibers that arise from cells within the cerebral cortex, pass through the medullary pyramid, and descend in the spinal cord. Many authorities say the pyramidal tracts include both the corticospinal and corticobulbar tracts. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quinolinic: It is produced by immune cells and slowly infiltrates the brain tissues after an injury. [NIH] Quinolinic Acid: 2,3-Pyridinedicarboxylic acid. A metabolite of tryptophan with a possible role in neurodegenerative disorders. Elevated CSF levels of quinolinic acid are significantly correlated with the severity of neuropsychological deficits in patients who have AIDS. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a
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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] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Nicotinic: One of the two major classes of cholinergic receptors. Nicotinic receptors were originally distinguished by their preference for nicotine over muscarine. They are generally divided into muscle-type and neuronal-type (previously ganglionic) based on pharmacology, molecular biology, and biophysical properties of the channels. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] 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]
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Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [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] 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] Restriction Mapping: Use of restriction endonucleases to analyze and generate a physical map of genomes, genes, or other segments of DNA. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] 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] Riluzole: A glutamate antagonist that has reported anticonvulsant activity. It has been shown to prolong the survival of patients with amyotrophic lateral sclerosis and has been approved in the United States to treat patients with ALS. [NIH] Rod: A reception for vision, located in the retina. [NIH] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical
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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] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sequela: Any lesion or affection following or caused by an attack of disease. [EU] 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] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Sertraline: A selective serotonin uptake inhibitor that is used in the treatment of depression. [NIH]
Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the
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GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silver Staining: The use of silver, usually silver nitrate, as a reagent for producing contrast or coloration in tissue specimens. [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] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [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] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and
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types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Speech Intelligibility: Ability to make speech sounds that are recognizable. [NIH] Sperm: The fecundating fluid of the male. [NIH] Spermidine: A polyamine formed from putrescine. It is found in almost all tissues in association with nucleic acids. It is found as a cation at all pH values, and is thought to help stabilize some membranes and nucleic acid structures. It is a precursor of spermine. [NIH] Spermine: A biogenic polyamine formed from spermidine. It is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at all pH values. Spermine is associated with nucleic acids, particularly in viruses, and is thought to stabilize the helical structure. [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] Staphylococcus: A genus of gram-positive, facultatively anaerobic, coccoid bacteria. Its organisms occur singly, in pairs, and in tetrads and characteristically divide in more than one plane to form irregular clusters. Natural populations of Staphylococcus are membranes of warm-blooded animals. Some species are opportunistic pathogens of humans and animals. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] 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] Striatum: A higher brain's domain thus called because of its stripes. [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
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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]
Substrate: A substance upon which an enzyme acts. [EU] 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] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Systemic: Affecting the entire body. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH]
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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] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]
Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] 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] Tomograph: An X-ray apparatus; an instrument that produces a relatively sharp image of a thin layer of the object, all other layers being blurred by predetermined relative motion of the roentgen tube, film, and subject. [NIH] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH]
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Tonicity: The normal state of muscular tension. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]
Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Transport Vesicles: Vesicles that are involved in shuttling cargo from the interior of the cell to the cell surface, from the cell surface to the interior, across the cell or around the cell to various locations. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] 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,
Dictionary 199
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]
Trophic: Of or pertaining to nutrition. [EU] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberculostatic: Inhibiting the growth of Mycobacterium tuberculosis. [EU] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] 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] 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] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] 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] 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]
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Venous: Of or pertaining to the veins. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Vital Capacity: The volume of air that is exhaled by a maximal expiration following a maximal inspiration. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Volition: Voluntary activity without external compulsion. [NIH] Voltage-gated: It is opened by the altered charge distribution across the cell membrane. [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]
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Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] 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]
202
INDEX 3 3-dimensional, 108, 139, 154, 189 A Abdomen, 154, 176, 178, 186, 195, 200 Aberrant, 19, 24, 154 Acetylcholine, 154, 162, 183 Actin, 33, 35, 109, 154, 181, 182 Adaptability, 154, 161 Adaptation, 154, 187 Adenine, 102, 154, 190 Adenosine, 103, 154, 186 Adenosine Triphosphate, 103, 154, 186 Adenovirus, 135, 154 Adolescence, 4, 154 Adrenal Medulla, 154, 161, 169, 170, 184 Adrenergic, 154, 168, 170, 196 Adverse Effect, 154, 186, 193 Aerobic, 154, 180 Afferent, 155, 188 Affinity, 155, 158, 194 Age of Onset, 19, 49, 53, 55, 94, 155 Agonist, 155, 168, 183 Alfalfa, 70, 155 Algorithms, 155, 159 Alkaline, 155, 156, 160 Alkaloid, 155, 163, 183 Alleles, 46, 60, 70, 72, 82, 104, 121, 155, 174, 175 Allergen, 155, 193 Alpha-1, 117, 121, 155 Alternative medicine, 155 Amantadine, 40, 155 Ambulatory Care, 155 Amino Acid Sequence, 156, 157, 170, 184 Amino Acids, 104, 108, 114, 156, 163, 170, 186, 188, 189, 192, 198 Aminooxyacetic Acid, 52, 156 Ammonia, 156, 173 Amnion, 156 Amniotic Fluid, 130, 132, 156 Amphetamines, 156, 163 Amplification, 69, 156 Amygdala, 156, 158, 178, 197 Anal, 156, 170, 171, 178 Analog, 13, 156 Analogous, 15, 156, 198 Anatomical, 156, 162, 175, 180, 192 Anemia, 116, 117, 120, 121, 126, 156 Anesthesia, 74, 156
Aneuploidy, 114, 115, 156 Animal model, 15, 21, 24, 25, 26, 28, 29, 33, 35, 44, 52, 91, 156 Anisotropy, 12, 156 Annealing, 157, 187 Antibiotic, 85, 157, 180, 195, 197 Antibodies, 20, 109, 157, 175, 187 Antibody, 52, 109, 155, 157, 164, 166, 170, 175, 176, 191, 193, 194 Anticoagulant, 157, 189 Anticonvulsant, 157, 160, 186, 192 Antigen, 155, 157, 164, 175, 176, 180, 193 Anti-infective, 157, 177 Anti-inflammatory, 12, 29, 84, 157 Anti-Inflammatory Agents, 29, 157 Antioxidant, 12, 157, 172, 185 Antiviral, 155, 157 Anuria, 157, 177 Anus, 156, 157, 164 Anxiety, 151, 157, 184 Apoptosis, 7, 14, 15, 27, 38, 60, 78, 103, 112, 157, 160 Aqueous, 157, 158, 166, 169 Arginine, 158, 174 Arterial, 158, 175, 189 Arteries, 158, 160, 165 Arterioles, 158, 160 Articulation, 158, 168 Aspartate, 22, 36, 51, 158 Assay, 13, 19, 23, 158 Astrocytes, 158, 179, 180 Asymptomatic, 70, 158 Ataxia, 24, 27, 33, 158, 197 Atrophy, 31, 37, 43, 60, 70, 158, 182 Atypical, 125, 158 Auditory, 90, 91, 158, 188 Autoradiography, 74, 158 Axons, 35, 158, 182, 184 B Bacteria, 101, 109, 113, 157, 158, 162, 171, 174, 180, 191, 195, 198, 199 Basal Ganglia, 31, 60, 158, 162, 175, 178, 190 Basal Ganglia Diseases, 158, 162, 175 Base, 8, 28, 82, 102, 103, 106, 108, 112, 113, 114, 137, 154, 158, 159, 167, 171, 177, 187, 197 Base Sequence, 113, 159, 171 Behavioral Symptoms, 85, 159
Index 203
Bewilderment, 159, 165 Bile, 159, 178 Bioavailable, 86, 159 Biochemical, 13, 25, 29, 33, 47, 117, 155, 159, 177, 193 Biological Markers, 31, 159 Biological Transport, 159, 167 Biomarkers, 22, 159 Biotechnology, 5, 39, 108, 135, 137, 142, 159 Biotransformation, 159 Blastocyst, 159, 165 Blood Coagulation, 159, 160, 197 Blood Glucose, 159, 174, 176 Blood pressure, 120, 159, 160, 175, 181, 194 Blood vessel, 124, 159, 160, 161, 162, 177, 194, 195, 197, 199 Body Fluids, 159, 160, 194, 199 Bone Marrow, 136, 160, 172, 175, 179 Buccal, 130, 132, 160 Bulimia, 63, 160 C Calcium, 47, 160, 164, 194 Calcium Signaling, 47, 160 Callus, 160, 169 Carbamazepine, 50, 160 Carbon Dioxide, 160, 167, 171, 192 Carcinogenic, 160, 176, 189 Cardiac, 160, 170 Cardiovascular, 139, 160, 193 Cardiovascular disease, 139, 160 Case report, 75, 160 Caspase, 22, 24, 27, 29, 38, 41, 65, 160 Catecholamine, 161, 168 Catheter, 94, 161 Caudate Nucleus, 158, 161, 166, 182 Cause of Death, 161, 167 Cell Cycle, 111, 112, 161 Cell Death, 19, 24, 27, 29, 35, 52, 59, 112, 157, 161, 182, 183 Cell Differentiation, 161, 193 Cell Division, 104, 111, 112, 124, 125, 158, 161, 173, 179, 181, 187, 189, 193 Cell membrane, 159, 161, 167, 170, 188, 200 Cell proliferation, 161, 193 Cell Respiration, 161, 180, 192 Cell Transplantation, 38, 96, 161 Central Nervous System, 29, 154, 156, 161, 162, 163, 172, 173, 180, 183, 185, 193 Centromere, 104, 107, 161 Cerebellar, 56, 60, 158, 161, 191, 198
Cerebellum, 161, 191 Cerebral, 8, 28, 37, 43, 60, 75, 158, 161, 162, 165, 166, 170, 171, 172, 190, 196 Cerebral Cortex, 8, 158, 161, 171, 190 Cerebral hemispheres, 158, 161, 162, 196 Cerebrovascular, 158, 160, 161, 197 Cerebrum, 80, 161, 196 Chaperonins, 162, 181 Character, 162, 167 Checkup, 95, 162 Chemotherapy, 85, 88, 162 Chin, 162, 180 Cholesterol, 103, 159, 162, 165 Cholinergic, 162, 183, 191 Cholinesterase Inhibitors, 162, 168 Chorea, 3, 21, 63, 90, 147, 151, 162 Choreatic Disorders, 162 Choroid, 162, 192 Chromatin, 32, 157, 162, 179 Chromosomal, 25, 112, 114, 115, 125, 126, 127, 129, 156, 162, 174, 181 Chromosome Fragility, 162, 199 Chronic, 12, 14, 88, 163, 168, 176, 177, 179, 195 Chronic Fatigue Syndrome, 88, 163 Cirrhosis, 163, 174 CIS, 23, 163, 172 Clamp, 21, 36, 163 Clinical Medicine, 138, 163, 188 Clinical trial, 9, 13, 14, 22, 26, 29, 89, 91, 135, 136, 139, 142, 163, 165, 168, 186, 189, 191 Cloning, 45, 52, 70, 159, 163 Coca, 163 Cocaine, 34, 163 Codon, 109, 163 Coenzyme, 11, 14, 15, 24, 163 Cofactor, 163, 189, 197 Cognition, 3, 75, 163 Collagen, 163, 171 Colon, 17, 118, 163, 164, 178 Colonoscopy, 120, 164 Colorectal, 48, 164 Colorectal Cancer, 48, 164 Comorbidity, 28, 164 Complement, 164, 172, 177, 193 Complementary medicine, 84, 164 Compulsion, 28, 164, 200 Computational Biology, 142, 164 Computed tomography, 165 Computerized axial tomography, 165 Computerized tomography, 43, 165
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Huntington Disease
Concentric, 165, 184 Conception, 111, 165, 171, 194 Concomitant, 38, 165 Confusion, 118, 152, 165, 168, 199 Connective Tissue, 160, 163, 165, 171, 172 Consciousness, 165, 167, 190 Constriction, 104, 107, 165, 177 Consultation, 126, 127, 130, 131, 165 Contraindications, ii, 165 Controlled study, 30, 165 Convulsions, 157, 165, 183 Coordination, 3, 24, 28, 161, 165 Coronary, 160, 165 Coronary heart disease, 160, 165 Corpus, 166, 182, 200 Corpus Striatum, 166, 182 Cortex, 19, 30, 35, 36, 83, 166, 188, 191 Cortical, 21, 24, 26, 31, 64, 75, 87, 89, 166, 170, 188, 193, 197 Creatine, 11, 15, 24, 56, 86, 91, 166 Creatinine, 166, 177 Crossing-over, 166, 191 Cultured cells, 24, 35, 166 Curative, 166, 197 Cyclic, 11, 166, 186 Cystamine, 46, 73, 86, 166 Cysteamine, 15, 46, 166 Cysteine, 24, 86, 166 Cystine, 166 Cytochrome, 166, 185 Cytokines, 35, 166, 180 Cytoplasm, 24, 101, 102, 103, 109, 157, 160, 161, 166, 173, 179, 184, 192 Cytosine, 102, 167, 190 Cytotoxic, 35, 167, 194 D De novo, 112, 167 Death Certificates, 120, 167 Degenerative, 147, 167 Deletion, 51, 114, 157, 167 Dementia, 63, 74, 115, 146, 167 Demethylation, 19, 167 Denaturation, 167, 187 Dendrites, 167, 182, 183 Deoxyribonucleic, 102, 167, 192 Deoxyribonucleic acid, 102, 167, 192 Deoxyribonucleotides, 167 Depolarization, 60, 167, 194 Diabetes Mellitus, 167, 174 Diagnostic procedure, 93, 167 Diffusion, 11, 58, 87, 159, 167 Digestion, 159, 167, 176, 178, 195, 199
Diploid, 156, 167, 181, 187, 199 Direct, iii, 22, 24, 28, 34, 35, 130, 131, 132, 163, 167, 168, 191, 196 Discrimination, 87, 132, 133, 138, 167 Discrimination Learning, 87, 167 Disease Progression, 12, 24, 29, 31, 32, 168 Disorientation, 165, 168 Distal, 29, 168, 189 Dominance, 16, 168 Donepezil, 50, 168 Dopamine, 38, 68, 78, 152, 155, 163, 168, 183, 186 Double-blind, 14, 30, 88, 168 Drug Combinations, 15, 168 Dwarfism, 17, 168 Dysarthria, 98, 168 Dyskinesia, 75, 92, 168 Dystonia, 25, 49, 168 Dystrophic, 48, 168 Dystrophy, 20, 25, 168 E Efficacy, 13, 14, 15, 17, 20, 33, 36, 50, 168 Elective, 76, 77, 168 Electric Conductivity, 157, 168 Electrolyte, 168, 177, 188, 194 Electrons, 157, 159, 168, 177, 179, 185, 190 Elementary Particles, 168, 169, 179, 189 Embryo, 111, 112, 113, 121, 156, 159, 161, 169, 188 Embryogenesis, 19, 169 Emulsion, 158, 169, 171 Endemic, 169, 195 Endogenous, 17, 18, 22, 168, 169, 170, 183, 198 Endonucleases, 169, 192 Endorphins, 169, 183 Enhancers, 27, 169 Enkephalins, 169, 183 Environmental Exposure, 159, 169 Environmental Health, 141, 142, 169 Enzymatic, 160, 164, 169, 187 Enzyme Inhibitors, 29, 169 Epidemic, 170, 195 Epidemiologic Studies, 159, 170 Epinephrine, 154, 168, 170, 183, 184, 199 Epitope, 22, 170 Erythrocytes, 156, 160, 170, 193 Ethnic Groups, 126, 129, 170 Eukaryotic Cells, 170, 176, 185, 199 Excitability, 84, 89, 170 Excitation, 156, 170, 183 Excitatory, 21, 36, 170, 173, 183
Index 205
Excitatory Amino Acids, 170, 183 Excitotoxicity, 14, 15, 21, 29, 34, 38, 170 Excrete, 157, 170, 177 Exocytosis, 35, 170 Exogenous, 159, 169, 170 Exon, 12, 18, 26, 31, 64, 170 Expiration, 170, 192, 200 Extracellular, 35, 158, 165, 170, 171, 194 Extracellular Matrix, 165, 170, 171 Extrapyramidal, 21, 155, 168, 171 Eye Color, 113, 171 Eye Infections, 154, 171 F Facial, 90, 171 Family Planning, 142, 171 Fat, 160, 165, 171, 178, 194 Fathers, 121, 171 Fatigue, 163, 171 Ferritin, 67, 109, 171 Fetus, 58, 129, 130, 132, 136, 171, 188, 195, 199 Fibroblasts, 56, 62, 83, 171 Fibrosis, 95, 113, 116, 120, 121, 171, 192 Fissure, 171, 188 Fixation, 171, 193 Forearm, 160, 171 Frameshift, 114, 171 Frameshift Mutation, 114, 171 Free Radicals, 157, 172 Frontal Lobe, 172, 188 Functional magnetic resonance imaging, 11, 172 G Gait, 42, 152, 172 Gallate, 88, 172 Ganglia, 43, 154, 158, 172, 182, 183, 186 Gas, 156, 160, 167, 172, 175, 183 Gastrin, 172, 175 Gene Expression, 10, 27, 30, 35, 97, 109, 110, 172 Gene Order, 64, 172 Gene Products, rev, 172 Gene Therapy, 26, 28, 134, 135, 136, 154, 172 General practitioner, 85, 172 Genes, env, 120, 172 Genetic Engineering, 159, 163, 172 Genomics, 44, 69, 74, 79, 81, 139, 173 Genotype, 18, 41, 57, 173, 186 Germ Cells, 112, 136, 173, 179, 194 Germline mutation, 112, 173, 174 Gland, 154, 173, 185, 189, 193, 195, 197
Glucose, 37, 38, 75, 159, 167, 173, 174, 176 Glutamate, 21, 29, 36, 38, 64, 86, 170, 173, 177, 180, 192 Glutamic Acid, 173, 183 Glutamine, 4, 8, 16, 173 Glycine, 173, 183 Glycoproteins, 173, 177, 180, 188 Governing Board, 173, 188 Granule, 173, 192 Granulocytes, 173, 178, 194, 200 Growth factors, 173, 180, 182 Guanine, 102, 173, 190 H Hair Color, 113, 173 Half-Life, 37, 173 Haploid, 10, 173, 187 Health Services, 173 Heart attack, 160, 174 Heat-Shock Proteins, 174, 181 Heat-Shock Proteins 90, 174, 181 Hemochromatosis, 129, 174 Hemodialysis, 174, 177 Hemoglobin, 103, 156, 170, 174 Hemoglobinopathies, 172, 174 Hemophilia, 121, 174 Hemorrhage, 174, 195 Hereditary mutation, 112, 173, 174 Heredity, 104, 172, 173, 174 Heterogeneity, 55, 155, 174 Heterozygote, 25, 174 Histone Deacetylase, 11, 15, 174 Histones, 104, 162, 174 Homeostasis, 16, 24, 174 Homologous, 64, 155, 166, 172, 174, 175, 193, 196 Homozygote, 25, 175 Hormonal, 158, 175 Hormone, 109, 159, 168, 170, 172, 175, 176, 177, 193, 197 Hybrid, 74, 175 Hydrogen, 159, 167, 175, 178, 181, 185, 186, 189 Hydrolysis, 159, 169, 175, 178, 186, 188, 189 Hypersensitivity, 155, 175, 193 Hypertension, 160, 175 Hypokinesia, 175, 185 Hypothalamic, 46, 175 Hypothalamus, 175, 178 I Iduronidase, 64, 175 Immune response, 157, 175, 193, 196, 200
206
Huntington Disease
Immune system, 175, 179, 199, 200 Immunization, 175, 193 Immunofluorescence, 37, 175 Immunohistochemistry, 21, 175 Impairment, 12, 59, 77, 96, 152, 158, 159, 168, 171, 175, 180 Implantation, 165, 175 In situ, 54, 176 In Situ Hybridization, 54, 176 In vitro, 24, 26, 27, 29, 35, 37, 59, 172, 176, 187, 197 In vivo, 12, 17, 22, 24, 29, 31, 33, 37, 38, 59, 60, 67, 97, 156, 172, 176 Infancy, 139, 176 Infection, 29, 162, 171, 176, 179, 183, 195, 200 Inflammation, 135, 157, 171, 176, 187 Informed Consent, 130, 133, 138, 176 Infusion, 94, 176 Initiation, 13, 16, 26, 38, 176, 198 Inositol, 176, 180 Inotropic, 168, 176 Insight, 19, 23, 27, 32, 35, 176 Insulin, 63, 176 Insulin-dependent diabetes mellitus, 176 Intermittent, 176, 179 Intestine, 164, 176, 177 Intoxication, 176, 201 Intracellular, 10, 20, 21, 23, 35, 160, 176, 177, 180, 188, 193 Intravenous, 74, 176, 177 Intrinsic, 13, 16, 21, 155, 177 Invasive, 177, 179 Involuntary, 3, 42, 158, 162, 177, 191 Iodine, 45, 177 Ion Channels, 21, 158, 177, 186, 196 Ions, 158, 168, 175, 177, 188 Iris, 171, 177 Ischemia, 158, 177, 183 Isoniazid, 53, 177 K Kainate, 55, 177 Karyotype, 106, 177 Kidney Failure, 115, 177 Kidney Failure, Acute, 177 Kidney Failure, Chronic, 177 Kinetic, 177 L Large Intestine, 164, 176, 177, 191, 194 Lesion, 178, 193, 196 Lethal, 36, 178 Leucocyte, 155, 178, 179
Leukemia, 172, 178 Life cycle, 39, 178 Ligases, 29, 178 Limbic, 156, 178, 188 Limbic System, 156, 178, 188 Linkage, 44, 54, 55, 63, 64, 89, 178 Lipid, 176, 178, 185 Lipid Peroxidation, 178, 185 Liver, 110, 159, 163, 166, 167, 169, 174, 178 Localization, 37, 44, 76, 175, 178, 182 Localized, 171, 176, 178, 187 Locomotion, 178, 187 Locomotor, 88, 178 Longitudinal Studies, 21, 178 Longitudinal study, 59, 178 Long-Term Care, 44, 179 Loop, 24, 179 Lymphatic, 176, 179 Lymphoblasts, 60, 68, 77, 179 Lymphocytes, 62, 157, 175, 178, 179, 200 Lymphoid, 157, 178, 179 Lysine, 174, 179 M Macroglia, 179, 180 Macrophage, 112, 179 Magnetic Resonance Imaging, 88, 179 Magnetic Resonance Spectroscopy, 72, 179 Malignant, 68, 179 Malnutrition, 158, 179, 182 Mammography, 120, 179 Manifest, 12, 26, 179 Medial, 23, 179 Mediate, 23, 35, 168, 179, 181 Medical Records, 120, 133, 179 MEDLINE, 142, 179 Meiosis, 16, 57, 111, 179, 196 Melanin, 177, 179, 186, 199 Melanoma, 179, 199 Membrane Glycoproteins, 180 Memory, 94, 96, 152, 167, 180 Meninges, 161, 180 Mental Disorders, 175, 180, 190 Mental Health, iv, 9, 55, 96, 141, 143, 180 Mental Retardation, 36, 125, 127, 129, 180 Mentors, 28, 180 Meta-Analysis, 96, 180 Metabolite, 12, 57, 159, 180, 190 Metabotropic, 36, 180 Microbe, 180, 198 Microbiology, 154, 158, 180 Microglia, 49, 158, 180
Index 207
Microorganism, 163, 180, 200 Minocycline, 24, 29, 65, 180 Miscarriage, 132, 180 Mitochondria, 10, 14, 102, 103, 115, 121, 122, 162, 180, 185 Mitosis, 111, 157, 181 Mitotic, 16, 23, 65, 181 Mobilization, 160, 181 Modeling, 15, 181 Modification, 17, 18, 29, 32, 63, 74, 172, 181 Molecular Chaperones, 13, 162, 174, 181 Monitor, 38, 166, 181, 184 Monosomy, 115, 156, 181 Morphological, 169, 181 Morphology, 23, 26, 88, 181 Mosaicism, 66, 112, 181 Motor nerve, 29, 181, 184 Motor Neurons, 29, 181 Muscle Contraction, 25, 181 Muscle Fibers, 181, 182 Muscular Atrophy, 33, 181 Mutagens, 172, 182 Myosin, 181, 182 Myotonic Dystrophy, 19, 124, 182, 199 N NCI, 1, 140, 163, 182, 186 Necrosis, 157, 182, 193 Neostriatum, 27, 161, 166, 182, 190 Nerve Degeneration, 182 Nerve Growth Factor, 38, 182 Nervous System, 17, 20, 124, 155, 161, 182, 183, 186, 196 Networks, 28, 182 Neural, 9, 25, 28, 58, 73, 155, 180, 182 Neural Pathways, 182 Neurites, 24, 48, 182 Neuroblastoma, 13, 182 Neurodegenerative Diseases, 10, 13, 23, 29, 33, 36, 158, 182 Neurologic, 15, 182 Neuromuscular, 146, 154, 183 Neuromuscular Junction, 154, 183 Neuronal atrophy, 16, 183 Neuronal Plasticity, 25, 183 Neuropathy, 63, 121, 183 Neuropeptides, 46, 183 Neurophysiology, 51, 61, 84, 90, 167, 182, 183 Neuroprotective Agents, 14, 183 Neuropsychology, 11, 28, 43, 64, 70, 76, 77, 90, 183
Neurotoxic, 38, 183 Neurotoxicity, 13, 26, 38, 183 Neurotoxin, 37, 183 Neurotransmitter, 21, 32, 35, 41, 74, 154, 162, 168, 170, 173, 177, 183, 184, 193, 196 Nicotine, 34, 183, 191 Nicotinic Antagonists, 34, 183 Nitrogen, 155, 171, 173, 177, 183, 199 Norepinephrine, 34, 154, 168, 183, 184 Nuclear Envelope, 23, 102, 184 Nuclear Localization Signal, 80, 184 Nuclear Medicine, 38, 45, 97, 184 Nuclear Pore, 184 Nuclei, 29, 35, 48, 156, 169, 172, 173, 174, 178, 179, 181, 184, 185, 189 Nucleic acid, 159, 167, 176, 182, 184, 188, 190, 192, 195 Nurse Practitioners, 130, 184 O Obsession, 164, 184 Obsessive-Compulsive Disorder, 28, 184 Oculomotor, 21, 59, 184 Oliguria, 177, 184 Optic Nerve, 184, 192 Organ Culture, 185, 197 Organelles, 16, 101, 102, 166, 185, 187 Outpatient, 185 Ovaries, 129, 185, 193 Overexpress, 37, 185 Ovum, 178, 185, 201 Oxidation, 157, 159, 166, 178, 185 Oxidative Phosphorylation, 11, 37, 103, 185 Oxidative Stress, 10, 14, 15, 37, 185 P Palliative, 185, 197 Pancreas, 159, 174, 176, 185, 199 Parkinsonism, 63, 185 Patch, 21, 185 Paternal Age, 61, 185 Paternity, 129, 185 Pathologic, 19, 37, 157, 165, 175, 185 Pathologic Processes, 157, 185 Pathologies, 36, 185 Pathophysiology, 18, 25, 26, 30, 185 PDQ, 140, 186 Pelvis, 154, 185, 186, 199 Peptide, 186, 188, 189 Peripheral Nervous System, 168, 169, 182, 183, 186, 196 Perivascular, 180, 186 PH, 41, 45, 68, 69, 186
208
Huntington Disease
Phagocytosis, 180, 186 Pharmacokinetic, 186 Pharmacologic, 33, 156, 173, 186, 198 Phenotype, 14, 15, 18, 19, 25, 26, 27, 28, 36, 49, 57, 88, 159, 186 Phenylalanine, 109, 186, 199 Phenytoin, 160, 186 Philately, 55, 186 Phosphodiesterase, 11, 44, 186 Phospholipases, 186, 194 Phosphorus, 72, 160, 186, 187 Phosphorylated, 163, 187 Phosphorylation, 11, 103, 187 Photoreceptor, 44, 187 Physical Examination, 127, 162, 187 Physiologic, 16, 29, 155, 173, 175, 187, 191, 198 Physiology, 24, 49, 154, 159, 183, 187 Pilot study, 86, 87, 187 Plants, 155, 160, 163, 173, 181, 184, 187, 198 Plasma, 58, 102, 157, 161, 174, 177, 187 Plasma cells, 157, 187 Plasticity, 9, 87, 187 Plastids, 162, 185, 187 Platelet Activation, 187, 194 Pneumonia, 165, 187 Point Mutation, 28, 187 Polymerase, 59, 187 Polymerase Chain Reaction, 59, 187 Polymorphic, 19, 69, 187 Polymorphism, 33, 42, 131, 188 Polypeptide, 156, 163, 188, 189, 201 Polyposis, 164, 188 Posterior, 156, 158, 161, 162, 177, 185, 188 Postherpetic Neuralgia, 155, 188 Postnatal, 25, 188, 195 Postsynaptic, 21, 22, 35, 188, 194, 196 Potassium, 34, 188 Potassium Channels, 34, 188 Potentiation, 21, 162, 188, 194 Practice Guidelines, 143, 188 Preclinical, 12, 20, 59, 70, 75, 78, 188 Precursor, 168, 169, 184, 186, 188, 195, 199 Prefrontal Cortex, 34, 68, 188 Prenatal, 50, 58, 68, 69, 76, 129, 132, 169, 188 Prenatal Diagnosis, 50, 58, 69, 188 Presynaptic, 21, 35, 38, 183, 188, 196 Prevalence, 49, 73, 117, 188 Prion, 37, 57, 188 Probe, 13, 26, 82, 189
Progression, 12, 14, 16, 22, 24, 29, 31, 60, 73, 80, 156, 189 Projection, 18, 21, 184, 188, 189, 191 Promoter, 10, 13, 18, 22, 79, 189 Prone, 115, 124, 189 Prophase, 189, 196 Prospective study, 178, 189 Prostate, 159, 189, 199 Protease, 37, 189 Protein Conformation, 13, 25, 156, 189 Proteolytic, 22, 155, 164, 189 Protocol, 38, 78, 135, 189 Protons, 175, 179, 189, 190 Proximal, 29, 38, 168, 188, 189 Psychiatric, 11, 18, 28, 40, 45, 159, 180, 189 Psychiatry, 7, 11, 25, 26, 28, 55, 58, 68, 72, 88, 171, 189, 190 Psychic, 180, 190, 193 Psychoactive, 190, 201 Psychology, 41, 164, 183, 190 Psychophysiology, 183, 190 Public Policy, 142, 190 Pulmonary, 159, 177, 190, 200 Pulmonary Artery, 159, 190, 200 Pulmonary Edema, 177, 190 Pulse, 181, 190 Purines, 159, 190 Putamen, 158, 166, 182, 190 Pyramidal Tracts, 171, 190 Pyrimidines, 159, 190 Q Quaternary, 189, 190 Quinolinic, 38, 190 Quinolinic Acid, 38, 190 R Race, 177, 190 Radiation, 74, 154, 158, 166, 168, 169, 172, 190, 191, 199, 201 Radiation therapy, 154, 168, 190 Radioactive, 54, 158, 173, 175, 176, 184, 191 Radiology, 58, 67, 184, 191 Radiopharmaceutical, 97, 191 Randomized, 14, 30, 40, 60, 79, 87, 88, 168, 191 Randomized clinical trial, 60, 191 Reactive Oxygen Species, 11, 191 Reagent, 18, 191, 194 Receptor, 22, 36, 38, 51, 55, 69, 78, 118, 154, 157, 168, 177, 180, 187, 191, 193 Receptors, Nicotinic, 183, 191 Recombinant, 32, 135, 191, 199
Index 209
Recombination, 16, 19, 75, 172, 191 Rectum, 157, 164, 172, 177, 189, 191 Red Nucleus, 158, 191 Refer, 1, 107, 111, 113, 118, 136, 160, 164, 169, 171, 178, 182, 191, 198 Reflex, 84, 191 Refraction, 157, 191, 195 Refractory, 12, 192 Regimen, 33, 168, 192 Reliability, 31, 98, 192 Reproductive cells, 114, 125, 126, 173, 174, 192 Respiration, 160, 181, 192 Restriction Mapping, 46, 192 Retina, 61, 162, 184, 192, 200 Retinoblastoma, 117, 192 Retroviral vector, 172, 192 Ribonucleic acid, 109, 192 Ribose, 154, 192 Ribosome, 109, 192, 198 Rigidity, 4, 185, 187, 192 Riluzole, 47, 192 Rod, 44, 163, 187, 192 S Scatter, 192, 199 Schizoid, 192, 201 Schizophrenia, 11, 68, 88, 122, 192, 201 Schizotypal Personality Disorder, 192, 201 Sclerosis, 12, 14, 25, 29, 37, 118, 192 Screening, 13, 76, 120, 129, 130, 132, 163, 186, 193 Secretion, 35, 168, 176, 180, 193, 199 Segregation, 191, 193 Seizures, 4, 160, 186, 193 Semisynthetic, 180, 193 Sensitization, 34, 193 Sequela, 85, 193 Sequencing, 137, 187, 193 Sequester, 13, 22, 24, 193 Serotonin, 183, 193, 199 Sertraline, 70, 193 Serum, 57, 86, 164, 177, 193 Sex Characteristics, 154, 193 Shock, 13, 162, 193, 198 Side effect, 20, 136, 139, 154, 168, 193, 196, 198 Signal Transduction, 34, 174, 176, 193 Signs and Symptoms, 3, 4, 123, 124, 129, 194 Silver Staining, 47, 194 Skeletal, 62, 162, 163, 168, 183, 194 Skeleton, 154, 194
Skull, 194, 197 Small intestine, 175, 176, 194 Social Work, 126, 194 Sodium, 88, 194 Soft tissue, 160, 194 Soma, 194 Somatic, 19, 20, 21, 67, 68, 78, 112, 115, 126, 154, 169, 178, 179, 181, 186, 188, 194 Somatic cells, 112, 115, 126, 179, 181, 194 Somatic mutations, 115, 194 Specialist, 130, 149, 194 Species, 25, 48, 77, 139, 161, 170, 175, 177, 179, 181, 190, 191, 194, 195, 196, 198, 199, 200, 201 Specificity, 16, 32, 36, 155, 194 Spectrum, 180, 195 Speech Intelligibility, 98, 195 Sperm, 16, 46, 111, 112, 114, 115, 124, 125, 126, 129, 136, 162, 173, 174, 192, 194, 195 Spermidine, 195 Spermine, 34, 195 Spinal cord, 29, 38, 158, 161, 162, 180, 182, 183, 186, 190, 191, 195 Sporadic, 60, 74, 182, 192, 195 Staphylococcus, 180, 195 Steel, 163, 195 Stem Cells, 38, 73, 195 Stillbirth, 127, 195 Stimulus, 170, 177, 191, 195, 197 Stomach, 172, 175, 194, 195 Stool, 164, 178, 195 Strand, 19, 102, 187, 195 Stress, 10, 13, 15, 29, 151, 161, 162, 185, 195 Striatum, 8, 17, 19, 27, 28, 30, 35, 36, 91, 182, 195 Stroke, 5, 120, 141, 147, 160, 183, 195 Subacute, 176, 195 Subclinical, 22, 176, 193, 195 Subspecies, 194, 196 Substance P, 180, 193, 196 Substrate, 24, 65, 168, 170, 178, 196 Supplementation, 86, 196 Supportive care, 186, 196 Suppression, 20, 34, 196 Sympathomimetic, 168, 170, 184, 196 Symptomatic, 11, 15, 22, 31, 52, 152, 155, 196 Symptomatic treatment, 155, 196 Synapse, 34, 154, 183, 188, 196, 198 Synapsis, 196 Synaptic, 21, 24, 35, 36, 51, 183, 194, 196 Synaptic Transmission, 183, 196
210
Huntington Disease
Systemic, 24, 33, 160, 170, 176, 191, 196 T Tardive, 75, 92, 196 Telencephalon, 158, 161, 196 Temporal, 25, 156, 197 Terminator, 163, 197 Tetracycline, 11, 180, 197 Thalamic, 64, 158, 197 Thalamic Diseases, 158, 197 Thalamus, 166, 178, 188, 197 Therapeutics, 17, 18, 20, 26, 91, 197 Thermal, 157, 174, 187, 197 Threshold, 19, 31, 88, 170, 175, 197 Thrombin, 189, 197 Thrombomodulin, 189, 197 Thrombosis, 189, 195, 197 Thyroid, 34, 129, 177, 197, 199 Thyroid Gland, 129, 197 Thyroid Hormones, 34, 197, 199 Tissue Culture, 13, 20, 182, 197 Tomograph, 38, 197 Tomography, 45, 179, 197 Tonicity, 168, 198 Toxic, iv, 9, 13, 14, 15, 25, 32, 101, 168, 169, 183, 198 Toxicity, 8, 13, 15, 16, 17, 26, 27, 29, 32, 33, 35, 36, 61, 88, 89, 135, 198 Toxicokinetics, 198 Toxicology, 15, 142, 198 Toxin, 15, 198 Trachea, 197, 198 Traction, 163, 198 Transcription Factors, 11, 30, 110, 198 Transduction, 160, 193, 198 Transfection, 159, 172, 198 Transgenes, 27, 198 Translation, 109, 110, 172, 198 Translational, 13, 25, 198 Transmitter, 154, 158, 168, 170, 177, 184, 198 Transplantation, 73, 175, 177, 198 Transport Vesicles, 23, 198 Trauma, 158, 182, 183, 197, 198 Tremor, 185, 198 Trinucleotide Repeat Expansion, 40, 124, 198 Trinucleotide Repeats, 199 Trisomy, 115, 156, 199 Trophic, 182, 199 Tryptophan, 163, 190, 193, 199
Tuberculosis, 177, 199 Tuberculostatic, 177, 199 Tumor marker, 159, 199 Tyrosine, 38, 168, 199 U Ubiquitin, 23, 37, 199 Ultraviolet radiation, 112, 199 Uremia, 177, 199 Urine, 157, 166, 177, 184, 199 Uterus, 129, 166, 185, 199 V Vaccine, 189, 199 Vacuoles, 185, 199 Vascular, 162, 176, 197, 199 Vasodilator, 168, 199 Vector, 20, 27, 32, 34, 134, 135, 198, 199 Vein, 177, 184, 199 Venous, 189, 200 Ventral, 175, 184, 200 Ventricle, 156, 161, 175, 190, 197, 200 Ventricular, 88, 200 Venules, 160, 200 Vertebrae, 195, 200 Vesicular, 35, 200 Veterinary Medicine, 142, 200 Viral, 27, 32, 83, 134, 172, 198, 200 Viral vector, 32, 200 Virulence, 198, 200 Virus, 134, 169, 172, 192, 198, 200 Viscera, 194, 200 Vital Capacity, 30, 200 Vitreous, 192, 200 Vitreous Body, 192, 200 Vitro, 26, 35, 129, 200 Vivo, 17, 29, 33, 200 Volition, 177, 200 Voltage-gated, 21, 200 W White blood cell, 112, 157, 179, 187, 200 Windpipe, 197, 201 Withdrawal, 38, 201 Womb, 199, 201 X Xenograft, 156, 201 X-ray, 165, 184, 190, 191, 197, 201 Y Yeasts, 186, 201 Z Zygote, 165, 181, 201 Zymogen, 189, 201
