Amyotrophic Lateral Sclerosis - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers 0497113279, 9780497113278, 9781429496100

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AMYOTROPHIC LATERAL SCLEROSIS A

3-in-1

Medical

Reference

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

AMYOTROPHIC LATERAL SCLEROSIS 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., 1960Amyotrophic Lateral Sclerosis: 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: 0-497-11327-9 1. Amyotrophic Lateral Sclerosis-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on amyotrophic lateral sclerosis. 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 AMYOTROPHIC LATERAL SCLEROSIS ....................................................... 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Amyotrophic Lateral Sclerosis?........................................................................................ 3 How Common Is Amyotrophic Lateral Sclerosis? ......................................................................... 4 What Genes Are Related to Amyotrophic Lateral Sclerosis?......................................................... 4 How Do People Inherit Amyotrophic Lateral Sclerosis? ............................................................... 5 Where Can I Find Additional Information about Amyotrophic Lateral Sclerosis? ....................... 5 References....................................................................................................................................... 7 What Is the Official Name of the ALS2 Gene? .............................................................................. 8 What Is the Normal Function of the ALS2 Gene? ......................................................................... 8 What Conditions Are Related to the ALS2 Gene?......................................................................... 8 Where Is the ALS2 Gene Located?................................................................................................. 9 References....................................................................................................................................... 9 What Is the Official Name of the SETX Gene?............................................................................ 10 What Is the Normal Function of the SETX Gene? ...................................................................... 10 What Conditions Are Related to the SETX Gene? ...................................................................... 10 Where Is the SETX Gene Located? .............................................................................................. 11 References..................................................................................................................................... 11 What Is the Official Name of the SOD1 Gene? ........................................................................... 12 What Is the Normal Function of the SOD1 Gene?...................................................................... 12 What Conditions Are Related to the SOD1 Gene?...................................................................... 12 Where Is the SOD1 Gene Located?.............................................................................................. 13 References..................................................................................................................................... 13 What Is the Official Name of the VAPB Gene? ........................................................................... 14 What Is the Normal Function of the VAPB Gene?...................................................................... 14 What Conditions Are Related to the VAPB Gene?...................................................................... 14 Where Is the VAPB Gene Located?.............................................................................................. 15 References..................................................................................................................................... 15 What Is the Official Name of the NEFH Gene? ........................................................................... 16 What Is the Normal Function of the NEFH Gene? ..................................................................... 16 What Conditions Are Related to the NEFH Gene? ..................................................................... 16 Where Is the NEFH Gene Located? ............................................................................................. 16 References..................................................................................................................................... 17 What Is the Official Name of the SMN1 Gene?........................................................................... 18 What Is the Normal Function of the SMN1 Gene? ..................................................................... 18 What Conditions Are Related to the SMN1 Gene? ..................................................................... 18 Where Is the SMN1 Gene Located? ............................................................................................. 19 References..................................................................................................................................... 19 What Is the Official Name of the SMN2 Gene?........................................................................... 20 What Is the Normal Function of the SMN2 Gene? ..................................................................... 20 What Conditions Are Related to the SMN2 Gene? ..................................................................... 21 Where Is the SMN2 Gene Located? ............................................................................................. 21 References..................................................................................................................................... 22 Federally Funded Research on Amyotrophic Lateral Sclerosis .................................................... 23 The National Library of Medicine: PubMed ................................................................................ 79 CHAPTER 2. ALTERNATIVE MEDICINE AND AMYOTROPHIC LATERAL SCLEROSIS ..................... 125 Overview.................................................................................................................................... 125 National Center for Complementary and Alternative Medicine................................................ 125 Additional Web Resources ......................................................................................................... 138

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General References ..................................................................................................................... 139 CHAPTER 3. PATENTS ON AMYOTROPHIC LATERAL SCLEROSIS .................................................. 140 Overview.................................................................................................................................... 140 Patent Applications on Amyotrophic Lateral Sclerosis ............................................................. 140 Keeping Current ........................................................................................................................ 143 CHAPTER 4. BOOKS ON AMYOTROPHIC LATERAL SCLEROSIS...................................................... 144 Overview.................................................................................................................................... 144 Book Summaries: Online Booksellers......................................................................................... 144 The National Library of Medicine Book Index ........................................................................... 145 CHAPTER 5. MULTIMEDIA ON AMYOTROPHIC LATERAL SCLEROSIS ........................................... 147 Overview.................................................................................................................................... 147 Bibliography: Multimedia on Amyotrophic Lateral Sclerosis.................................................... 147 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 149 Overview.................................................................................................................................... 149 The Basics: Genes and How They Work..................................................................................... 149 Genetic Mutations and Health................................................................................................... 160 Inheriting Genetic Conditions ................................................................................................... 166 Genetic Consultation ................................................................................................................. 174 Genetic Testing .......................................................................................................................... 176 Gene Therapy ............................................................................................................................. 182 The Human Genome Project and Genomic Research................................................................. 185 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 188 Overview.................................................................................................................................... 188 NIH Guidelines.......................................................................................................................... 188 NIH Databases........................................................................................................................... 189 Other Commercial Databases..................................................................................................... 192 The Genome Project and Amyotrophic Lateral Sclerosis ........................................................... 192 APPENDIX C. PATIENT RESOURCES .............................................................................................. 197 Overview.................................................................................................................................... 197 Patient Guideline Sources.......................................................................................................... 197 Finding Associations.................................................................................................................. 202 Resources for Patients and Families........................................................................................... 203 ONLINE GLOSSARIES................................................................................................................ 204 Online Dictionary Directories ................................................................................................... 207 AMYOTROPHIC LATERAL SCLEROSIS DICTIONARY.................................................... 208 INDEX .............................................................................................................................................. 271

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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 amyotrophic lateral sclerosis 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 amyotrophic lateral sclerosis, 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 amyotrophic lateral sclerosis, 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 amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis, 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 amyotrophic lateral sclerosis. The Editors

1

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

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

What Is Amyotrophic Lateral Sclerosis?3 Amyotrophic lateral sclerosis is a progressive disease that affects the control of muscle movement by damaging motor neurons, which are specialized nerve cells in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). More than 90 percent of amyotrophic lateral sclerosis cases occur in people with no family history of the disorder (sporadic cases). The cause of sporadic cases remains largely unknown. Only a

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=amyotrophiclateralsclerosis.

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small percentage of amyotrophic lateral sclerosis cases are caused by a known genetic mutation; these cases are referred to as inherited or familial. The first signs and symptoms of amyotrophic lateral sclerosis may be so subtle that they are overlooked. The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Speech may become slurred, and later there is difficulty chewing or swallowing. The muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue wastes away (atrophies). Individuals with this disorder lose their strength, the ability to walk, and use of their hands and arms. In late stages of the disease, breathing becomes difficult because the muscles of the respiratory system weaken. Most people with amyotrophic lateral sclerosis die from respiratory failure. Different types of familial amyotrophic lateral sclerosis are distinguished by genetic cause, pattern of inheritance, age when symptoms begin, and disease progression. Onset of symptoms in adulthood is characteristic of amyotrophic lateral sclerosis types 1 and 8. Symptoms of type 1 usually begin between 40 and 60 years of age and progress rapidly. Most individuals with type 1 amyotrophic lateral sclerosis die of respiratory failure within 3 to 5 years of the onset of symptoms. Symptoms of type 8 amyotrophic lateral sclerosis begin earlier than type 1 (between 25 and 44 years of age) but progress slowly over several years to several decades. Juvenile or early onset of symptoms is characteristic of amyotrophic lateral sclerosis types 2 and 4. Type 2 symptoms usually begin in early childhood or adolescence and slowly worsen for 10 to 15 years. Symptoms of type 4 amyotrophic lateral sclerosis typically begin before age 25 and slowly progress over several decades. Additional types of amyotrophic lateral sclerosis have been reported, but the responsible mutations have not been adequately described.

How Common Is Amyotrophic Lateral Sclerosis? An estimated 5,000 people in the United States are diagnosed with amyotrophic lateral sclerosis each year. Worldwide, this disorder occurs in 4 to 8 per 100,000 individuals. Only a small percentage of cases arise from a known genetic cause. About 3 percent of sporadic cases and 20 percent of familial cases are considered type 1. Types 2, 4, and 8 are rare disorders, reported in a small number of families.

What Genes Are Related to Amyotrophic Lateral Sclerosis? Mutations in the ALS2 (http://ghr.nlm.nih.gov/gene=als2), SETX (http://ghr.nlm.nih.gov/gene=setx), SOD1 (http://ghr.nlm.nih.gov/gene=sod1), and VAPB (http://ghr.nlm.nih.gov/gene=vapb) genes cause amyotrophic lateral sclerosis. Variations of the NEFH (http://ghr.nlm.nih.gov/gene=nefh), SMN1 (http://ghr.nlm.nih.gov/gene=smn1), and SMN2 (http://ghr.nlm.nih.gov/gene=smn2) genes increase the risk of developing amyotrophic lateral sclerosis. Each type of familial amyotrophic lateral sclerosis is caused by mutations in a specific gene. Type 1 is caused by mutations in the SOD1 gene, type 2 by ALS2 mutations, type 4 by mutations in the SETX gene, and type 8 by VAPB mutations. These mutations contribute to the decline and death of motor neurons, which leads to muscle weakness and atrophy. Not

Studies

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all familial cases are due to SOD1, ALS2, SETX, or VAPB mutations. Other genes are thought to cause amyotrophic lateral sclerosis, but they have not been identified or fully characterized. Mutations in the NEFH gene appear to increase the risk of developing amyotrophic lateral sclerosis. Research findings also suggest that a decrease in the number of SMN1 or SMN2 genes leads to an increased chance of developing this disorder. It is unclear how variations in these gene lead to an increased risk.

How Do People Inherit Amyotrophic Lateral Sclerosis? The pattern of inheritance varies with the type of amyotrophic lateral sclerosis. Type 2 amyotrophic lateral sclerosis is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder. Amyotrophic lateral sclerosis types 1, 4, and 8 are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Studies in Sweden and Finland, however, revealed a small number of type 1 cases that are inherited in an autosomal recessive pattern.

Where Can I Find Additional Information about Amyotrophic Lateral Sclerosis? You may find the following resources about amyotrophic lateral sclerosis 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.194

•

National Institute of Neurological Disorders and Stroke: ALS fact sheet: http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophicl ateralsclerosis.htm

•

National Institute of Neurological Disorders and Stroke: Senataxin gene linked to juvenile-onset ALS: http://www.ninds.nih.gov/news_and_events/news_articles/news_article_als4.htm MedlinePlus - Health Information

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Encyclopedia: Amyotrophic lateral sclerosis: http://www.nlm.nih.gov/medlineplus/ency/article/000688.htm

•

Health Topic: Amyotrophic Lateral Sclerosis: http://www.nlm.nih.gov/medlineplus/amyotrophiclateralsclerosis.html

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Educational Resources - Information Pages •

American Speech-Language-Hearing Association: http://www.asha.org/public/speech/disorders/Amyotrophic-lateral-sclerosis.htm

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Duke Center for Human Genetics: http://www.chg.duke.edu/diseases/als.html

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KidsHealth (Nemours Foundation): http://kidshealth.org/kid/grownup/conditions/als.html

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Mayo Clinic: http://www.mayoclinic.org/lou-gehrigs-disease/index.html

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New York Online Access to Health (NOAH): http://www.noah-health.org/en/bns/disorders/lougehrig/index.html

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Orphanet: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=803

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World Federation of Neurology-ALS: http://www.wfnals.org Patient Support - for Patients and Families

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Les Turner Amyotrophic Lateral Sclerosis Foundation: http://www.lesturnerals.org/als.htm

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Muscular Dystrophy Association: http://als.mdausa.org/

•

National Organization for Rare Disorders (NORD): http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Amyotrophic+L ateral+Sclerosis

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Project ALS: http://www.projectals.org

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The ALS Association: http://www.alsa.org/als

•

The ALS Society of Canada: http://www.als.ca/ Professional Resources

You may also be interested in these resources, which are designed for healthcare professionals and researchers. •

Gene Reviews - Clinical summary: http://ghr.nlm.nih.gov/condition=amyotrophiclateralsclerosis/show/Gene+Reviews;js essionid=62691805C4C5F3409543E26AE3172532

•

Gene Tests - DNA tests ordered by healthcare professionals: http://ghr.nlm.nih.gov/condition=amyotrophiclateralsclerosis/show/Gene+Tests;jsessi onid=62691805C4C5F3409543E26AE3172532

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•

ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22amyotrophic+lateral+sclerosis%22?recru iting=false

•

PubMed - Recent literature: http://ghr.nlm.nih.gov/condition=amyotrophiclateralsclerosis/show/PubMed;jsessioni d=62691805C4C5F3409543E26AE3172532

•

OMIM - Genetic disorder catalog: http://ghr.nlm.nih.gov/condition=amyotrophiclateralsclerosis/show/OMIM;jsessionid =62691805C4C5F3409543E26AE3172532

References These sources were used to develop the Genetics Home Reference condition summary on amyotrophic lateral sclerosis. •

Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128-35. Epub 2004 Apr 21. PubMed citation

•

Gene Reviews: Amyotrophic lateral sclerosis overview

•

Hand CK, Rouleau GA. Familial amyotrophic lateral sclerosis. Muscle Nerve. 2002 Feb;25(2):135-59. Review. PubMed citation

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Jackson M, Llado J, Rothstein JD. Therapeutic developments in the treatment of amyotrophic lateral sclerosis. Expert Opin Investig Drugs. 2002 Oct;11(10):1343-64. Review. PubMed citation

•

Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Dec;75(6):933-47. Epub 2004 Oct 11. No abstract available. PubMed citation

•

Manfredi G, Xu Z. Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion. 2005 Apr;5(2):77-87. Review. PubMed citation

•

National Institute of Neurological Disorders and Stroke: ALS fact sheet

•

Rao SD, Weiss JH. Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci. 2004 Jan;27(1):17-23. Review. No abstract available. PubMed citation

•

Strong MJ, Kesavapany S, Pant HC. The pathobiology of amyotrophic lateral sclerosis: a proteinopathy? J Neuropathol Exp Neurol. 2005 Aug;64(8):649-64. Review. PubMed citation

•

Veldink JH, Kalmijn S, Van der Hout AH, Lemmink HH, Groeneveld GJ, Lummen C, Scheffer H, Wokke JH, Van den Berg LH. SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS. Neurology. 2005 Sep 27;65(6):820-5. Epub 2005 Aug 10. PubMed citation

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A summary of the genes related to amyotrophic lateral sclerosis is provided below:

What Is the Official Name of the ALS2 Gene?4 The official name of this gene is “amyotrophic lateral sclerosis 2 (juvenile).” ALS2 is the gene's official symbol. The ALS2 gene is also known by other names, listed below.

What Is the Normal Function of the ALS2 Gene? The ALS2 gene provides instructions for making a protein called alsin. Alsin is produced in a wide range of tissues, with highest amounts in the brain. It is also abundant in motor neurons, the specialized nerve cells in the brain and spinal cord that control the movement of muscles. The function of alsin, however, is unknown. It may play a role in regulating cell membrane organization, movement of molecules inside the cell, and assembly of the network of filaments and tubules (cytoskeleton) that gives shape and structure to the cell contents.

What Conditions Are Related to the ALS2 Gene? Amyotrophic Lateral Sclerosis - Caused by Mutations in the ALS2 Gene Two ALS2 mutations that cause type 2 amyotrophic lateral sclerosis have been identified. These mutations delete a single DNA building block (base pair), which disrupts the instructions for producing alsin. As a result, alsin is unstable and decays rapidly, or it is disabled and cannot function properly. It is unknown how the loss of functional alsin protein causes the death of motor neurons and the symptoms of amyotrophic lateral sclerosis, type 2. Infantile-Onset Ascending Hereditary Spastic Paralysis - Caused by Mutations in the ALS2 Gene Two ALS2 mutations that cause type 2 amyotrophic lateral sclerosis have been identified. These mutations delete a single DNA building block (base pair), which disrupts the instructions for producing alsin. As a result, alsin is unstable and decays rapidly, or it is disabled and cannot function properly. It is unknown how the loss of functional alsin protein causes the death of motor neurons and the symptoms of amyotrophic lateral sclerosis, type 2.

4

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=als2;jsessionid=62691805C4C5F3409543E26AE3172532.

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Juvenile Primary Lateral Sclerosis - Caused by Mutations in the ALS2 Gene Several ALS2 mutations have been identified in patients with infantile-onset ascending hereditary spastic paralysis. These mutations change or delete one or more DNA building blocks (base pairs), which disrupts the instructions for producing alsin. As a result, alsin is unstable and decays rapidly, or it is disabled and cannot function properly. It is unknown how the loss of functional alsin protein causes the death of motor neurons and the symptoms of infantile-onset hereditary spastic paralysis.

Where Is the ALS2 Gene Located? Cytogenetic Location: 2q33.2 Molecular Location on chromosome 2: base pairs 202,273,521 to 202,353,982

The ALS2 gene is located on the long (q) arm of chromosome 2 at position 33.2. More precisely, the ALS2 gene is located from base pair 202,273,521 to base pair 202,353,982 on chromosome 2.

References These sources were used to develop the Genetics Home Reference gene summary on the ALS2 gene. •

Devon RS, Helm JR, Rouleau GA, Leitner Y, Lerman-Sagie T, Lev D, Hayden MR. The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings. Clin Genet. 2003 Sep;64(3):210-5. PubMed citation

•

Eymard-Pierre E, Lesca G, Dollet S, Santorelli FM, di Capua M, Bertini E, BoespflugTanguy O. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet. 2002 Sep;71(3):518-27. PubMed citation

•

Gros-Louis F, Meijer IA, Hand CK, Dube MP, MacGregor DL, Seni MH, Devon RS, Hayden MR, Andermann F, Andermann E, Rouleau GA. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann Neurol. 2003 Jan;53(1):144-5. No abstract available. PubMed citation

•

Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA,

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Amyotrophic Lateral Sclerosis

Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001 Oct;29(2):166-73. PubMed citation •

Kress JA, Kuhnlein P, Winter P, Ludolph AC, Kassubek J, Muller U, Sperfeld AD. Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Ann Neurol. 2005 Nov;58(5):800-3. PubMed citation

•

Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Dec;75(6):933-47. Epub 2004 Oct 11. No abstract available. PubMed citation

•

Millecamps S, Gentil BJ, Gros-Louis F, Rouleau G, Julien JP. Alsin is partially associated with centrosome in human cells. Biochim Biophys Acta. 2005 Aug 15;1745(1):84-100. Epub 2005 Jan 19. PubMed citation

•

Otomo A, Hadano S, Okada T, Mizumura H, Kunita R, Nishijima H, Showguchi-Miyata J, Yanagisawa Y, Kohiki E, Suga E, Yasuda M, Osuga H, Nishimoto T, Narumiya S, Ikeda JE. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum Mol Genet. 2003 Jul 15;12(14):1671-87. PubMed citation

•

Yamanaka K, Vande Velde C, Eymard-Pierre E, Bertini E, Boespflug-Tanguy O, Cleveland DW. Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):16041-6. Epub 2003 Dec 10. PubMed citation

What Is the Official Name of the SETX Gene?5 The official name of this gene is “senataxin.” SETX is the gene's official symbol. The SETX gene is also known by other names, listed below.

What Is the Normal Function of the SETX Gene? The SETX gene provides instructions for making a protein called senataxin. Senataxin is produced in a wide range of tissues, including the brain, spinal cord, and muscles. Its function is unknown. On the basis of its structure, senataxin is thought to play a role in processing RNA, a molecule similar to DNA. RNA makes up the cellular machinery that produces proteins from information contained in DNA. Senataxin may help ensure that protein production is error-free.

What Conditions Are Related to the SETX Gene? Amyotrophic Lateral Sclerosis - Caused by Mutations in the SETX Gene Researchers have identified three SETX mutations that cause type 4 amyotrophic lateral sclerosis. These mutations change one of the protein building blocks (amino acids) used to 5

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

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make senataxin. It is unknown how mutations in the SETX gene lead to the signs and symptoms of type 4 amyotrophic lateral sclerosis. Other Disorders - Caused by Mutations in the SETX Gene Researchers have identified three SETX mutations that cause type 4 amyotrophic lateral sclerosis. These mutations change one of the protein building blocks (amino acids) used to make senataxin. It is unknown how mutations in the SETX gene lead to the signs and symptoms of type 4 amyotrophic lateral sclerosis.

Where Is the SETX Gene Located? Cytogenetic Location: 9q34.3 Molecular Location on chromosome 9: base pairs 134,129,103 to 134,220,192

The SETX gene is located on the long (q) arm of chromosome 9 at position 34.3. More precisely, the SETX gene is located from base pair 134,129,103 to base pair 134,220,192 on chromosome 9.

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

Blair IP, Bennett CL, Abel A, Rabin BA, Griffin JW, Fischbeck KH, Cornblath DR, Chance PF. A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34. Neurogenetics. 2000 Sep;3(1):1-6. PubMed citation

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Chance PF, Rabin BA, Ryan SG, Ding Y, Scavina M, Crain B, Griffin JW, Cornblath DR. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet. 1998 Mar;62(3):633-40. PubMed citation

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Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW,

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Amyotrophic Lateral Sclerosis

Fischbeck KH, Timmerman V, Cornblath DR, Chance PF. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128-35. Epub 2004 Apr 21. PubMed citation •

Duquette A, Roddier K, McNabb-Baltar J, Gosselin I, St-Denis A, Dicaire MJ, Loisel L, Labuda D, Marchand L, Mathieu J, Bouchard JP, Brais B. Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy. Ann Neurol. 2005 Mar;57(3):408-14. PubMed citation

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Entrez Gene

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Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Dec;75(6):933-47. Epub 2004 Oct 11. No abstract available. PubMed citation

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Moreira MC, Klur S, Watanabe M, Nemeth AH, Le Ber I, Moniz JC, Tranchant C, Aubourg P, Tazir M, Schols L, Pandolfo M, Schulz JB, Pouget J, Calvas P, Shizuka-Ikeda M, Shoji M, Tanaka M, Izatt L, Shaw CE, M'Zahem A, Dunne E, Bomont P, Benhassine T, Bouslam N, Stevanin G, Brice A, Guimaraes J, Mendonca P, Barbot C, Coutinho P, Sequeiros J, Durr A, Warter JM, Koenig M. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet. 2004 Mar;36(3):225-7. Epub 2004 Feb 08. PubMed citation

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OMIM: senataxin

What Is the Official Name of the SOD1 Gene?6 The official name of this gene is “superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)).” SOD1 is the gene's official symbol. The SOD1 gene is also known by other names, listed below.

What Is the Normal Function of the SOD1 Gene? The SOD1 gene provides instructions for making an enzyme called superoxide dismutase, which is abundant in cells throughout the body. This enzyme neutralizes supercharged oxygen molecules (called superoxide radicals). Superoxide radicals, which are byproducts of normal cell processes, can damage cells if their levels are not controlled by superoxide dismutase. To function properly, the superoxide dismutase enzyme must bind to copper and zinc.

What Conditions Are Related to the SOD1 Gene? Amyotrophic Lateral Sclerosis - Caused by Mutations in the SOD1 Gene More than 100 SOD1 mutations that cause type 1 amyotrophic lateral sclerosis have been identified. Most of these mutations change one of the building blocks (amino acids) used to 6

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=sod1;jsessionid=62691805C4C5F3409543E26AE3172532.

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make the enzyme superoxide dismutase. The most common change, which occurs in 50 percent of Americans with type 1 amyotrophic lateral sclerosis, replaces the amino acid arginine with the amino acid valine at position 4 in the enzyme. (This mutation is written as Arg4Val). Other types of mutations result in an enzyme of abnormal size.

Where Is the SOD1 Gene Located? Cytogenetic Location: 21q22.1 Molecular Location on chromosome 21: base pairs 31,953,805 to 31,963,114

The SOD1 gene is located on the long (q) arm of chromosome 21 at position 22.1. More precisely, the SOD1 gene is located from base pair 31,953,805 to base pair 31,963,114 on chromosome 21.

References These sources were used to develop the Genetics Home Reference gene summary on the SOD1 gene. •

Gene Review: Amyotrophic Lateral Sclerosis

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Giess R, Holtmann B, Braga M, Grimm T, Muller-Myhsok B, Toyka KV, Sendtner M. Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene. Am J Hum Genet. 2002 May;70(5):1277-86. PubMed citation

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Hand CK, Rouleau GA. Familial amyotrophic lateral sclerosis. Muscle Nerve. 2002 Feb;25(2):135-59. Review. PubMed citation

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Jonsson PA, Ernhill K, Andersen PM, Bergemalm D, Brannstrom T, Gredal O, Nilsson P, Marklund SL. Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis. Brain. 2004 Jan;127(Pt 1):73-88. Epub 2003 Oct 08. PubMed citation

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Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Dec;75(6):933-47. Epub 2004 Oct 11. No abstract available. PubMed citation

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Amyotrophic Lateral Sclerosis

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Rao SD, Weiss JH. Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci. 2004 Jan;27(1):17-23. Review. No abstract available. PubMed citation

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Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001 May 31;344(22):1688-700. Review. No abstract available. PubMed citation

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Selverstone Valentine J, Doucette PA, Zittin Potter S. Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. Annu Rev Biochem. 2005;74:563-93. Review. PubMed citation

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Siddique T, Lalani I. Genetic aspects of amyotrophic lateral sclerosis. Adv Neurol. 2002;88:21-32. Review. No abstract available. PubMed citation

What Is the Official Name of the VAPB Gene?7 The official name of this gene is “VAMP (vesicle-associated membrane protein)-associated protein B and C.” VAPB is the gene's official symbol. The VAPB gene is also known by other names, listed below.

What Is the Normal Function of the VAPB Gene? The VAPB gene provides instructions for making a protein that is found in cells throughout the body. Little is known about the role of the VAPB protein. Research indicates that this protein is associated with the membrane that surrounds the endoplasmic reticulum, a specialized structure within cells. Among its many functions, the endoplasmic reticulum folds newly formed proteins and prepares them for transit within the cell or to the cell surface. To function efficiently, the endoplasmic reticulum relies on a system that detects a buildup of unfolded or misfolded proteins. The cell's response to prevent or correct this buildup is called the unfolded protein response. Researchers suggest that the VAPB protein may play an important role in the unfolded protein response.

What Conditions Are Related to the VAPB Gene? Amyotrophic Lateral Sclerosis - Caused by Mutations in the VAPB Gene Researchers have identified one VAPB mutation in people with amyotrophic lateral sclerosis type 8. This mutation changes one of the building blocks (amino acids) used to make the VAPB protein. In this protein's string of amino acids, the 56th amino acid, proline, is replaced with the amino acid serine. This mutation is written as Pro56Ser or P56S. It is unclear how the VAPB mutation leads to the loss of nerve cells that control muscle movement, a characteristic feature of amyotrophic lateral sclerosis. Researchers suggest that the P56S mutation impairs the unfolded protein response. As a result, misfolded and unfolded proteins may accumulate to a level that is toxic to nerve cells.

7

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

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Spinal Muscular Atrophy - Caused by Mutations in the VAPB Gene Researchers have identified one VAPB mutation in people with amyotrophic lateral sclerosis type 8. This mutation changes one of the building blocks (amino acids) used to make the VAPB protein. In this protein's string of amino acids, the 56th amino acid, proline, is replaced with the amino acid serine. This mutation is written as Pro56Ser or P56S. It is unclear how the VAPB mutation leads to the loss of nerve cells that control muscle movement, a characteristic feature of amyotrophic lateral sclerosis. Researchers suggest that the P56S mutation impairs the unfolded protein response. As a result, misfolded and unfolded proteins may accumulate to a level that is toxic to nerve cells.

Where Is the VAPB Gene Located? Cytogenetic Location: 20q13.33 Molecular Location on chromosome 20: base pairs 56,397,650 to 56,455,368

The VAPB gene is located on the long (q) arm of chromosome 20 at position 13.33. More precisely, the VAPB gene is located from base pair 56,397,650 to base pair 56,455,368 on chromosome 20.

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

Kanekura K, Nishimoto I, Aiso S, Matsuoka M. Characterization of amyotrophic lateral sclerosis-linked pro56ser mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). J Biol Chem. 2006 Aug 4; [Epub ahead of print]. PubMed citation

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Nishimura AL, Al-Chalabi A, Zatz M. A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population. Hum Genet. 2005 Sep 27;:1-2 [Epub ahead of print]. PubMed citation

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Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M. A mutation in the vesicletrafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Nov;75(5):822-31. Epub 2004 Sep 15. PubMed citation

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Amyotrophic Lateral Sclerosis

OMIM

What Is the Official Name of the NEFH Gene?8 The official name of this gene is “neurofilament, heavy polypeptide 200kDa.” NEFH is the gene's official symbol. The NEFH gene is also known by other names, listed below.

What Is the Normal Function of the NEFH Gene? The NEFH gene provides instructions for making a protein component (subunit) of neurofilaments. Neurofilaments, which are assembled from light, medium, and heavy subunits, are essential for normal nerve function. The NEFH gene produces the heavy subunit. Neurofilaments form a structural framework that helps to define the shape and size of nerve cells. Cross-linking or bridging between neurofilaments maintains the diameter of nerve cells, which is important for the conduction of nerve impulses. Neurofilaments are the most abundant structural protein in motor neurons, the specialized nerve cells in the brain and spinal cord that control muscle movement. The heavy subunit is made up of three regions: the head, which regulates assembly of neurofilaments; a coiled midsection; and a tail with branches that interact with other proteins and neurofilaments. The tail region has a segment called the KSP motif that plays an important role in regulating the functions of neurofilaments.

What Conditions Are Related to the NEFH Gene? Amyotrophic Lateral Sclerosis - Increased Risk from Variations of the NEFH Gene NEFH gene mutations have been detected in a small percentage of individuals with amyotrophic lateral sclerosis. In some cases, unaffected family members of people with this disorder also have a NEFH mutation. Based on these observations, a mutation in the NEFH gene appears to increase the risk of developing amyotrophic lateral sclerosis but does not directly cause this disorder.

Where Is the NEFH Gene Located? Cytogenetic Location: 22q12.2 Molecular Location on chromosome 22: base pairs 28,206,218 to 28,217,278 8

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=nefh;jsessionid=62691805C4C5F3409543E26AE3172532.

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The NEFH gene is located on the long (q) arm of chromosome 22 at position 12.2. More precisely, the NEFH gene is located from base pair 28,206,218 to base pair 28,217,278 on chromosome 22.

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

Al-Chalabi A, Andersen PM, Nilsson P, Chioza B, Andersson JL, Russ C, Shaw CE, Powell JF, Leigh PN. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet. 1999 Feb;8(2):157-64. PubMed citation

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Al-Chalabi A, Miller CC. Neurofilaments and neurological disease. Bioessays. 2003 Apr;25(4):346-55. PubMed citation

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Garcia ML, Singleton AB, Hernandez D, Ward CM, Evey C, Sapp PA, Hardy J, Brown RH Jr, Cleveland DW. Mutations in neurofilament genes are not a significant primary cause of non-SOD1-mediated amyotrophic lateral sclerosis. Neurobiol Dis. 2005 Aug 2; [Epub ahead of print]. PubMed citation

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Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Dec;75(6):933-47. Epub 2004 Oct 11. No abstract available. PubMed citation

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Lariviere RC, Julien JP. Functions of intermediate filaments in neuronal development and disease. J Neurobiol. 2004 Jan;58(1):131-48. Review. PubMed citation

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Omary MB, Coulombe PA, McLean WH. Intermediate filament proteins and their associated diseases. N Engl J Med. 2004 Nov 11;351(20):2087-100. No abstract available. PubMed citation

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Tomkins J, Usher P, Slade JY, Ince PG, Curtis A, Bushby K, Shaw PJ. Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport. 1998 Dec 1;9(17):3967-70. PubMed citation

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Amyotrophic Lateral Sclerosis

What Is the Official Name of the SMN1 Gene?9 The official name of this gene is “survival of motor neuron 1, telomeric.” SMN1 is the gene's official symbol. The SMN1 gene is also known by other names, listed below.

What Is the Normal Function of the SMN1 Gene? The SMN1 gene provides instructions for making a protein called SMN, which stands for "survival of motor neuron." The SMN protein is found throughout the body, with high levels in the spinal cord. This protein is particularly important for the survival of specialized nerve cells, called motor neurons, located in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Healthy motor neurons are critical because they control muscle movement. In cells, the SMN protein plays an important role in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. Messenger RNA begins as a rough draft (pre-mRNA) and goes through several processing steps to a mature form. The SMN protein helps to assemble the cellular machinery needed to process premRNA. The SMN protein may have additional functions in nerve cells. Research findings indicate that the SMN protein is important for the specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are required for the transmission of impulses from nerve to nerve and from nerves to muscles.

What Conditions Are Related to the SMN1 Gene? Spinal Muscular Atrophy - Caused by Mutations in the SMN1 Gene Normally, each cell has two copies of the SMN1 gene. About 95 percent of individuals with spinal muscular atrophy have mutations that delete all or some of the DNA in both copies of this gene. As a result, little or no SMN protein is made. In about 5 percent of people with this disorder, one copy of the SMN1 gene has a deletion, and the other copy has a mutation that affects the building blocks (amino acids) used to make the SMN protein. Researchers have identified nearly 30 mutations that affect amino acids and impair the function of the SMN protein. Amyotrophic Lateral Sclerosis - Increased Risk from Variations of the SMN1 Gene Normally, each cell has two copies of the SMN1 gene. About 95 percent of individuals with spinal muscular atrophy have mutations that delete all or some of the DNA in both copies of this gene. As a result, little or no SMN protein is made. In about 5 percent of people with this disorder, one copy of the SMN1 gene has a deletion, and the other copy has a mutation that affects the building blocks (amino acids) used to make the SMN protein. Researchers

9

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=smn1.

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have identified nearly 30 mutations that affect amino acids and impair the function of the SMN protein.

Where Is the SMN1 Gene Located? Cytogenetic Location: 5q13 Molecular Location on chromosome 5: base pairs 70,256,523 to 70,284,592

The SMN1 gene is located on the long (q) arm of chromosome 5 at position 13. More precisely, the SMN1 gene is located from base pair 70,256,523 to base pair 70,284,592 on chromosome 5.

References These sources were used to develop the Genetics Home Reference gene summary on the SMN1 gene. •

Boda B, Mas C, Giudicelli C, Nepote V, Guimiot F, Levacher B, Zvara A, Santha M, LeGall I, Simonneau M. Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells. Eur J Hum Genet. 2004 Sep;12(9):729-37. PubMed citation

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Briese M, Esmaeili B, Sattelle DB. Is spinal muscular atrophy the result of defects in motor neuron processes? Bioessays. 2005 Sep;27(9):946-57. Review. PubMed citation

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Cartegni L, Hastings ML, Calarco JA, de Stanchina E, Krainer AR. Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Am J Hum Genet. 2006 Jan;78(1):63-77. Epub 2005 Nov 16. PubMed citation

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Frugier T, Nicole S, Cifuentes-Diaz C, Melki J. The molecular bases of spinal muscular atrophy. Curr Opin Genet Dev. 2002 Jun;12(3):294-8. Review. PubMed citation

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Gubitz AK, Feng W, Dreyfuss G. The SMN complex. Exp Cell Res. 2004 May 15;296(1):51-6. Review. PubMed citation

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Jablonka S, Sendtner M. Molecular and cellular basis of spinal muscular atrophy. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Sep;4(3):144-9. Review. PubMed citation

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Amyotrophic Lateral Sclerosis

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Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Wirth B, Burghes AH, Prior TW. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002 Jan-Feb;4(1):20-6. PubMed citation

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Ogino S, Wilson RB. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum Genet. 2002 Dec;111(6):477-500. Epub 2002 Oct 03. Review. PubMed citation

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Ogino S, Wilson RB. Spinal muscular atrophy: molecular genetics and diagnostics. Expert Rev Mol Diagn. 2004 Jan;4(1):15-29. Review. PubMed citation

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OMIM

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Paushkin S, Gubitz AK, Massenet S, Dreyfuss G. The SMN complex, an assemblyosome of ribonucleoproteins. Curr Opin Cell Biol. 2002 Jun;14(3):305-12. Review. PubMed citation

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Pellizzoni L, Yong J, Dreyfuss G. Essential role for the SMN complex in the specificity of snRNP assembly. Science. 2002 Nov 29;298(5599):1775-9. PubMed citation

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Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am J Med Genet A. 2004 Oct 15;130(3):307-10. PubMed citation

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Veldink JH, Kalmijn S, Van der Hout AH, Lemmink HH, Groeneveld GJ, Lummen C, Scheffer H, Wokke JH, Van den Berg LH. SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS. Neurology. 2005 Sep 27;65(6):820-5. Epub 2005 Aug 10. PubMed citation

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Wirth B, Brichta L, Schrank B, Lochmuller H, Blick S, Baasner A, Heller R. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum Genet. 2006 May;119(4):422-8. Epub 2006 Mar 1. PubMed citation

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Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000;15(3):228-37. Review. PubMed citation

What Is the Official Name of the SMN2 Gene?10 The official name of this gene is “survival of motor neuron 2, centromeric.” SMN2 is the gene's official symbol. The SMN2 gene is also known by other names, listed below.

What Is the Normal Function of the SMN2 Gene? The SMN2 gene provides instructions for making a protein called SMN, which stands for "survival of motor neuron." The SMN protein is found throughout the body, with high levels in the spinal cord. This protein is particularly important for the survival of specialized 10

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=smn2;jsessionid=62691805C4C5F3409543E26AE3172532.

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nerve cells, called motor neurons, located in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Healthy motor neurons are critical because they control muscle movements. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version (called isoform d) is full size and fully functional. The other versions are smaller and unstable. The full-size SMN protein made from the SMN2 gene is identical to the protein made from a similar gene called SMN1. A much smaller amount of full-size SMN protein is produced from the SMN2 gene compared to the SMN1 gene, however. In cells, the SMN protein plays an important role in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. Messenger RNA begins as a rough draft (pre-mRNA) and goes through several processing steps to a mature form. The SMN protein helps to assemble the cellular machinery needed to process premRNA. The SMN protein may have additional functions in nerve cells. Research findings indicate that the SMN protein is important for the specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are required for the transmission of impulses from nerve to nerve and from nerves to muscles.

What Conditions Are Related to the SMN2 Gene? Amyotrophic Lateral Sclerosis - Increased Risk from Variations of the SMN2 Gene Some studies suggest that a decreased number of SMN2 genes in each cell may be associated with an increased risk of developing amyotrophic lateral sclerosis. These studies found that people with amyotrophic lateral sclerosis were more likely to have only one copy of the SMN2 gene in each cell, instead of the usual two copies, compared to people unaffected by this disorder. Less SMN protein is produced as a result of the reduced number of SMN2 genes. Researchers propose that people with a reduced amount of SMN protein have an increased chance of developing amyotrophic lateral sclerosis. Spinal Muscular Atrophy - Course of Condition Modified by Extra Copies of the SMN2 Gene Some studies suggest that a decreased number of SMN2 genes in each cell may be associated with an increased risk of developing amyotrophic lateral sclerosis. These studies found that people with amyotrophic lateral sclerosis were more likely to have only one copy of the SMN2 gene in each cell, instead of the usual two copies, compared to people unaffected by this disorder. Less SMN protein is produced as a result of the reduced number of SMN2 genes. Researchers propose that people with a reduced amount of SMN protein have an increased chance of developing amyotrophic lateral sclerosis.

Where Is the SMN2 Gene Located? Cytogenetic Location: 5q13 Molecular Location on chromosome 5: base pairs 69,381,105 to 69,409,174

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Amyotrophic Lateral Sclerosis

The SMN2 gene is located on the long (q) arm of chromosome 5 at position 13. More precisely, the SMN2 gene is located from base pair 69,381,105 to base pair 69,409,174 on chromosome 5.

References These sources were used to develop the Genetics Home Reference gene summary on the SMN2 gene. •

Boda B, Mas C, Giudicelli C, Nepote V, Guimiot F, Levacher B, Zvara A, Santha M, LeGall I, Simonneau M. Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells. Eur J Hum Genet. 2004 Sep;12(9):729-37. PubMed citation

•

Briese M, Esmaeili B, Sattelle DB. Is spinal muscular atrophy the result of defects in motor neuron processes? Bioessays. 2005 Sep;27(9):946-57. Review. PubMed citation

•

Cartegni L, Hastings ML, Calarco JA, de Stanchina E, Krainer AR. Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Am J Hum Genet. 2006 Jan;78(1):63-77. Epub 2005 Nov 16. PubMed citation

•

Gubitz AK, Feng W, Dreyfuss G. The SMN complex. Exp Cell Res. 2004 May 15;296(1):51-6. Review. PubMed citation

•

Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Wirth B, Burghes AH, Prior TW. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002 Jan-Feb;4(1):20-6. PubMed citation

•

Ogino S, Wilson RB. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum Genet. 2002 Dec;111(6):477-500. Epub 2002 Oct 03. Review. PubMed citation

•

Ogino S, Wilson RB. Spinal muscular atrophy: molecular genetics and diagnostics. Expert Rev Mol Diagn. 2004 Jan;4(1):15-29. PubMed citation

•

Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am J Med Genet A. 2004 Oct 15;130(3):307-10. PubMed citation

•

Veldink JH, Kalmijn S, Van der Hout AH, Lemmink HH, Groeneveld GJ, Lummen C, Scheffer H, Wokke JH, Van den Berg LH. SMN genotypes producing less SMN protein

Studies

23

increase susceptibility to and severity of sporadic ALS. Neurology. 2005 Sep 27;65(6):820-5. Epub 2005 Aug 10. PubMed citation •

Wirth B, Brichta L, Schrank B, Lochmuller H, Blick S, Baasner A, Heller R. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum Genet. 2006 May;119(4):422-8. Epub 2006 Mar 1. PubMed citation

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Wirth B. Spinal muscular atrophy: state-of-the-art and therapeutic perspectives. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Jun;3(2):87-95. Review. PubMed citation

Federally Funded Research on Amyotrophic Lateral Sclerosis The U.S. Government supports a variety of research studies relating to amyotrophic lateral sclerosis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.11 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 amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis. The following is typical of the type of information found when searching the CRISP database for amyotrophic lateral sclerosis: •

Project Title: ABERRANT MITOCHONDRIAL HANDLING OF CALCIUM IN ALS Principal Investigator & Institution: Garcia-Chacon, Luis E.; Physiology and Biophysics; University of Miami-Medical School 1507 Levante Avenue Coral Gables, Fl 33124 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2008 Summary: (provided by applicant): This project will study the role of abnormal mitochondrial function in motor nerve terminals in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mitochondria take up cytosolic Ca2+ during repetitive stimulation at mouse motor nerve terminals. Studies have detected abnormalities in mitochondrial Ca2+ handling and abnormal mitochondrial depolarizations following repetitive stimulation of motor terminals in a mouse model for ALS: Stimulationinduced changes in mitochondrial [Ca2+] and in mitochondrial membrane potential using fluorescent indicator dyes and confocal microscopy will be measured. Proposed experiments will compare mutant and wild-type mice, and also carry out these

11 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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Amyotrophic Lateral Sclerosis

measurements in normal mice with partially inhibited electron transport chain activity, one of the proposed mechanisms for ALS pathogenesis. Young mice that have yet to develop signs of disease will be used and compared to previous results from older, affected mice. Finally, the degree of denervation of motor end-plates after marked neuronal activity will be measured with fluorescent markers for both the nerve terminal cytoplasm and the muscle end-plate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVITY-DEPENDENT REGULATION OF SYNAPSES BY SHANK Principal Investigator & Institution: Hung, Albert Y.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this project is to investigate the role of a newly discovered postsynaptic protein, Shank, in the regulation of dendritic spine morphology and cytoskeleton. Local electrical stimulation induces growth of dendritic spines, suggesting that synaptic activity directly modulates neuronal architecture and circuitry. The molecular basis for these activitydependent changes is not known, but probably involves postsynaptic proteins that interact with receptors and/or cytoskeletal elements. Shank acts as a putative scaffold for multiple glutamate receptor subtypes and also binds to the actinbinding protein cortactin, which has been implicated in dynamic cytoskeletal rearrangement and translocates to synapses in response to glutamate. This study examines the role of Shank in the regulation of dendritic spines and its in vivo function through three specific aims. First a combination of cell biological, biochemical, and dominant inhibitory approaches will be used to determine the mechanism for glutamateregulated cortactin translocation to synapses, and to identify if Shankcortactin interaction is required for this response. Second, how Shank induces spine growth will be studied by structurefunction analysis. Finally, a genetic approach, generation of a Shank1 "knockout" mouse, will be used to investigate the role of Shank proteins in brain development, in postsynaptic receptor organization, and in learning and memory. The longterm goal of the candidate is to understand how aberrant synaptic transmission contributes to neurologic disease. Synapses are the signal processing units of the brain, and overexcitation of synapses by glutamate is thought to play a role in both acute neuronal injury (such as stroke and seizure) and chronic neurodegenerative conditions (including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis). Understanding how postsynaptic proteins, such as Shank, regulate activitydependent synaptic plasticity may shed light on mechanisms of glutamate toxicity. The immediate goal is to obtain training in the most uptodate techniques in molecular genetics, protein biochemistry, and cellular neurobiology, sponsored by Dr. Morgan Sheng, which will enable him to become a productive, independent molecular neurologist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MICRONESIA

AGE

RELATED

NEURODEGENERATIVE

DISEASES

IN

Principal Investigator & Institution: Galasko, Douglas R.; Associate Professor; Neurosciences; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2004; Project Start 01-MAR-1997; Project End 31-MAR-2007 Summary: (provided by applicant): In this renewal of the program project Grant, we will continue to investigate neurodegenerative disorders on Guam, namely Parkinson-

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Dementia Complex (PDC), Amyotrophic Lateral Sclerosis (ALS) and late-life dementia. The unifying feature among these disorders is the pathological finding of neurofibrillary tangles. We hypothesize that interactions between aging, genetics and environment may determine which type of clinical phenotype results. We will use a multidisciplinary approach to determine rates of disease and risk factors, identify susceptibility genes and potential mechanisms of disease, investigate biochemical and radiological markers that may assist in early diagnosis and differential diagnosis, and carry out clinicopathological studies. There will be 3 cores: Administrative and Data core; Clinical core (on Guam and in San Diego), and: Neuropathology-Brain Bank core, in New York. There will be 4 research subprojects. Subproject by Galasko: 'Prevalence and incidence of dementia among elderly Chamorros' aims to measure the prevalence and incidence of PDC and dementia among Chamorros and assess risk factors. Subproject by Schellenberg: 'Genetic studies of ALS, PDC and Dementia on Guam' aims to perform genome-wide searches for genetic alterations associated with ALS and PDC, and to examine candidate genes for PDC and dementia. Subproject by Kaye: 'MRI of Neurodegenerative Disease among aging Chamorros' aims to carry out volumetric analyses of the hippocampus and other brain regions to identify markers of disease and assist in early diagnosis. Subproject by Lee: 'PHF-tau in neurodegenerative diseases of Guam' will assess oxidative markers related to brain lesions in ALS, PDC and dementia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AGGREGATION OF PROTEINS IN AGE-RELATED DISEASES Principal Investigator & Institution: Sherman, Michael Y.; Professor; Biochemistry; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 021182394 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2006 Summary: The cause of many age-related neurodegenerative disorders, including Parkinson's disease, ALS, and several polyglutamine expansion diseases, is accumulation in neurons of various mutant or damaged polypeptides. These toxic abnormal proteins can aggregate in cells and form large inclusion bodies, and there is an ongoing discussion in the field how aggregation of these proteins influences neurotoxicity. Recently it became clear that in contrast to protein aggregation in a test tube, aggregation of damaged or mutant polypeptides in vivo is a complicated tightly regulated process that involves many cellular factors. This proposal is designed to identify cellular components that promote aggregation of abnormal proteins. The proposal is based on a yeast model of human polyglutamine (polyQ) expansion diseases. This model allowed us to demonstrate that there are two distinct steps in polyQ aggregation - (1) seeding and (2) growth of aggregates. These steps require two distinct sets of cellular components, including a prion-like protein Rnql in a prion conformation. This model will be used for screens for cellular mutations that affect various steps of polyQ aggregation. Mutants with defects in polyQ aggregation will be tested for their ability to carry out various steps of the aggregation process. Then, it will be established which of the newly identified cellular factors that promote polyQ aggregation are also involved in aggregation of mutant proteins important for development of other agerelated diseases, including synphilin 1, ataxin 1 and PABP2. This work will lay the basis for further study of mechanisms of protein aggregation in neurons and aged mammalian cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Amyotrophic Lateral Sclerosis

Project Title: ANDROGEN TARGETS IN A SIMPLE BEHAVIORAL SYSTEM. Principal Investigator & Institution: Jordan, Cynthia L.; Associate Professor; Psychology; Michigan State University 301 Administration Bldg East Lansing, Mi 48824 Timing: Fiscal Year 2006; Project Start 15-DEC-2002; Project End 31-DEC-2009 Summary: (provided by applicant): Androgens influence the survival and growth of a neuromuscular system, the spinal nucleus of the bulbocavernosus (SNB) and its target muscles, the levator ani (LA) and the bulbocavernosus (BC). Proposed experiments will test whether LA/BC muscle fibers are direct cellular targets for androgens. Focus will be on LA/BC muscle fibers as prime mediators of androgenic influences on the SNB system because 1) androgens act directly on LA/BC muscles to regulate their survival and growth, and the survival and growth of SNB motoneurons and 2) androgen receptors (ARs) are enriched in muscle fibers of the LA/BC compared to other skeletal muscles. Proposed experiments will utilize two newly created transgenic mouse models that either over or under express ARs in their muscle fibers. These two models will be used to evaluate whether ARs in muscle fibers are necessary and/or sufficient for androgens to rescue the SNB system from death in development and promote expression of calcitonin gene-related peptide by SNB motoneurons in adulthood. Transgenic males will be compared to controls males (wild-type males and/or males that have a dysfunctional AR gene) and standard cellular approaches will be applied to answer these questions. Finally, males in some transgenic lines that overexpress ARs in muscle fibers show a progressive, late-onset neuromuscular degenerative disease that mimics Spinal Bulbar Muscular Atrophy (SBMA), a neurodegenerative disease in humans caused by a mutation in the AR gene (expansion of CAG repeats). SBMA afflicts primarily men in mid-life. Some proposed experiments are aimed at characterizing the emergent phenotype and the underlying pathology of this disease, and its liganddependence using behavioral, cellular and molecular methods. Relevance: Despite the essential role motoneurons have in all aspects of human life, motoneurons are susceptible to disease, and undergo selective demise in diseases such as Spinal Bulbar Muscular Atrophy (SBMA) and Amyotrophic Lateral Sclerosis (ALS). As part of the normal course of development, androgenic hormones prevent some motoneurons from dying and curiously, these same motoneurons are selectively spared in SBMA and ALS. We propose to study transgenic mouse models that have an altered expression of androgen receptors in skeletal muscle fibers to better understand how hormones regulate the survival of motoneurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISORDERS

ARTICULATORY

KINEMATICS

IN

NEUROGENIC

SPEECH

Principal Investigator & Institution: Weismer, Gary G.; Professor; Waisman Ctr/Mr & Human Devlmt; University of Wisconsin Madison Suite 6401 Madison, Wi 537151218 Timing: Fiscal Year 2004; Project Start 01-DEC-1998; Project End 31-MAR-2009 Summary: (provided by applicant): This is a proposal to study the articulatory underpinnings of speech intelligibility deficits in the neurogenic speech disorders associated with Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS). The proposed work uses x-ray microbeam (articulatory kinematic), speech acoustic, and speech intelligibility measures to address a major descriptive need, as well as a clinically- and theoretically-relevant hypothesis. Very little is known about lingual behavior in dysarthrias, and what is known about labial and mandibular behavior in dysarthria is confined to a limited type of speech material and measurement strategy.

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The present proposal includes a variety of speech materials to allow a broad characterization of articulatory kinematics (and the speech acoustic and intelligibility results of those motions) for speech production behavior. One way in which the articulatory kinematics will be characterized is by means of a measure of articulatory working space (i.e., parameterization of ranges). A central hypothesis is that there is a relationship between the size of these articulatory working spaces defined kinematically on the one hand, and the size of the acoustic working spaces and speech intelligibility on the other hand. Specifically, we test the idea, in several ways, that articulatory reduction is the primary segmental reason for reduced intelligibility in persons with ALS and PD. The hypothesis has been shown in the first funding period to hold across speakers within each of the two disorder groups, and will now be studied within neurologicallyimpaired speakers who are asked to control speech variables such as rate, loudness, and clarity so as to create variation in the magnitude of articulatory movements. Another major area of study is to identify the nature and possible disorder of articulatory coordination in dysarthria. Dysarthria is often described as having a prominent component of articulatory dyscoordination, but the small amount of relevant data that exist have not revealed the kind of frank coordination disorder that might be expected from typical textbook descriptions. A finding from the first funding cycle of small abnormalities in the degree of coordination, but an essentially-normal 'form' of coordination for a particular phonetic sequence will be followed up with analyses of additional sequences, as well as with the inclusion of analyses of articulatory scale in these patients and in neurologically-healthy controls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASTROCYTES AND MOTOR NEURON APOPTOSIS Principal Investigator & Institution: Beckman, Joseph S.; Director; None; Oregon State University P.O. Box 1086 Corvallis, or 973391086 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2006 Summary: (provided by applicant) Through a long lasting collaboration between Dr. Luis Barbeito, we have made major progress towards l unraveling how oxidative stress involving peroxynitrite formation causes the death of motor neurons in Amyotrophic Lateral Sclerosis (ALS). We have proposed a novel mechanism to explain how Zndeficient SOD may cause motor neuron disease and have together coauthored 12 papers on these subjects over the past 7 years. Most recently, we have found that astroglia can play a pathogenic role in motor neuron degeneration. It is well known that reactive astrocytes surround degenerating motor neurons in ALS patients as well as in transgenic mice and rats over-expressing ALS mutant SOD-1. We found that peroxynitrite triggers a long-lasting phenotypic transformation in astrocytes, which promotes apoptosis of motor neurons cultured on the monolayers by mechanisms dependent on nitric oxide (NO) and peroxynitrite formation. Preliminary data implicates astrocytic synthesis of nerve growth factor (NGF) and its precursor form proNGF in triggering motor neuron apoptosis through activation of the "low affinity" NGF receptor p75NTR. We hypothesize that zinc-deficient SOD plus nitric oxide will activate astrocytes and contribute to the progression of motor neuron death through activating NGF/p75NTR signaling. To test this hypothesis, we propose to characterize whether zinc deficient SOD can make astrocytes reactive and induce NGF synthesis and secretion. The pro-apoptotic activity of the different NGF forms will be tested on cultured motor neurons and in vivo studies will be performed to analyze whether blockade of NGF/p75NTR pathway in G93A transgenic mice affect disease progression. These additional studies will provide important insight into astrocytes could contribute

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Amyotrophic Lateral Sclerosis

to the progressive death of motor neurons in ALS. Halting the progressive death of motor neurons in ALS could be of huge clinical significance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AXONAL TRANSPORT OF NEUROFILAMENTS Principal Investigator & Institution: Brown, Anthony; Associate Neuroscience; Ohio State University 1960 Kenny Road Columbus, Oh 43210

Professor;

Timing: Fiscal Year 2004; Project Start 01-APR-1999; Project End 31-MAR-2008 Summary: (provided by applicant): Cytoplasmic accumulations of neurofilaments are a hallmark pathological feature of a number of human neurodegenerative diseases, most notably amyotrophic lateral sclerosis. These neurofilamentous accumulations are thought to be caused by changes in the mechanisms of slow axonal transport, which move cytoskeletal and cytosolic proteins along axons from their site of synthesis in the nerve cell body. We have recently observed the slow axonal transport of neurofilament protein in cultured nerve cells. The proteins move in the form of filamentous structures that may represent single neurofilament polymers. Contrary to the widely held view that slow axonal transport is a slow, synchronous and exclusively anterograde movement, we found that the filaments actually move at very fast rates, approaching the rate of fast axonal transport, and that the movements are also infrequent, bidirectional and highly asynchronous. Based on these observations, we have proposed a new model for slow axonal transport in which the actual rate of movement is fast, but the overall rate is slow because the rapid movements are interrupted by prolonged pauses. In this application, we propose to use live-cell fluorescence imaging strategies to test specific aspects of this hypothesis. In Aim 1 we will test the hypothesis that the moving filaments represent single neurofilament polymers. We expect that these experiments will also reveal the tracks along which the filaments move. In Aim 2 we will test the hypothesis that moving and stationary filaments differ in their phosphorylation state at specific epitopes and that they differ in their association with specific microtubule motor proteins. In Aim 3 we will test the hypothesis that rapidly moving filaments are delivered to the tip of growing axons in sufficient quantity to support the elaboration of the axonal neurofilament array during axon growth. We will also test the hypothesis that the growth cone is a site of frequent reversals in the direction of filament movement and that the frequency and/or directionality of filament movements in the distal axon is regulated in response to the rate of axon growth. The long-term goal of our research is to determine the mechanism and regulation of neurofilament protein transport along axons and the mechanisms that lead to the accumulation of neurofilaments in neurofilamentous neuropathies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BICARBONATE ENHANCES PEROXIDATION OF SOD/ALS MUTANTS Principal Investigator & Institution: Kalyanaraman, Balaraman; Professor and Chairman; Biophysics; Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, Wi 532260509 Timing: Fiscal Year 2005; Project Start 01-JUL-2000; Project End 31-JAN-2009 Summary: (provided by applicant): Long-term goal: The broad long-term objectives of this revised application are to understand the direct and indirect mechanisms by which human copper, zinc superoxide dismutase (hSOD1) mutants associated with familial and sporadic amyotrophic lateral sclerosis (ALS) disease cause selective toxicity to

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motor neurons. Hypotheses: (i) Bicarbonate anion (HCO3-) enhances the covalent aggregation of hSOD1 and hSOD1-ALS mutants via carbonate radical anion (CO3 -)mediated oxidative degradation of tryptophan residue (Trp-32) to kynurenine-type products, and (ii) Transfection of motor neuron cells (NSC-34) and neuroblastoma cells (SH-SY5Y) with familial ALS mutants (e.g., G93A) stimulates ceramide signaling, mitochondrial reactive oxygen species (ROS), transferrin iron uptake, proteasomal dysfunction and apoptosis or programmed death of neuronal cells. Specific Aims: Initially, the direct mechanism of covalent aggregation of isolated hSOD1 and ALS hSOD1 mutant mediated by CO3 - radical will be determined. Next, we will assess mitochondrial generation of ROS, transferrin iron signaling, protein aggregation, proteasome inhibition, and apoptosis in ALS hSOD1-transfected cells. Finally, the influence of ceramide, a bioactive lipid second messenger, on ROS generation in hSOD1WT and hSOD1G93A-transfected cells will be determined. The effects of iron supplementation and mitochondria-targeted spin probes on ALS disease progression and survival in ALS mutant mice will be assessed. Methods: Analytical techniques to be used will include EPR spin-trapping, MALDI-TOF, NMR, and fluorescence. Novel targeted oxidant-specific probes will be used. Significance: The proposed research will merge the oxidation and aggregation hypotheses in ALS SOD1-dependent toxicity using isolated hSOD1 proteins, and explore ceramide-induced oxidant signaling in G93Atransfected cells, and G93A mutant mice. Understanding the molecular basis of ALS SOD1 mutant toxicity will help improve overall strategies for developing effective drug therapy for ALS. Novelty: The use of state-of-the-art analytical techniques coupled with syntheses of mitochondria-targeted spin probes and fluorescent probes should yield new insights on the molecular mechanism for increased toxicity of ALS SOD1 mutants in motor neuron cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOSYNTHESIS AMINOCYCLITOLS

APPROACH

TO

NOVEL

BIOACTIVE

Principal Investigator & Institution: Mahmud, Taifo; Professor; Pharmaceutical Sciences; Oregon State University P.O. Box 1086 Corvallis, or 973391086 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2008 Summary: (provided by applicant): The increase of multi drug resistance (MDR) among pathogenic bacteria and fungi towards currently used antibiotics coupled with the lack of effective and safe medications to combat various physiological and regulatory disorders such as autoimmune diseases (e.g., multiple sclerosis, amyotrophic lateral sclerosis, etc.) and cancer urgently require new drug discovery. The CTN aminocyclitols, a relatively newly recognized class of microbial secondary metabolites, has great potential to be developed as drugs for various physiological disorders and infectious diseases. This is due to their resemblance to sugar moieties, which are widely involved in various ways in structural and physiological systems in living organisms. In this application, we propose to study the biosynthesis of C7N aminocyclitol-containing natural products and to use the knowledge obtained to develop pharmaceutically important leads via biosynthetic-based structure modifications. The study will be carried out with three different compounds: (1) the antifungal agent validamycin (in S. hygroscopicus); (2) the antibiotic pyralomicin (in Nonomuraea spiralis); and (3) the antitumor cetoniacytone (in Actinomyces sp.). The long-term objectives of this study include developing new CTN aminocyclitol-based drugs to combat infectious diseases and physiological disorders, improving production yields and/or providing alternative production strategies of clinically important CTN aminocyclitol compounds, and

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Amyotrophic Lateral Sclerosis

providing insights about the occurrence and distribution of this class of natural products in nature. The approach employs molecular genetics, enzymology, and chemistry to access, utilize and manipulate CTN aminocyclitol biosynthesis genes that direct precursor formation and other genes involved in the tailoring processes to create novel biologically active compounds. The study includes cloning and elucidation of the biosynthetic gene clusters of validamycin, pyralomicin, and cetoniacytone; elucidation of the newly discovered 2-epi-5-epi-valiolone pathway; characterization of the key biosynthetic enzymes; and use the information obtained to create novel bioactive aminocyclitols. The knowledge and methods that arise from these studies will be directly applicable to expanding the chemical diversity in other families of bioactive natural products. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APOPTOSIS

CASPASE

CLEAVAGE

OF

MEF2

MEDIATES

NEURONAL

Principal Investigator & Institution: Lipton, Stuart A.; Professor and Director; Burnham Institute for Medical Research 10901 North Torrey Pines Road La Jolla, Ca 92037 Timing: Fiscal Year 2004; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Apoptotic neuronal cell death may play a role in many acute and chronic neurologic disorders. These disorders range from acute stroke, head trauma and epilepsy to more chronic states, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, HIV-associated dementia, and glaucoma. Moreover, a contributing factor to such damage is excessive excitation of glutamate receptors, particularly (but not exclusively) the N-methyI-D-aspartate (NMDA) subtype of glutamate receptor because of its high permeability to Ca 2+ and subsequent free radical generation. The aim of this proposed research project is to uncover the role of myocyte enhancer factor-2 (MEF2) transcription factors in this excitotoxic/apoptotic process in neurons during ischemic stroke in vivo. MEF2 transcription factors are activated by p38 mitogen-activated protein kinase during neuronal and myogenic differentiation. Recent work has shown that stimulation of this pathway is anti-apoptotic in stem cells but pro-apoptotic in mature neurons exposed to mild excitotoxic or other stresses. Here, preliminary data in vitro show that mild excitotoxic (NMDA) insults to mature cerebrocortical neurons activate caspases-3, -7, in turn cleaving MEF2A, C and D isoforms. Endogenous MEF2 cleavage fragments containing a truncated transactivation domain but preserved DNA binding domain are shown to block MEF2 transcriptional activity via dominant interference. In vitro transfection of constitutively-active/uncleavable MEF2 (MEF2-CA) rescues MEF2 transcriptional activity following NMDA insult and prevents neuronal apoptosis. Conversely, dominant-interfering MEF2 (MEF2-DN) abrogates neuroprotection by MEF2C-CA. Our underlying hypothesis is that these results obtained in vitro can now be applied in vivo using tetracycline (or doxycycline, "dox")-controlled transgenic mice expressing these MEF2-CA and MEF2-DN transgenes. This grant will define a novel pathway to neuronal apoptosis in ischemia via caspase-catalyzed cleavage of MEF2. The Specific Aims are as follows: 1. To characterize anti-apoptotic effects of MEF2-CA in stroke using dox-controlled transgenic mice. 2. To characterize the effect of caspase cleavage fragments of MEF2 as dominant interfering forms that contribute to stroke damage using dox-controlled transgenic mice that express doxycycline-controlled, MEF2 cleavage products. 3. To characterize MEF2 transcriptional activity in vivo after an hypoxic/ischemic (stroke) insult but prior to cell loss using a MEF2-indicator mouse

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that has been engineered to activate the LacZ gene in accord with the degree of MEF2 transcriptional activity (designated des-mef2-LacZ). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CER ON CAM ANTIOXIDANT THERAPIES (CERCAT) Principal Investigator & Institution: Frei, Balz B.; Professor and Endowed Chair; None; Oregon State University P.O. Box 1086 Corvallis, or 973391086 Timing: Fiscal Year 2004; Project Start 26-SEP-2003; Project End 31-MAY-2008 Summary: This Program Project is based in the Linus Pauling Institute, an emerging international leader in research and education on micronutrients and antioxidants, and one of a few centers in the US to focus entirely on health promotion and disease prevention by dietary and CAM approaches. The Center of Excellence for Research on Complementary and Alternative Medicine (CAM) Antioxidant Therapies (CERCAT) will investigate two specific categories of CAM antioxidants: (i) Antioxidants that modulate the cellular redox environment and, thus, cell signaling and transcriptional activation, e.g. by affecting critical thiols with a low pKa or upregulating endogenous antioxidant systems. The CAM antioxidants to be investigated from this category are dithiol compounds (e.g. alpha-Iipoic acid) and metal chelators (e.g. EDTA and desferrioxamine). (ii) Highly conjugated or aromatic compounds that inhibit tyrosine nitration by peroxynitrite and other reactive nitrogen species. The principal antioxidant to be examined in this category is uric acid. Using cell culture studies and relevant animal models, CERCAT will determine the molecular and cellular mechanisms of action of these CAM antioxidants, and their safety and efficacy in treating amyotrophic lateral sclerosis (ALS) and cardiovascular diseases (CVD) and reversing the loss of cellular resistance to stress that occurs with aging. These goals of CERCAT are buttressed by NCCAM's "increased emphasis on studies of the mechanism underlying CAM approaches" and its "FY 2003 Research Priorities" of "studies of the biology of EDTA chelation therapy in animal models of CVD" and "neurodegenerative disorders using in vitro studies and animal models." CERCAT's research goals will be accomplished through three highly interactiveprojects: 1) "Metal chelators and thiols in endothelial function, and CVD" (Balz Frei); 2) "Lower vulnerability to toxins in aging by treatment with lipoic acid" (Tory Hagen); and 3) "CAM antioxidants and ALS" (Joseph Beckman). Center Investigators will be aided by an Administrative Core, which handles budgetary, reporting, and external advisory needs. In summary, CERCAT will investigate the efficacy of CAM antioxidants in ALS, CVD and aging, and provide the essential knowledge about the underlying mechanisms, dose-response effects, and relevant biological targets to advance these CAM therapies to human trials; equally important, the studies will test for untoward effects that might discourage CAM antioxidant therapies from proceeding to human studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL TRIAL OF AMYOTROPHIC LATERAL SCLEROSIS.

CELEBREX

IN

SUBJECTS

WITH

Principal Investigator & Institution: Pestronk, Alan; Professor; Clinical Research Center; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2004; Project Start 06-MAY-2004; Project End 31-MAR-2005 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL TRIAL OF HIGH DOSE COQ10 IN ALS - QALS-CLIN Principal Investigator & Institution: Kaufmann, Petra; Neurology; Columbia University Health Sciences Research Administration New York, Ny 100323702 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is one of the most devastating neurological diseases leading to death typically in 3 years of onset. Treatment is severely limited, and no cure is available. Oxidative stress and mitochondrial dysfunction have been implicated in ALS pathophysiology. Coenzyme Q 10 (CoQ 10), a mitochondrial cofactor and powerful antioxidant, prolongs survival in the transgenic ALS mouse model and slows functional decline in other human neurodegenerative disease. CoQ 10 is a nonprescription dietary supplement with an excellent safety profile and central nervous system penetration. Thus, we propose to conduct a 2-stage phase II, randomized, placebo-controlled, double-blind, multi-center clinical trial of high-dose, solubilized CoQ 10 against placebo (target enrollment 185 patients at 18 clinical sites). This project will test the hypothesis that CoQ 10 reduces functional decline in patients with ALS. Aim 1 will consist of two stages. Stage 1 identifies which of two CoQ 10 doses is preferable (1000 mg. or 2000 mg. daily). Stage 2 compares the selected dose against placebo to assess whether evidence of efficacy is sufficient to justify proceeding to a future phase III trial. The primary outcome measure is the change in ALS Functional Rating Scale revised (ALSFRSr) score from baseline (randomization) to 9 months. We chose the ALSFRSr because: (1) It measures daily living functional abilities, a clinically meaningful outcome; (2) it is a validated predictor of survival; and (3) its ease of administration will minimize subject dropout. Aim 2 will determine whether CoQ 10 affects secondary measures: (1) forced vital capacity, (2) fatigue severity, (3) health-related quality-of-life, and (4) serum oxidative stress markers. Because median disease duration is short, the pool of ALS clinical trial participants at any given time is quite limited. Survival as an outcome measure is the gold standard for phase HI trials, but requires a large sample size. Because several new agents will soon be available for clinical testing, it is vital to reduce the number of patients required for phase II trials if these agents are to be tested in a timely, effective way. Aim 3 will evaluate alternative outcome measures to determine if their use can decrease the sample size required for ALS trials (see QALS-STAT). If CoQ 10 is effective in reducing functional decline in ALS, after phase III confirmation this knowledge will have an immediate impact on clinical practice and our understanding of ALS pathophysiology. This application is the clinical part (QALS-CLIN) of two separate, but highly coordinated units, which together constitute QALS (Clinical Trial of High Dose CoQ 10 in ALS). A separate R01 grant proposal (QALS-STA T, PI JLP Thompson) has been submitted for conduct of the statistical operations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL TRIAL OF HIGH DOSE COQ10 IN ALS-QALS-=STAT Principal Investigator & Institution: Thompson, John L.; Biostatistics; Columbia University Health Sciences Research Administration New York, Ny 100323702 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): QALS-CLIN and QALS-STAT are two independent, but highly coordinated units, which together constitute QALS, a two-stage, phase II, randomized, placebo-controlled, double-blind, multi-center clinical trial of Coenzyme Q10 against placebo (target enrollment 185 patients at 18 clinical sites). The first stage identifies, which of two doses of CoQ10 is preferred (1,000 mg. or 2,000 mg. daily), using

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a selection procedure to hold the number of patients required to a minimum. The second stage compares the preferred dose against placebo to assess whether there is sufficient evidence of efficacy to justify proceeding to a phase III trial. The primary outcome measure is the change in Amyotrophic Lateral Sclerosis Functional Rating Scale revised (ALSFRSr) score from baseline (randomization) to 9 months, which preliminary research has validated as a surrogate for the gold standard of survival. Four pre-specified secondary supporting hypotheses are also tested. Alternative outcome measures, based on ALSFRSr subscores that may prove more sensitive, will be explored in tertiary analyses as candidates for future trials. The goals of QALS-STAT are: 1) To minimize follow-up-time and number of patients required. 2) To conduct, efficiently integrate, and be responsible for all QALS data management and statistical operations. 3) To transmit to the Clinical Coordinating Center (CCC) in a timely fashion all of the data which the principal investigator of QALS CLIN needs to meet her responsibilities, in terms of ensuring patient safety and directing all clinical operations. Goal 1 is accomplished by the selection procedure, and the use of a surrogate endpoint, which cuts follow-up time by 50%. Goal 2 is achieved by a Statistical Analysis Center, whose personnel have extensive experience in coordination, data management, and programming for clinical trials, as well as their statistical requirements. Goal 3 is ensured by an Operations Committee of QALS-CLIN and QALS-STAT investigators and senior coordinators, which meets frequently under tightly specified and controlled communication protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISEASES

COMPARATIVE

MODELING

OF

NEURODEGENERATIVE

Principal Investigator & Institution: Link, Christopher D.; Professor; Inst for Behavioral Genetics; University of Colorado at Boulder 572 Ucb Boulder, Co 80309 Timing: Fiscal Year 2004; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Numerous age-associated neurodegenerative diseases [e.g., Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), etc.] are associated with aggregation of disease-specific proteins. The finding that the genes encoding these proteins are mutated in some familial forms of these diseases strongly argues that these aggregating proteins cause these diseases. However, for all these diseases the relationship between protein aggregation and cellular pathology has not been clearly established. It is also unknown if the common association of protein aggregation with these diseases reflects a common underlying toxic mechanism, or, alternatively, a common downstream result of cell pathology. We will seek to identify the molecular consequences resulting from the aggregation of three different disease-associated proteins by individually expressing these proteins in a transgenic Caenorhabditis elegans model system. These molecular consequences will be determined by DNA microarray-based gene expression studies and co-immunoprecipitation analyses. Comparison of the molecular responses to expression of different disease-associated proteins will allow identification of common and disease-specific responses. We will then use the molecular genetic tools available in C. elegans to manipulate these molecular responses to determine their role in disease protein toxicity. These studies will directly test whether there is a common underlying toxic mechanism for these neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Amyotrophic Lateral Sclerosis

Project Title: CONTROL OF SYNAPTIC GLUTAMATE RELEASE Principal Investigator & Institution: Mennerick, Steven J.; Assistant Professor; Psychiatry; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2006; Project Start 01-JUL-2000; Project End 31-MAY-2011 Summary: (provided by applicant): In the central nervous system (CNS), glutamate and gamma-aminobutyric acid (GABA) are major excitatory and inhibitory neurotransmitters respectively. Balance between glutamate and GABA actions is critical for proper CNS function. Excessive glutamate accumulation has been associated with neuronal damage in a myriad of neurological and neuropsychiatric disorders including epilepsy, stroke, amyotrophic lateral sclerosis and others. We hypothesize that the CNS may have endogenous mechanisms by which glutamate release is selectively dampened, thereby maintaining or resetting the balance between excitation and inhibition during excessive activity. Novel ameliorative strategies might arise from better understanding and exploiting endogenous mechanisms that the nervous system itself uses to restore balance between excitation and inhibition. We explore two homeostatic mechanisms that, at the level of presynaptic vesicle release, depress glutamate release selectively over GABA release. The first synaptic adaptation is an acute change in vesicle release probability at glutamate but not GABA synapses. Glutamate synapses possess more "reluctant vesicles" than GABA synapses, identifiable with short trains of action potentials that fail to release otherwise accessible vesicles. Reluctant vesicles may be present at a distinct set of presynaptic terminals from willing vesicles or may arise within terminals as a result of stimulus-dependent factors. We propose to study the mechanisms and regulation of reluctant vesicles. We hypothesize a rapid-onset, calciumdependent feedback mechanism is particularly important in vesicle reluctance. The second synaptic adaptation is a persistent change in glutamate vesicle availability that outlives the inducing stimulus. We show that normal action potential activity suffices to inactivate a small percentage of glutamate vesicles, and that the number of inactivated vesicles is increased by augmenting neuronal activity. We hypothesize that the persistent changes differ mechanistically from other more commonly studied forms of persistent synaptic plasticity and that the changes are induced by local presynaptic calcium influx, which alters the number of functionally active presynaptic terminals. By better understanding the modulation of vesicle release probability and availability, we may learn to exploit the mechanisms for clinical benefit in disorders of excitotoxicity, and we will broaden our understanding of the reliability and malleability of glutamate synapses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORD BLOOD CELLS IN ALS: REPLACEMENT OF PROTECTION? Principal Investigator & Institution: Garbuzova-Davis, Svitlana N.; Assistant Professor; Saneron Ccel Therapeutics, Inc. 3802 Spectrum Blvd. Tampa, Fl 33612 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2006 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease affecting motor neurons in the spinal cord, brainstem and cortex. We have previously shown that transplanting neuronal cells into the spinal cord delays the onset of motor symptoms in the G93A mouse model of ALS, but developing a potential treatment strategy around a committed neuronal cell or cell-line is not appropriate when there is widespread neurodegeneration as in ALS. Stem cells with their putative migratory abilities and multipotentiality may be able to protect dying

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motor neurons and prevent disease progression. However, the mechanism behind these effects is unknown. We hypothesize that stem cells from umbilical cord blood (hUCB) will have a neuroprotective effect through modulation of immune effectors. The purpose of this project is to determine whether the mononuclear hUCB (MNC hUCB) cell population can serve as a novel source of transplant cells to ameliorate behavioral deficits and extend lifespan in the G93A mouse model of ALS. In Aim 1 we will determine a dose response relationship between MNC hUCB transplantation in the ALS mouse and motor function and lifespan of the mouse. In Aim 2 we will determine the distribution and migration potential of the transplanted MNC hUCB cells to areas of degeneration and if they may adopt immune phenotypes in vivo. In Aim 3 we will determine the effect of the transplanted cells on host immune inflammatory response by examining cytokine expression in G93A mice. The results of this study may provide the basis for developing a novel, non-invasive therapy, easily accessed by ALS patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CREATINE IN AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Rosenfeld, Jeffrey; Carolinas Medical Center Box 32861, 1000 Blythe Blvd Charlotte, Nc 282322861 Timing: Fiscal Year 2004; Project Start 15-SEP-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder selectively affecting motor neurons resulting in progressive weakness. Currently there is no known cure and a specific etiology has not been identified. Creatine is a nutritional supplement that improves mitochondrial function and has been shown to protect motor neurons in animal models of ALS. Based on our preliminary results presented in this proposal, creatine may also improve strength in patients with ALS.The Specific Aims of this proposal are to: 1) Determine whether treatment with creatine results in an acute increase in muscle strength and whether that effect is sustained with chronic therapy. 2) Determine whether chronic treatment with creatine will slow the progressive deterioration of motor and pulmonary function in patients with ALS. 3) Determine whether administration of loading doses of creatine followed by chronic treatment is safe in patients with ALS.This will be a phase III, double-blind, placebo-controlled, multi-center safety and efficacy study of creatine in 100 patients with ALS treated for nine months. The primary outcome measures are changes in disease progression rate as measured by 1) the maximum voluntary isometric contraction (MVIC) strength of ten arm muscle groups (bilateral shoulder and elbow flexion-extension and grip strength and 2) manual muscle testing (MMT) of the same ten arm muscle groups. Secondary endpoints include the rate of decline of forced vital capacity (FVC, percent predicted), the change in the ALS functional rating scale (ALSFRS-R), the SF-12 (quality of life instrument), and the safety and tolerability of creatine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYCLOOXYGENASE 2 AND ISCHEMIC NEURONAL INJURY Principal Investigator & Institution: Graham, Steven H.; Professor & Vice Chairman; Neurology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 01-JUN-1999; Project End 31-MAY-2008 Summary: (provided by applicant): Cyclooxygenase, the enzyme that catalyzes the production of prostaglandins from arachidonic acid, has long been thought to play a

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role in exacerbating injury due to cerebral ischemia via its vascular and inflammatory effects. Recently it has been found that the inducible isoform of the enzyme, cyclooxygenase 2 (COX2), is expressed in high levels within neurons. We hypothesize that COX2 activity within the neuron itself promotes cell death after hypoxia/ischemia. The proposed experiments are designed to test whether COX2 activity exacerbates anoxic injury by oxidative stress, production of prostaglandins including the cyclopentenone prostaglandins, or both. The following specific aims are proposed: 1. Test whether COX2 activity exacerbates anoxic injury through production of oxidative stress via peroxidase activity. 2. Test whether COX2 activity exacerbates anoxic injury through production of prostaglandins via cyclooxygenase activity. 3. Test whether 15deoxy-delta(12,14) -PGJ2 or other prostaglandins activate PPARgamma receptor binding and exacerbate anoxic neuronal death via activation of the PPARgamma receptor. COX2 activity has been implicated in the pathogenesis of stroke and neurodegenerative diseases, including Atzheimer's disease and amyotrophic lateral sclerosis. The current studies will address the mechanisms by which COX2 activity can directly injure neurons and thus could lead to new therapeutic strategies for stroke and neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPLETION OF MITOCHONDRIAL S-NITROSOTHIOLS IN ALS Principal Investigator & Institution: Mannick, Joan B.; Associate Professor; Medicine; Univ of Massachusetts Med Sch Worcester 55 Lake Avenue North Worcester, Ma 01655 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): There is increasing evidence that mitochondrial dysfunction contributes to amyotrophic lateral sclerosis (ALS) pathogenesis. However the causes of mitochondrial dysfunction in ALS are not known. We hypothesize that familial ALS-associated SOD1 mutants aberrantly deplete S-nitrosothiols (SNOs) in mitochondria leading to mitochondrial degeneration and motor neuron death. Snitrosothiols are peptides and proteins that have an NO group attached to a cysteine residue. Peptide SNOs are potent antioxidants and neuroprotective. S-nitrosylation of critical cysteine residues on proteins is emerging as a mechanism of signal transduction regulation. Therefore aberrant depletion of mitochondrial SNOs is likely to be a toxic gain-of-function of SOD1 mutants. This is a novel testable working hypothesis in a virtually unexplored area in the ALS field. In support of our hypothesis, our preliminary data indicate that peptide and protein SNOs are located primarily in the mitochondria of cell lines expressing wild-type SOD1. Moreover, SNO levels are significantly decreased in the mitochondria of cells expressing SOD1 mutants. In specific aim 1 of the proposed studies we will extend our preliminary studies in cell lines to an in vivo animal model and determine if mitochondrial SNO levels are decreased in the spinal cord of mutant SOD1 transgenic mice before or at the time of onset of muscle weakness. In specific aim 2 we will determine if restoration of mitochondrial SNO levels improves mitochondrial function and the viability of cells expressing mutant SOD1. If we confirm our hypothesis, then in future studies we will determine if SNO donor compounds improve the survival of mutant SOD1 transgenic mice. Our long term goal is to determine if SNO donor compounds (which have been used for decades in the treatment of coronary artery disease with limited toxicity) have therapeutic efficacy in patients with ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIAGNOSTIC AND SURROGATE MARKERS FOR ALS Principal Investigator & Institution: Paige, Lisa A.; Metabolon, Inc. Durham, Nc 277134409 Timing: Fiscal Year 2005; Project Start 01-FEB-2005; Project End 31-JUL-2006 Summary: (PROVIDED BY APPLICANT): Environmental and genetic factors are believed to contribute to Neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Parkinson's, Huntington and Alzheimer's diseases. In general, these diseases are poorly understood at the molecular and biochemical levels with no effective therapies. A better understanding of environmental triggers that influence disease development and the interplay between these exposures and a person's underlying genetic susceptibility will result in earlier detection, better understanding of disease mechanisms, and ultimately the design of prevention strategies. Metabolomics is a powerful new technology platform for the comprehensive study of the metabolome, the repertoire of bio-chemicals (or small molecules) present in cells, tissue and body fluid. It can provide signatures for disease states in ways not possible before and maps these changes to aberrent biochemical pathways. Environmental insults and genetic mutations leave long lasting changes in the metabolome that can be captured in modified signatures. In the proposed studies we will extend our current observations of biochemical abnormalities (signatures) in the sera of ALS patients, both familial and sporadic, but using the new chemically capable metabolomic platform. We will confirm the specificity of these signatures by comparing them to signatures from patients with general neuropathies, myopathies and other neurodegenerative diseases. Specific aims for Phase I: 1. Collect clinical data and plasma samples from subjects with ALS and disease and non-disease comparison groups. 2. Begin to identify unique metabolomic profiles for sporadic ALS (SALS) and familial ALS (FALS) by comparing to those from patients with peripheral nervous system disorders, other neurodegenerative disorders and healthy controls. In Phase II we will propose to develop diagnostic and surrogate marker products for ALS. Long-term goals are to use metabolomics as a powerful tool to map environmental factors that contribute to the development of neurodegnerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISCOVERING SMALL MOLECULES TO RESCUE SOD-1 FOLDING Principal Investigator & Institution: Wigley, William C.; Reata Pharmaceuticals, Inc. Suite 150 Irving, Tx 75063 Timing: Fiscal Year 2005; Project Start 15-FEB-2005; Project End 31-JAN-2006 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal adultonset neurodegenerative disease characterized by selective loss of motor neurons and atrophy of skeletal muscle. ALS is the most common motor neuron disease in the adult population, affecting 30,000 in the United States alone. Approximately 15% to 20% of familial ALS cases are associated with dominant missense mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene. A pathologic feature of both sporadic and familial ALS is the accumulation of potentially toxic proteinaceous inclusions containing misfolded SOD1 in the cytosol of degenerating neurons. A series of recent studies strongly suggest that ALS results from a gain of toxic function, which arises either during early steps of inclusion formation or from the inclusions themselves. In this regard, the discovery of compounds that affect SOD1 misfolding would be a major step toward the development of drugs for the treatment and prevention of ALS. To date however, the search for such compounds has been hindered by a lack of appropriate

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high-throughput screening (HTS) methods. Reata Discovery, Inc., the applicant organization, has obtained an exclusive license to a novel, proprietary cell-based HTS method that directly monitors SOD1 folding and solubility in live cells. Using this method, we have established a tight correlation between reporter signal and the published effects of disease-associated mutations on the stability of SOD1. Notably, this system is sensitive and has excellent dynamic range in mammalian cells, providing up to a 50-fold difference in signal between wild type SOD1 and the most severe mutations. Based upon this robust assay, Reata has initiated a program to identify small drug-like compounds that impact SOD1 misfolding. The proposed funding will significantly enhance this effort by expanding the scope of compound libraries and supplementing internal funds that Reata has already committed to the program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF STARGAZIN ON AMPA RECEPTOR CHANNEL FUNCTION Principal Investigator & Institution: Patneau, Doris K.; Anatomy and Cell Biology; Osu Center of Health Sciences 1111 W 17Th St Tulsa, Ok 741071898 Timing: Fiscal Year 2006; Project Start 01-JAN-2006; Project End 31-DEC-2008 Summary: (provided by applicant): The ionotropic glutamate receptors are critical for the normal development and function of the nervous system, and for the processes underlying learning and memory. Glutamate receptors have also been implicated in the etiology of several pathological conditions, including Alzheimer's, Huntington's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy and brain damage following stroke. The proposed experiments will provide significant new information regarding regulation of the channel properties of AMPA receptors, the major glutamate receptor subtype mediating fast excitatory synaptic transmission in the brain. Stargazin is a transmembrane protein that is known to act as a molecular chaperone in trafficking of AMPA receptors to the cell surface. However, as an associated membrane protein, stargazin could also affect AMPA receptor channel function. Preliminary data document significant effects of stargazin on AMPA receptor desensitization that appear to be distinct from its effects on trafficking. Studies are proposed that will (1) identify the specific effects of stargazin on gating and desensitization of the AMPA channel; (2) identify the regions of interaction between stargazin and the AMPA receptor that mediate these functional effects, and; (3) determine the underlying mechanism for TARP modulation of AMPA receptors. Stargazin will be co-expressed with recombinant AMPA receptors in HEK 293 cells, as well as native AMPA receptors in cultured rat hippocampal neurons and mouse cerebellar granule cells. Functional effects on agonistevoked and synaptic responses will be examined using patch-clamp recording from single cells. Molecular techniques will be applied to determine whether the regions of the stargazin protein that mediate trafficking and effects on channel function can be distinguished. Further experiments will involve manipulations of AMPA receptor proteins to attempt to disrupt the effects of stargazin on channel function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FLUORESCENT NEUROCHEMISTRY

SENSORS

TO

INVESTIGATE

ZINC

Principal Investigator & Institution: Lippard, Stephen J.; Professor of Chemistry; Chemistry; Massachusetts Institute of Technology 77 Massachusetts Ave Cambridge, Ma 02139

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Timing: Fiscal Year 2004; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): The long-term goal of this research is to provide bright fluorescent sensors for zinc to investigate its neurochemistry. Zinc occurs at high concentrations in vesicles located in presynaptic neurons of the hippocampus and is released into the synaptic cleft in response to a physiological signal. We hypothesize that such zinc release can be used to map neural networks by following the temporal and positional pattern of fluorescence changes that occur following stimulation. Uncontrolled release of neuronal zinc, for example in response to ischemia, leads to Zninduced death of cortical neurons. The sensors devised here will provide a powerful tool for tracking zinc levels suspected to correlate with such events as well as neurological diseases, including familial amyotrophic lateral sclerosis and Alzheizemer's disease. The proposal focuses on the design and synthesis of three classes of ligands for selective zinc binding, each giving rise to a fluorescent response. The sensors are all derivatives of fluorescein, chosen for its high quantum yield, long wavelength excitation and emission properties, and ability to be manipulated chemically. The first class of ligands improves the brightness of the fluorescence upon Zn2+-binding, which is quenched by photoinduced electron transfer (PET) until zinc binding restores it. This kind of sensor is typified by preliminary work with the "Zinpyr" family of molecules, which contain fluorescein functionalized at the 4' and 5' positions with bis(2-pyridylmethyl)aminomethyl zinc-binding moieties. A second approach affords ratioable fluorophores by coordination of zinc to the nitrogen atom of a hybrid rhodamine/fluorescein skeleton that we designate as "rhodafluor" ligands. Here, both the unbound and bound sensors fluoresce, but emit at different wavelengths. The third class of molecules to be synthesized and investigated positions the zinc-binding moiety as a spacer between pendant fluorescent donor/acceptor pairs that undergo resonance energy transfer (ET) more efficiently upon zinc binding. All the synthetic routes are modular and convergent, allowing for systematic variation of the Zn2+-binding unit to access a wide range of dissociation constants and solubility properties. The structures, formation constants, rates of formation and dissociation, solubility, solution stability, and fluorescence lifetimes of the zinc complexes of these sensors will be investigated. Their cellular localization will be studied by one- and two-photon microscopic methods. A strategy for attaching the sensors to the extracellular surface of post-synaptic neurons to monitor zinc arrival after synaptic firing will be pursued. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL DISSECTION OF RET SIGNALING PATHWAYS Principal Investigator & Institution: Jain, Sanjay; Surgery; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899 Timing: Fiscal Year 2004; Project Start 15-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): RET is a single membrane tyrosine kinase receptor that mediates signaling of GDNF family ligands (GFLs) in association with GFRalpha coreceptors. Aberrant RET signaling results in a number of human diseases and developmental abnormalities, including multiple endocrine neoplasia type 2 syndromes, Hirschsprung disease (intestinal ganglionosis), and developmental abnormalities of the peripheral nervous and urogenital systems in mice. GFL signaling is also important for the survival of neuronal populations such as midbrain dopaminergic neurons and spinal cord motor neurons, which degenerate in Parkinson disease and amyotrophic lateral sclerosis (ALS), respectively. The molecular defects in the signaling pathways that result in the wide variety of RET-mediated abnormalities are largely unknown. This lack of knowledge is an impediment for the creation of rationally designed medical

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interventions for these conditions. Similar to other receptor tyrosine kinases (RTKs), RET signals through interactions between key phosphotyrosine docking sites and their cognate adaptor proteins. Signals emanating from these interactions are important in RET-mediated regulation of cellular processes such as proliferation, migration, and axonal outgrowth, whereas the perturbation of these processes ultimately leads to diseases. The candidate proposes to characterize mice expressing RET mutants lacking key adaptor docking sites in order to associate these mutations with alterations in key cellular processes that lead to developmental deficits in the peripheral nervous and urogenital systems. As aberrations in RET-stimulated proliferation is central to its role in tumorigenesis and developmental abnormalities, the candidate will utilize engineered fibroblast cell lines to study this aspect of RET biology in further detail. These in vitro assays will be used in conjunction with lentivirus delivery of specific siRNAs to identify signaling components (adaptor proteins) and pathways (MAPK, PLCgamma) that signal through particular RET docking sites to regulate proliferation. The identification of specific components of this signaling pathway will be helpful ultimately in developing targeted therapeutics for these tumors and in enhancing our understanding of nervous system development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL GENOMICS OF C.ELEGANS USED TO STUDY DISEASE Principal Investigator & Institution: Buttner, Edgar A.; Molecular and Cellular Biology; Harvard University 1350 Massachusetts Avenue Cambridge, Ma 02138 Timing: Fiscal Year 2004; Project Start 01-AUG-2001; Project End 31-JUL-2007 Summary: (Applicant's Abstract): My long-term objective is to develop and analyze invertebrate models to obtain a mechanistic understanding of hereditary human neurological diseases. The nematode Caenorhabditis elegans will be used for genetic analysis of loss-of-function diseases such as lissencephaly (LIS), and gain-of-function diseases, such as familial amyotrophic lateral sclerosis (FALS). Loss-of-function neurological diseases will be modeled by disrupting C. elegans disease gene homololues. Gain-of-function neurodegenerative disorders will be modeled by generating transgenic worms carrying gain-of-function disease transgenes. The powerful genetics of C. elegans will then be applied to analyze the molecular basis of neuronal cell death or dysfunction in these disorders. Suppressor and enhancer screens will be performed to identify novel genes that interact with loss-of-function disease gene homologues or gain-of-function disease transgenes, an approach not possible in transgenic mice. Such novel genes may not only provide insight into the molecular mechanisms of action of neurological disease genes, but may also constitute potential therapeutic targets. Genetic analysis of diverse aspects of C. elegans development has identified genes and pathways relevant to disease. Studies of apoptosis in C. elegans defined genes composing a programmed cell death pathway that is conserved in human. The creation of worm models of neurological diseases will provide an opportunity to study how upstream disease genes and downstream cell-death genes might interact. Because a large number of disease gene homologues have been identified in C. elegans, the project could in principal establish an approach with future applications to a wide range of neurological disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GAMMA - SECRETASE CLEAVAGE OF THE P75 RECEPTOR Principal Investigator & Institution: Chao, Moses V.; Professor; Skirball Institute; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 31-MAY-2011 Summary: (provided by applicant): The neurotrophins, NGF, BDNF, NT-3 and NT-4, represent a family of proteins essential for the development of the vertebrate nervous system. In addition to classical effects upon neuronal cell survival, neurotrophins also can regulate axonal and dendritic growth, synaptic structure and connections, neurotransmitter release, long-term potentiation and synaptic plasticity. Each neurotrophin can signal through two different cell surface receptors, Trk receptor tyrosine kinases and the p75 neurotrophin receptor, a member of the TNF receptor superfamily. Given the wide number of activities now associated with neurotrophins, it is likely additional regulatory events and signaling systems are involved. In this application, we will focus on a new and unexpected mechanism. Intramembraneous cleavage of the p75 receptor by ?-secretase results in the release of the intracellular domain. This is the first known example of this activity in the TNF receptor superfamily. Significantly, the cleavage of p75 has been mapped to the same location as amyloid precursor protein (APR). Cleavage-resistant forms of p75 have been created to test the functional significance of y-secretase cleavage and the effect on p75 signaling activities. The functional consequences of p75 cleavage will be tested upon Trk receptor signaling, as well as axonal regeneration events. The p75 receptor is known to interact with cytoplasmic proteins that can translocate to the nucleus. Among many proteins that interact with p75, we will follow SC-1, a novel zinc finger protein that translocates to the nucleus. Since p75 is frequently upregulated after injury, these studies will provide further insight into mechanisms responsible for neurotrophins during inflammation and neurodegenerative disease states, such as Alzheimer's dementia and amyotrophic lateral sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC DETERMINANTS OF OXYGEN TOXICITY Principal Investigator & Institution: Culotta, Valeria C.; Associate Professor; Environmental Health Sciences; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2004; Project Start 01-AUG-1993; Project End 31-JUL-2005 Summary: This research focuses on Cu/Zn superoxide dismutase (SOD1), an important anti-oxidant enzyme that scavenges superoxide and predominantly localizes to the cytosol of eukaryotes. The function of SOD1 has been somewhat enigmatic because superoxide is thought to largely arise from mitochondria, where a second SOD (Mn SOD2) already exists. Through studies in bakers yeast, we have been exploring the biology of Cu/Zn SOD1. Previously, we discovered the CCS metallochaperone that inserts the catalytic Cu co-factor into SOD1. CCS co-localizes with SOD1 primarily in the cytosol, but recently we found that both proteins also reside in the intermembrane space of the mitochondria where active SOD1 may directly combat respiratory sources of superoxide. By exploiting yeast and mammalian systems, the current Aims are designed to unravel the striking link between SOD1 and the mitochondria. AIM l: To identify the sources of oxidative damage relevant to Cu/Zn SOD1. The role of mitochondria in causing rapid aging and oxidative damage to yeast lacking SOD1 will be determined. Metabolic sources of superoxide will be identified through a genetic screen. AIM 2: To understand the physiology of mitochondrial Cu/Zn SOD1. The functions of cytosolic

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Amyotrophic Lateral Sclerosis

versus mitochondria SOD1 will be differentiated and the mechanism of mitochondrial import of SOD1 probed. We will also begin to address the possible implications for mitochondrial SOD1 in SOD1-linked cases of Amyotrophic Lateral Sclerosis. AIM 3: To define the CCS-independent pathway of copper delivery for SOD1. Mammalian SOD1 acquires a limited level of copper independent of CCS. We will now test whether this pathway occurs in mitochondria and will employ yeast genetics to identify factor(s) other than CCS that activate mammalian SOD1 with copper. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC EPIDEMIOLOGY OF ALS IN VETERANS Principal Investigator & Institution: Schmidt, Silke A.; Medicine; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2004; Project Start 19-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating, incurable and rapidly fatal disorder of the motor neurons responsible for voluntary muscle movement. Genes responsible for the familial form of ALS have been identified, but the majority of ALS is sporadic and has a complex etiology with contributions of both genetic and environmental factors. The hypothesis that geneenvironment (GxE) interaction may play a substantial role in ALS pathogenesis is supported by studies of high-risk clusters in the Western Pacific Islands. ALS is a disease of high priority for the Department of Veterans Affairs (VA) since an increased incidence of the disease has been reported in deployed compared to non-deployed Gulf War veterans. Recently, the VA has initiated a National Registry of veteran ALS patients, which is expected to recruit approximately 1,500 patients with blood samples over the next three years. Given this unique resource, the explosion of data from the Human Genome Project, and the development of new laboratory and statisticalgenetic analysis tools, the time is ripe for new approaches to dissecting the etiology of ALS, with an emphasis on uncovering complex GxE interactions. The specific aims of the study proposed here are to (1) ascertain 3,000 veteran controls frequency-matched to the ALS Registry patients by age, sex, ethnicity and branch of military service; (2) collect environmental risk factor information from ALS patients and controls, building upon an instrument currently used in other ALS studies, which will be modified and expanded to include military-specific exposure assessment; (3) genotype nuclear DNA of ALS patients and controls for single-nucleotide polymorphisms (SNPs) in a number of putative candidate genes, using an efficient DNA pooling strategy combined with highthroughput individual genotyping; (4) genotype mitochondrial haplogroups of ALS patients and controls; and (5) perform statistical analysis of case-control and case-only data to identify main effects of genetic and non-genetic risk factors for ALS as well as GxE interaction. Both traditional regression-based well as novel computationally intensive methods will be employed. Genetic and environmental effects on disease progression will also be examined. Our study will not only be of great relevance for the veteran population, but is also likely to improve our understanding of ALS in the general population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GLUTAMATE TRANSPORT REGULATION AND SYNAPTIC PLASTICITY Principal Investigator & Institution: Eskin, Arnold; Professor and Chair; Biology and Biochemistry; University of Houston 4800 Calhoun Rd Houston, Tx 772045037

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Timing: Fiscal Year 2004; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: A number of properties of a neuron change in a coordinated fashion to store a given type of memory. Our long- term goal is to determine which properties of neurons change, and how these properties are regulated during formation of memories. Regulation of glutamate transporter activity may be necessary during increases in synaptic efficacy to maintain the fidelity of synaptic transmission and to avoid toxicity that might occur if glutamate is elevated in the synaptic cleft for too long. Thus, we hypothesize that increases in glutamate transporter activity will accompany increases in synaptic efficacy at glutamatergic synapses, especially ones involving long-term changes in synaptic efficacy. This hypothesis will be tested in vitro by investigating regulation of glutamate uptake after induction of LTP and in vivo by investigating regulation of glutamate uptake after contextual fear conditioning. Area CA1 of the rat hippocampus will be used in most experiments. We will use a multidisciplinary approach including electrophysiology, biochemistry and behavioral analysis to investigate the regulation of glutamate uptake. The proposed research has four specific aims. Most of the experiments in Specific Aims 1-3 will investigate regulation of glutamate transport during two different forms of LTP (E- and L-LTP). Aim 1 is to characterize the mechanisms involved in the increase in glutamate uptake produced by high frequency stimulation. Aim 2 is to determine whether induction of LTP increases the expression of glutamate transporters, and what mechanisms are involved in the increase in expression. Aim 3 is to investigate the relationship between LTP and changes in glutamate uptake and expression of glutamate transporters. Aim 4 is to determine whether an associative learning paradigm, contextual fear conditioning, produces an increase in glutamate transport in the hippocampus in vivo. In our lab, recent studies have shown that glutamate uptake is regulated during long-term memory in Aplysia, and preliminary results indicate that glutamate uptake is regulated during LTP in the rat hippocampus as well. Thus, the results of these studies will likely indicate that regulation of glutamate transport is a general phenomenon at glutamatergic synapses involved in synaptic plasticity. As glutamate is a remarkably potent and rapidly acting neurotoxin, fundamental studies of long-term regulation of glutamate transport should aid solutions to brain trauma and diseases such as amyotrophic lateral sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLUTAMATE TRANSPORTERS IN THE CNS Principal Investigator & Institution: Robinson, Michael B.; Associate Professor; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2004; Project Start 01-MAY-1997; Project End 31-MAY-2006 Summary: (provided by applicant): The acidic amino acids, glutamate (Glu) and aspartate, are the predominant excitatory neurotransmitters in the mammalian central nervous system (CNS). Although there are millimolar concentrations of these excitatory amino acids (EAAs) in brain, extracellular concentrations are maintained in the low micromolar range to facilitate crisp synaptic transmission and to limit the neurotoxic potential of these EAAs. A family of Na+-dependent high affinity transporters is responsible for the regulation and clearance of extracellular EAAs. This project represents a collaborative effort between two laboratories that have defined the biochemical, pharmacological, and pathophysiological properties of these transporters. In this competitive renewal, we propose to focus on studies of one of the astroglial transporters, GLT-1/EAAT2. There is a substantial body of evidence to suggest that this transporter mediates the largest percentage of transport activity in the mammalian

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Amyotrophic Lateral Sclerosis

forebrain. The expression (protein and mRNA) of this transporter is regulated in several interesting ways, increasing dramatically during the period of synaptogenesis and astrocyte differentiation. Unlike the two other forebrain transporters, expression of GLT1 is largely restricted to the CNS and astrocytic expression is dependent upon the presence of neurons both in vivo and in vitro. Finally, we and others have documented abnormal expression of this transporter in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Essentially nothing is known about the mechanisms responsible for this regulation of GLT-1. Therefore in Specific Aims I-III, we propose a strategy to study the mechanisms that control GLT-1 expression and assembly. We and others have shown that inhibition of these transporters increases the susceptibility of the tissue to excitotoxic insults, but it is not known if overexpression can be neuroprotective. Therefore in Specific Aim IV, we propose to determine if overexpression of GLT-1 is neuroprotective in animals models of ALS and against excitotoxic insults using both in vitro and in vivo models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEALTH PREFERENCE ASSESSMENT IN PARKINSON'S DISEASE Principal Investigator & Institution: Siderowf, Andrew D.; Assistant Professor; Neurology; University of Pennsylvania Office of Research Services Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 01-AUG-2000; Project End 31-JUL-2006 Summary: The candidate is a fellowship-trained neurologist dedicated to a career in the evaluation of health services for patients with Parkinson's Disease (PD) and other neurodegenerative diseases. This application proposes a comprehensive program designed to allow the candidate to become an independent investigator in this area. The University of Pennsylvania has outstanding clinical and academic resources to support this proposal. The training component entails formal graduate education in clinical epidemiology and medical economics, specifically focusing on health services research. This training will satisfy the degree requirements for a Master of Science in Clinical Epidemiology (MSCE). The research component is an evaluation of the validity, reliability and responsiveness of preference-based outcomes in PD. These outcomes are a type of health related quality-of-life measure in which the desirability of a given health state is explicitly valued relative to alternative health states. The main use of preferencebased outcomes is in cost-effectiveness analysis (CEA). In practice, societal preferences, which are the recommended metric for CEA, are difficult to measure. As a result, prescored multi-attribute health classification systems have been developed to approximate these preferences. The central hypothesis of the research component is that these prescored systems may not reflect societal preferences for health states encountered in PD. The specific aims of this study are: 1) To produce a series of vignettes describing PDrelated health states, and to elicit societal preference weights for these vignettes; 2) To conduct a cross sectional study comparing this set of preferences to values derived from pre-scored multi- attribute health classification systems, and to preferences elicited from patients and caregivers; and 3) To conduct a longitudinal study to measure the reliability and responsiveness of preference-based measures in PD patients and their caregivers. The results from this study will have a direct application to all future CEA for PD-related interventions. In addition, the insights gained may be applied to other neuro-degenerative diseases including Alzheimer's Disease and Amyotrophic Lateral Sclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIGH RESOLUTION HYBRID FT-ICR MASS SPECTROMETER Principal Investigator & Institution: Loo, Joseph A.; Professor; Biological Chemistry; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2006; Project Start 01-AUG-2006; Project End 31-JUL-2007 Summary: (PROVIDED BY APPLICANT): A high-resolution hybrid Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer with capabilities for top-down protein sequencing and rapid duty-cycle LC-tandem MS measurements for bottom- up proteomics is requested. This instrument will be a vital component to support the specific aims of over 11 NIH-funded projects. The projects involve a variety of protein structure/function-related research, including the determination of protein-protein and protein-ligand interactions, protein phosphorylation, and the identification of protein biomarkers for disease detection and prognosis. The research will impact a range of human health issues, including neurodegenerative diseases, such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), respiratory illnesses, cardiovascular and inflammatory diseases, and cancer. The hybrid FT-ICR mass spectrometer will be capable of sub-2 parts-per-million mass measurement accuracy for both intact peptides/proteins and product ions derived from MS/MS experiments. It will include a storage trapping device for increased dynamic range and have capabilities for rapid data dependent LC-MS/MS, and a resolving power sufficient to measure the isotope distribution of large, intact proteins for improved mass accuracy. Unique to this system will be capabilities for electron capture dissociation (ECD) and infrared multiphoton dissociation (IRMPD), ion activation methods advantageous for top-down protein sequencing and identification/localization of post-translational modifications. ECD greatly improves the ability to dissociate intact proteins to derive complete sequence information, as well as holding the promise of detection of post-translational modifications. An instrument with these unique capabilities is not available currently at UCLA. The instrument will be a centerpiece and will be supported and administered by the newly-created Molecular Instrumentation Center at UCLA, and it will serve researchers from across the institution. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HORMONAL EFFECTS ON BEHAVIOR AND SPINAL CORD MORPHOLOGY Principal Investigator & Institution: Breedlove, S Marc.; Professor; Psychology; Michigan State University 301 Administration Bldg East Lansing, Mi 48824 Timing: Fiscal Year 2004; Project Start 01-APR-1990; Project End 31-JUL-2009 Summary: (provided by applicant): We will examine the influence of steroid hormones, specifically androgens, on a neuromuscular system that responds to these hormones throughout life. Previous work has shown that androgens maintain the bulbocavernosus (BC) and levator ani (LA) muscles of developing male rats. These striated perineal muscles are normally present in females at birth but, in the absence of androgen, the muscles die. A single injection of androgen to newborn female rats will preserve the muscles for life. The BC/LA muscles are innervated by motoneurons in the spinal nucleus of the bulbocavernosus (SNB). Androgenic sparing of the BC/LA target muscles also indirectly spares the SNB motoneurons from developmental apoptosis. The present project will study the effects that androgenic hormones continue to exert on the SNB system in adulthood. Castration of adult male rats triggers a host of changes in the structure and function of the SNB system. For example, the somata and dendrites of

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SNB motoneurons, as well as the neuromuscular junctions (NMJs) these motoneurons make upon the target muscles, shrink following castration. Testosterone (T) therapy can prevent and/or reverse this shrinkage. We have found that T cannot maintain SNB somata size when we pharmacologically block the N-methyl-d-aspartate (NMDA) type glutamate receptor. This effect of NMDA blockade seems to be specific to SNB motoneurons and to the effect of T. We propose to determine whether NMDA blockade also prevents the effects of T on SNB dendrites and NMJs. We have found that SNB motoneurons, but not other nearby motoneurons, increase their expression of the gene for the NMDA receptor subtype 1 (NMDAR1). So the androgen-induced increase in NMDA receptor stimulation of SNB motoneurons may contribute to maintaining soma size. We will use a mosaic analysis to ask whether androgen acts directly upon SNB motoneurons to increase their expression of the NMDAR1 message. We will also determine whether SNB motoneurons express a newly discovered NMDA receptor subtype (NMDAR3), whether androgen manipulations alter NMDAR3 expression, and if so whether this is a cell-autonomous response of the motoneurons. These studies should lead to a better understanding of neuromuscular systems, of the influence of steroid hormones on the spinal cord, and the etiology of several neuromuscular disorders including amyotrophic lateral sclerosis and Kennedy's syndrome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION AND CHARACTERIZATION OF THE ALS4 GENE Principal Investigator & Institution: Chance, Phillip F.; Professor and Chief; Pediatrics; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2004; Project Start 01-AUG-2002; Project End 31-MAY-2007 Summary: (Adapted from applicant?s abstract): Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disorder associated with severe loss of motor neurons in the brain, brainstem and spinal cord. ALS typically has a rapid course and leads to death within 3 to 5 years after the onset of clinical symptoms. Approximately 10 percent of cases are thought to have a genetic basis and are referred to as "familial ALS." One form of familial ALS (ALS1) maps to chromosome 21q22 and is associated with mutations in the Cu/Zn superoxide dismutase (SOD1) gene. While ALS is a type is a disorder that is almost exclusively seen in adults, there are forms of ALS that have onset in childhood or adolescence, and manifest a chronic, slowly progressive course. This type of ALS is termed "juvenile ALS." We identified a region on chromosome 9q34 which harbors the gene for an autosomal dominant form of juvenile ALS. The various forms of ALS and juvenile ALS are devastating neurological disorders lacking a defined pathophysiological basis and any effective therapies. The purpose of this application is to identify and characterize the gene for juvenile ALS mapping to chromosome 9q34, also known as the ALS4 locus. Specific Aim (1) is to search for mutations in known candidate genes mapping within the ALS4 candidate region on chromosome 9q34 in order to identify the gene for ALS4. Specific Aim (2) is to search for additional transcripts as candidate genes for ALS4 by direct cDNA selection and other positional cloning methods, if our evaluation of the known candidate genes from the critical region fails to yield the causal gene. Specific Aim (3) is to characterize the genomic structure of the ALS4 gene by standard molecular genetic approaches and to determine the expression pattern of the ALS4 gene and the ALS protein by nucleic acid hybridization and immunohistochemical methods using specific probes and/or antibodies. Specific Aim (4) is to identify the functional domains of the ALS gene by sequence-similarity comparisons and analysis of homologous and orthologous genes from other species and by biochemical analysis. Specific Aim (5) is to develop an animal model of ALS4 by

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introducing an identified disease-causing mutation into the germline of the mouse by employing either transgenesis or gene targeting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IGF-I/ALS TRIAL Principal Investigator & Institution: Sorenson, Eric J.; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2004; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by the applicant): The objective of this trial is to determine whether IGF-1 slows progression of weakness in ALS. 300 patients with ALS will be enrolled for 2 years of treatment with a study drug or Placebo. The study will be double-blind, with equal randomization of patients to Placebo or drug. The primary end-point will be the rate of change in Manual Muscle Testing score (MMT). Secondary end-points will be tracheotomy-free survival and change in the ALSFRS score over the 2-year study period. Enrollment will be limited to those with a disease duration of less than 24 months, and a Manual Muscle Testing score of less than 8. The study is designed to detect a 30% difference in survival over the two-year treatment period. Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder that causes progressive muscle weakness and death within 4 years of onset. Its overall incidence is about 2 cases/100,000 in the United States. Except for a very small minority of cases, the cause is unknown. The disease is incurable and only Riluzole has been proven to be effective in slowing the disease. Riluzole effects are modest and more effective treatments for ALS are desirable. IGF-1 had demonstrated neurotropic effects in animal and tissue culture models of motor neuron disease. These findings have led to an interest in its potential use in ALS patients. Clinical trials have been completed in the United States, Europe, and Japan with conflicting conclusions. Previous Clinical Trials in ALS have utilized global measures of function, electrophysiological measures of muscle function, mechanical measurement of maximum force generated by Voluntary Isometric Contraction of Muscle (MVIC) or Manual Muscle Testing (MMT). Loss-of-function and death in ALS is primarily due to loss of muscle strength. Muscle strength is directly related to the underlying pathology (loss-of-motor neurons). To obtain a definitive answer as to the beneficial effects of IGF-1 in ALS, we will assess the most direct and objective effects of the disease, directly, by assessing muscle strength testing, survival and functional performance. The preliminary data from our prior trial allows design of a Phase III treatment trial that will yield a definitive result about the treatment effect of IGF-1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMAGING THE PATHOPHYSIOLOGY OF AMN IN MICE AND HUMANS Principal Investigator & Institution: Eichler, Florian S.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2006; Project Start 01-JUN-2006; Project End 31-MAY-2011 Summary: (provided by applicant): The proposed interdisciplinary study allows the candidate to further develop his knowledge of MR physics and expertise in imaging studies of adrenomyeloneuropathy (AMN), a form of adrenoleukodystrophy (ALD), while providing rigorous exposure to the clinical and biological side of this research. The goal is to increase the candidate's expertise in multiple areas necessary to his proposed research project and future career development. These areas include genetics

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of peroxisomal disorders, lipid metabolism, and spatial aspects of nuclear magnetic resonance spectroscopy. The proposal builds nicely on the candidate's prior experience with Dr. Moser at Johns Hopkins and extends his studies to the animal model. The candidate is in a world-renown environment for both MR imaging and neuroscience. This Award will provide the guidance and tools necessary for him to become a successful, independent researcher. The 5 year research training program consists of 1) coursework and mentoring relationships on the science of high-field magnetic resonance that the candidate is currently lacking, 2) a 2 year rigorous training in animal imaging, and 3) collaborative translational studies with experts in the field of lipid metabolism and peroxisomal disorders. The research portion of this application will allow him to examine the histopathological and biochemical correlate of advanced MR techniques in the mouse model of ALD. This has never been done before and likely to reveal insight into the fundamental dynamics of demyelination. Further, the proposal encompasses application of novel therapeutics to normalize lipid metabolism and stabilize myelin membrane integrity. Hypotheses include: 1) in the animal model of ALD, measures of diffusion tensor imaging can assess the density of white matter tracts in the mouse and measures of single voxel proton MR spectroscopy reflect changes in lipid composition of the brain, and 2) in ALD patients, metabolic changes seen on proton MR spectroscopic imaging herald lesion development on conventional MRI. Our results will yield a noninvasive means of gauging the effects of experimental and therapeutic manipulations of lipid chemistry upon specific neuroanatomic structures. Ultimately, insights gained in these studies of ALD/AMN may prove beneficial to other neurodegenerative diseases, such as amyotrophic lateral sclerosis or Parkinson's and Alzheimer's diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INCREASED MOTONEURONS

PERSISTENT

SODIUM

CURRENT

IN

SOD1

Principal Investigator & Institution: Heckman, Charles J.; Professor; Physiology; Northwestern University 750 N. Lake Shore Drive, 7Th Chicago, Il 60611 Timing: Fiscal Year 2005; Project Start 01-APR-2005; Project End 31-MAR-2010 Summary: (provided by applicant): One of the leading hypotheses for motoneuron degeneration in ALS is excitotoxicity, in which excessive calcium entry leads to cell death. Most work on excitotoxicity has focused on ligand-gated channels activated by the excitatory neurotransmitter glutamate. In contrast, this proposal focuses on the possibility that ALS alters voltage-gated channels and thus alters the intrinsic excitability of the motoneuron. We have shown that a specific type of sodium (Na+) channel is markedly elevated in motoneurons cultured from a transgenic mouse model of ALS (the SOD1 model). This current is NaP, the persistent component of the total Na+ current generating the action potential. NaP is a major factor controlling the number of action potentials per time generated in response to a given amount of synaptic input. Because each action potential allows calcium to enter the cell, elevated NaP in ALS motoneurons could play a major role in excitotoxic death. The goals of this proposal are to investigate mechanisms of the aberrant upregulation of NaP in mutant SOD1 motoneurons and to assess how drugs that change NaP influence motoneuron survival. Studies are carried out in culture, in vitro in a slice preparation, and in vivo in the intact animal, all using the mutant SOD1 mouse. Aim 1 considers the issue of whether molecular subtypes or densities of the Na channels themselves change. Aim 2 focuses on potential changes in the regulation of NaP in response to acute and chronic drug administration. The monoamines serotonin and norepinephrine enhance NaP and likely

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play a particularly important role in its normal regulation. In Aim 3, the effects of NaPspecific drugs studied in aim 2 are evaluated for their effect on motoneuron survival both in culture and in the intact mouse. A key question addressed by Aims 2 and 3 is whether the monoamines further increase NaP above its already high levels in mutant SOD1 motoneurons. If so, then standard anti-depressant drugs may actually exacerbate motoneuron degeneration. In Aim 4, we evaluate whether, as predicted from our cell culture work, NaP is upregulated at a very early stage in life. Presence of enhanced NaP in very young animals would indicate that this aberrant property may play a significant role in the disease onset. These studies will play an essential role in determining if NaP makes an important contribution to motoneuron degeneration in ALS. Moreover, the results may prove invaluable in establishing new therapeutic strategies Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INDUCIBLE SITE-SPECIFIC EXPRESSION OF MUTANT SOD1 Principal Investigator & Institution: Roos, Raymond P.; Professor; Neurology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons (MN). Approximately 10% of ALS cases are familial (known as FALS), and approximately 25% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase type 1 (SOD1). There is convincing evidence that mutant (MT) SOD kills MN because of toxicity rather than a deficiency in dismutase activity. However, the basis for this toxicity remains unclear as does effective treatment for this devastating fatal disease. Surprisingly, although mice that carry MTSOD with its endogenous promoter as a transgene develop MN disease (MND), a restricted expression of MTSOD in neurons or astrocytes fails to induce MND. In this proposal, we hypothesize that MTSOD requires expression early in embryonic life in MN in order to cause an ALS phenotype. In order to test this hypothesis, we will generate a transgenic mouse that selectively expresses MTSOD in MN (and some interneurons) starting early in embryonic life. The MTSOD expression will be inducible so that we will also be able to determine how early expression must occur and how long this expression has to last in order to kill MN. In addition, these mice will also express a luciferase reporter gene in MN, so that the mice can provide a source for dissociated spinal cord cell cultures with tagged MN for use in screens for effective drugs in ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INDUCTION OF IMMUNE TOLERANCE TO FASL-EXPRESSING ES CELL Principal Investigator & Institution: Sonntag, Kai-Christian; Mc Lean Hospital (Belmont, Ma) 115 Mill Street Belmont, Ma 02478 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): The potential of pluripotent embryonic stem (ES) cells to develop into functional mature cells or tissue has high implication in finding new treatments for diseases including neurodegenerative disorders. This includes the potential use of ES cells as cell replacement therapy in neurological diseases, such as Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and ischemia. However, survival of call grafts requires systemic immunosuppression, which severely compromises the entire host immune system

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leading to complications in clinical transplantation. An optimal therapy would be, therefore, the induction of specific tolerance to the donor cells by otherwise preserving functional immune responses. Fas ligand (FasL, CD178, or CD95L) is a type II membrane protein and is expressed in activated lymphocytes and cells in "immuneprivileged" sites such as the testis, the eye, and the CNS. Its receptor Fas (CD95 or Apo1), a type I membrane protein and a member of the TNF receptor family, is expressed on various immune-reactive hematopoietic cell types including activated NK and T calls, non-lymphoid calls such as immature myeloid cells, monocytes, and polymorphic mononucleocytes. Fas-expressing cells undergo apoptosis upon interaction with FasL, a process that is involved in regulating cellular immunity and it has been shown that FasL can be used as an immunomodulatory tool to protect allogeneic or xenogeneic cells against cellular immune responses. Here, I hypothesize that ES cell grafts in the brain, which express FasL, are protected against the host cellular immune response abolishing the need for systemic immunosuppressive drug treatment. For this, I will genetically engineer mouse ES cells to express FasL and test their survival ability in the host brain of rats without further immunosuppression. Furthermore, I will analyze the effects of FasL expression on transplanted cells towards modulating the host immune response. Results from this work will have implications for immunomodulation of ES cell grafts in both allogeneic and xenogeneic transplantation settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF SELECTIVE TOXICITY OF SOD1 MUTANTS IN ALS Principal Investigator & Institution: Crow, John P.; Pharmacology and Toxicology; University of Arkansas Med Scis Ltl Rock 4301 W Markham St Little Rock, Ar 72205 Timing: Fiscal Year 2004; Project Start 15-JUN-2001; Project End 31-MAY-2006 Summary: (provided by applicant): In 1993, it was first reported that a mutation to the gene coding for Cu,Zn superoxide dismutase (SOD1) was associated with a form of familial amyotrophic lateral sclerosis (ALS). Since that time, more than 70 single amino acid mutations to SOD1 have been found to cause ALS in humans. Mice transgenic for any one of several of the human SOD1 mutants develop progressive and ultimately lethal paralysis in a time-dependent manner reminiscent of human ALS. Studies in transgenic mice clearly indicate that SOD1 is toxic via a gained function because the mutant produces disease even in the presence of marked increases in total SOD1 enzyme activity. Despite the overwhelming evidence for a gained toxic function, the exact nature of that function has remained elusive. Equally puzzling has been the fact that SOD1 mutants are toxic only to motor neurons even though they are expressed in all cell types. Based on published results, in vitro characterizations of SOD1 mutants, studies in cultured motor neurons, and preliminary data from transgenic mice, we have formulated a hypothesis which may explain how all ALS-associated SOD1 mutations can be toxic via a common mechanism and why toxicity is manifested only in motor neurons. HYPOTHESIS: We are proposing that zinc-deficient (copper-containing) SOD1 is the common toxic phenotype of ALS-associated SOD1 mutants, that zinc-deficient SOD1 is injurious via its ability to utilize ascorbate, oxygen, and nitric oxide to catalyze the formation of the cytotoxin peroxynitrite, and that neurofilament proteins--which avidly bind zinc and are very abundant in motor neurons--contribute to the formation of zinc-deficient SOD1 preferentially in motor neurons. This study proposes: Specific Aim 1) to measure zinc-deficient SOD1 in the most widely used animal model of ALS (G93A transgenic mice) and determine the factors responsible for its accumulation, Specific Aim 2) to determine the conditions which lead to SOD1-mediated oxidant generation

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and its potential relationship to toxic protein aggregation, and Specific Aim 3) to evaluate the in vivo efficacy of two classes of compounds which protect cultured motor neurons from the toxic effects of zinc-deficient SOD1 and which enhance survival in G93A mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS FOR TAU INVOLVEMENT IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Roberson, Erik D.; J. David Gladstone Institutes 1650 Owens St San Francisco, Ca 94158 Timing: Fiscal Year 2006; Project Start 01-APR-2006; Project End 31-MAR-2011 Summary: (provided by applicant): Alzheimer's disease (AD) and related neurodegenerative disorders are a major source of morbidity and mortality, particularly with the increasingly aged population of the United States. Pathology involving the microtubule-associated protein tau is a common feature of many such diseases, including AD, frontotemporal lobar degeneration, many forms of Parkinsonism, and amyotrophic lateral sclerosis. This proposal describes a training plan for the development of an academic neurologist interested in the molecular mechanisms of dementing diseases, particularly tau. The research plan focuses on the role of tau in AD pathology testing the hypothesis that tau is critical for the neuronal dysfunction induced by amyloid-beta (Abeta) in amyloid precursor protein (APP) transgenic mice. Preliminary studies indicate that tau removal prevents most behavioral and pathological abnormalities in APP mice at 4-7 months of age. Specific Aim 1 extends this observation, studying older APP mice to examine how long the effects of Abeta remain taudependent and determining the effect of changing tau expression after AD is produced and dysfunction is apparent. Specific Aim 2 considers signaling pathways that might mediate interactions between Abeta and tau, with an emphasis on the tyrosine kinase Fyn. Specific Aim 3 studies downstream mechanisms for tau's role, specifically regulation of axonal transport and APP processing. The candidate has a Ph.D. in neuroscience and an M.D. with residency training in neurology. He is committed to a career in academic medicine studying the basic mechanisms of neurodegenerative diseases. To that end, the research proposal and career development plan build on his prior training in basic neuroscience, biochemistry, electrophysiology, and clinical neurology to provide expertise in transgenic mouse models, behavioral analysis, histology, and viral vectors. Dr. Lennart Mucke, who specializes in transgenic mouse models of neurodegenerative disease, is the candidate's sponsor. The mentoring and research experience described in this proposal will facilitate the candidate's goal of an independent faculty research position. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF NEURONAL SPECIFIC TRANSCRIPTION Principal Investigator & Institution: Gill, Grace B.; Associate Professor; Pathology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 01-JUL-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Transcription factors play essential roles in the processes of neuronal cell fate determination and expression of the mature neuronal phenotype that are necessary for normal development and function of the brain. My laboratory is investigating expression of the cyclin-dependent kinase 5 (cdk5) activator p35 as a model to understand the molecular mechanisms of cell type-specific

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transcription in neurons. The heterodimeric cdk5/p35 kinase plays a role in many neuronal processes ranging from neuronal migration and axon guidance to synaptic plasticity and drug addiction. Furthermore, improper cdk5 activity, caused by association with a proteolytic fragment of p35, has been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis. A repeated GC box element in the p35 promoter is necessary and sufficient for neuronspecific gene expression. The studies described in this proposal are designed to test the hypothesis that the mechanisms that regulate the levels and activity of the GC boxbinding transcription factors Sp1, Sp3 and Sp4 during neurogenesis contribute to neuronal-specific expression of p35. The specific aims of this research are to (1) determine which Sp transcription factors are important for GC box-dependent expression of p35 in neurons, (2) determine the mechanisms that regulate Sp transcription factor stability during neurogenesis, and (3) determine how SUMO-1 mediated repression of Sp3 is relieved in post-mitotic neurons. In addition to advancing our specific knowledge of the transcriptional mechanisms that regulate activity of the cdk5/p35 kinase, these studies will provide a paradigm for understanding how cell type-specific regulation of transcription factor levels and activity controls neuronal specific expression of many genes whose expression depends on GC box promoter elements. Since disturbances of the finely tuned transcriptional program in neurons are associated with developmental abnormalities and disease, it is imperative to increase our understanding of the molecular mechanisms that underlie cell type-specific gene expression in neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METABOTROPIC NEURODEGENERATION

GLUTAMATE

RECEPTORS

IN

Principal Investigator & Institution: Young, Anne B.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 15-AUG-1995; Project End 31-JUL-2005 Summary: Description (From the applicant's abstract): Human neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) are characterized by adult onset, progressive neurologic dysfunction, and a paucity of effective therapies. These common disorders produce substantial disability, and their importance to public health is expected to increase as the population ages. One or more causative genes have now been isolated for familial forms of each of these four devastating neurologic illnesses, making possible the development of transgenic mouse models. Although such animals now exist, the exact mechanisms by which mutant genes cause neurologic disease remains unclear. Unless the etiologic mechanisms underlying the neurodegenerative diseases are clearly identified, rational therapeutic interventions will be impossible. The neurotransmitter glutamate has been implicated as a causative factor in the etiology of neurodegenerative disorders. Specifically, one class of glutamate receptors, the metabotropic glutamate receptors (mGluRs), may be specifically abnormal in many of the neurodegenerative disorders. This project will examine metabotropic glutamate receptors in transgenic mouse models of AD, PD, HD, and ALS using ligand binding, in situ hybridization, immunohistochemistry, and Western blotting. Alteration of mGluR expression level is also predicted to have direct implications for the abnormal synaptic functioning which is characteristic of neurodegenerative diseases. Thus, we will also explore glutamate-related intracellular signaling pathways in the brains of transgenic mice. Finally, if mGluR dysfunction is an important part of disease etiology, drugs

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targeting mGluRs may ameliorate symptoms in certain of these models. We will test if administration of mGluR-active medications improves clinical outcome in mouse models of these diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICROGLIA: DEGENERATION/REGENERATION

ROLE

IN

MOTONEURON

Principal Investigator & Institution: Streit, Wolfgang J.; Professor of Neuroscience; Neuroscience; University of Florida 219 Grinter Hall Gainesville, Fl 32611 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): The causes that underlie primary degeneration of motoneurons in ALS remain unknown. This proposal will investigate a novel hypothesis regarding ALS pathogenesis, namely, that dysfunctional microglia are, in part, responsible for motoneuron degeneration. The rationale for this hypothesis is twofold: on one hand experimental studies in rodents suggest that microglial activation is essential for rescuing acutely injured motoneurons and for facilitating their regeneration, and on the other hand there is now evidence that microglial cells undergo structural deterioration in the aged and, particularly, in the Alzheimer's disease brain. The latter observations suggest that progressive structural deterioration of microglia over long periods of time results in microglial malfunction and dwindling glial support to neurons, which ultimately causes neurodegeneration. We now propose to investigate whether dystrophic microglia are present in motor neuron disease (MND). The specific aims are as follows: 1) To examine post-mortem human tissue specimens from individuals who died with ALS to determine if the incidence of dystrophic microglial cells is higher than in age-matched non-ALS individuals. 2) To determine if dystrophic microglial cells are present in the recently generated transgenic ALS rat carrying the SOD1/G93A mutation. 3) To determine the effect of minocycline treatment on axotomyinduced microglial activation in wildtype Sprague Dawley rats. This last set of studies is intended to represent a proof-of-principle experiment, which will test recent claims that minocycline delays the onset of MND by inhibiting microglial activation. If this claim is true, an attenuation of axotomy-induced microglial activation with minocycline should result in delayed or impaired motoneuron regeneration after axotomy. Collectively, these studies may provide a new lead into the pathogenesis of ALS, i.e. that dystrophy and dysfunction of microglia may be involved. In addition, the minocycline experiments will help to further assess the usefulness of this drug for possible treatment of ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODELS OF SBMA MOTOR NEURON DEGENERATION Principal Investigator & Institution: La Spada, Albert R.; Assistant Professor; Laboratory Medicine; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2004; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: X-linked spinal and bulbar muscular atrophy (SBMA or Kennedy's disease) is a progressive neuromuscular disorder characterized pathologically by degeneration of lower motor neurons. In 1991, expansion of a CAG trinucleotide repeat was identified in the coding region of the androgen receptor (AR) gene of SBMA patients. In addition to SBMA, seven other neurodegenerative disorders are caused by CAG repeat expansions that encode elongated polyglutamine tracts. Molecular and genetic studies of the CAG/polyglutamine repeat diseases suggest that the polyglutamine tract expansion has a toxic gain-of- function effect, the basis of which remains unknown. The purpose of this

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grant proposal is to determine the molecular basis of neuronal cell death in SBMA. To achieve this goal, we have initiated studies aimed at recapitulating AR polyglutamine neurotoxicity in mice and in cell culture. For producing an in vivo model of SBMA, we have generated AR yeast artificial chromosomes (YACs) carrying 100 CAG repeats. These AR YACs have been introduced into the mouse germline by fusing yeast cells carrying the AR YACs with mouse embryonic stem (ES) cells. In addition to an in vivo model of SBMA, we are attempting to develop in vitro models of AR polyglutamine neurotoxicity. We have demonstrated cellular toxicity of mutant AR expression constructs in HEK-293T cells, a non-neuronal cell line. We are attempting to extend this finding to motor neuron-like cell lines, MN-1 and NSC-34, and are also establishing primary cultures of cortical, hippocampal, and spinal motor neurons. Once we have produced accurate in vivo and in vitro models of SBMA, we will examine the role of apoptotic pathways in SBMA pathogenesis by evaluating whether caspase activation and/or p53 participate in AR polyglutamine neurotoxicity. We will use our in vivo and in vitro models to determine what functions of the AR protein are required for SBMA disease pathogenesis. Animal and cell culture models of AR polyglutamine neurotoxicity will allow us to identify alterations in gene expression in diseased motor neurons and cell lines by performing microarray expression comparisons. As SBMA, amyotrophic lateral sclerosis and autosomal spinal muscular atrophy all show motor neuron cell death, any toxic factors or degenerative pathways that we identify in our studies may be relevant to these and other motor neuron diseases. In addition to allowing us to track the molecular events that lead to neuronal cell death, animal and cell culture models of SBMA will allow us to design novel treatments and test potential therapies for this motor neuron disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 2004; Project Start 01-JAN-2000; Project End 31-JAN-2005 Summary: The interleukin-1beta converting enzyme (caspase-1 or caspase-1) cell death gene family, also known as the caspase family, plays an important role in apoptosis. Evidence indicates that caspase- 1 is involved in mediating brain damange in ischemia, trauma, and in amyotrophic lateral sclerosis. We have evidence implicating caspase-1 as an important mediator of cell dysfunction and disease progression in Huntington s disease (HD). The broad objective of this project is to evaluate the mechanisms of caspase-1-mediates disease progression in HD. Preliminary results indicate that caspase1 is activated in human and mouse HD brain specimens. In addition, inhibiting caspase function slows the progression and delays the mortality in a mouse model of HD. The specific aims are: 1) evaluate the expression and activation status of different members of the caspase family in human and mouse HD brain specimens, 2) evaluate the role of mature IL-1beta, a product of caspase-1 activation, in the pathogenesis of HD, 3) determine whether bc1-2 might be a neuroprotector in HD, and whether its effects might be synergistic with caspase-1 inhibition, 4) evaluate pharmacological approaches to slow the progression of HD, and 5) evaluate the mechanism of inhibition of weight loss in HD mice by caspase-1 inhibition, 6) evaluate the impact of HD on neural stem cell proliferation and differentiation. Significance: To elucidate the mechanistic pathways by which caspase-1 mediates disease progression and death in HD. Since caspase-1-mediated cell death is a common pathway shared by a variety of neurological

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disorders, understanding the mechanistic pathways mediating neurodegeneration in HD should provide important information for the development of treatments for diseases sharing this cell death pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR BASIS OF GLUTAMATE TRANSPORT Principal Investigator & Institution: Grewer, Christof Theodor.; Physiology and Biophysics; University of Miami-Medical School 1507 Levante Avenue Coral Gables, Fl 33124 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2008 Summary: (provided by applicant): In the mammalian brain the extracellular concentration of the excitatory neurotransmitter glutamate is, among other factors, controlled by transporters, which actively take up glutamate into glial cells and neurons. The broad aim of this proposal is to investigate the molecular mechanisms by which these transporters accomplish this glutamate uptake. Recombinant glutamate transporters will be expressed in HEK293 cells and Xenopus oocytes, and currents that originate from electrogenic glutamate transport will be recorded using the patch clamp technique. Currents will be induced by glutamate concentration jumps generated within 100 mus, allowing the resolution of rapid transporter reaction steps in time. The hypotheses that guide this research are: Both inward and outward glutamate transport occur via a multistep electrogenic mechanism; charged amino acids in the transmembrane segments contribute to the function and electrogenicity of the transporter; translocation of glutamate across the membrane requires molecular movement of the transport protein. Experiments with the following specific aims will test these hypotheses: (1) To determine the reaction steps associated with outward glutamate transport, by investigating the sequence and voltage dependence of intracellular Na+ and glutamate binding. (2) To determine the contributions of conserved charged amino acids to transporter function and electrogenicity, by investigating transporters with specifically charge-neutralized amino acids. (3) To characterize molecular movement of the transporter machinery by determining which parts of the transporter move and at what steps during a complete transport cycle they move. Movement of the transporter will be detected by the movement of charges attached to the transporter at specific sites. Understanding the molecular mechanism of glutamate transport will give insight into the involvement of glutamate transporters in acute and slowly progressing neurodegenerative diseases, such as stroke, amyotrophic lateral sclerosis, and Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOTOR SYSTEM DEVELOPMENT IN THE ABSENCE OF CELL DEATH Principal Investigator & Institution: Oppenheim, Ronald W.; Professor; Anatomy and Neurobiology; Wake Forest University Health Sciences Medical Center Blvd WinstonSalem, Nc 27157 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2008 Summary: (provided by applicant): The major objective of the proposed research is to examine the development of the neuromuscular system in a mouse model in which programmed cell death (PCD) of motoneurons has been eliminated by genetic deletion of pro-apoptotic genes. The use of this model will allow us to address issues of basic biology such as the adaptive significance of PCD in the nervous system and whether

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excess neurons can be functionally incorporated into the developing nervous system. Neuroanatomical, physiological and behavioural methods will be employed to examine both spinal and cranial motoneurons. We well determine whether rescued neurons differentiate normally; and whether physiological and behavioural assays of neuromuscular function are affected by the presence of tens of thousands of rescued motoneurons. Additionally, we plan to take advantage of the fact that even following injury, motoneurons in these mice can survive. Accordingly, we will cross these mice with a mouse model of Amyotrophic Lateral Sclerosis (ALS), the SOD1 mutant, and determine whether the pathological signs of motoneuron disease are ameliorated. In both the developmental and SOD1 studies, treatment with neurotrophic factors (NTFs) will be used in an attempt to optimize the development and maintenance of the neuromuscular system. The use of mice lacking motoneuron cell death provides a unique opportunity to examine: (1) the widely accepted but largely untested assumption that the PCD of neurons during development subserves essential adaptive functions that if perturbed would result in neurobehavioral dysfunction; and (2) the role of PCD and neurotrophic factors in a mouse model of ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MTOR ACTIVATION AND FUNCTION DURING CNTF SIGNALING Principal Investigator & Institution: Reeves, Steven A.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114

Assistant

Professor;

Timing: Fiscal Year 2004; Project Start 24-JUL-1998; Project End 31-JAN-2008 Summary: (provided by applicant): Signal transduction initiated by the neuroregulatory cytokine ciliary neurotrophic factor (CNTF) has been shown to promote neuronal survival in the injured or diseased nervous system. These findings have provided a basis for using CNTF as a therapeutic agent aimed at the treatment or prevention of a variety of neuropathological diseases, including amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, stroke, and several forms of cerebellar ataxias. The precise manner in which CNTF activates and coordinately regulates the signaling cascades it employs for its neuroprotective effects remains largely undefined. One important component in this cascade that we have recently identified is the mammalian target of rapamycin (mTOR). The TOR proteins have been shown to be key regulators of a diverse set of cell processes, and recent reports have indicated that mTOR may play a critical role in synaptic plasticity and memory. We hypothesize that mTOR is a critical link in one or more of the CNTF signal transduction pathways. Thus the research we are proposing in this application aims to determine the mechanism by which CNTF activates mTOR and to identify the role(s) that mTOR plays in CNTF-stimulated sympathetic neurons. This work could identify novel targets for therapies aimed at the treatment or prevention of a variety of central nervous system disorders as well as provide a sound scientific foundation for the clinical use of CNTF and CNTF analogues now being tested in clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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

Project Title: NANOSCALE IRON PHASES IN NEURODEGENERATIVE DISEASES Principal Investigator & Institution: Dobson, Jon P.; Keele University Keele St5 5Bg, England Keele, Timing: Fiscal Year 2004; Project Start 15-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): AIMS:. To develop multi-modal imaging methods for high-resolution mapping of iron in neurodegenerative brain tissue. To examine the magnetic properties of neurodegenerative tissue for the possible presence of anomalous magnetic iron oxides. To examine the effects of biogenic, magnetic iron biominerals (primarily magnetite) on amyloid-beta aggregation in vitro. Research Design & Methods: The primary method for mapping iron distribution in tissue sections is via synchrotron x-ray scanning which will be conducted at Argonne National Laboratory. This technique will be used to identify iron anomalies eventually on a cellular level. And to compose composit images using a variety of imaing techniques. This work will enable correlation of iron anomalies and structural form to specific cellular and tissue structures for the first time. Examination of the magnetic properties of neurodegenerative tissue will be carried out pdmarily using Superconducting Quantum Interference Device (SQUID) magnetometry and Magnetic Force Microscopy (MFM). Using these methods the magnetic iron biominerals in the tissue will be characterized

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and compared to published data on non-pathologic and epileptic tissue samples. This will provide information on the relative abundance and type of magnetic iron biomineral present in the tissue and will help to either confirm or refute preliminary studies of nanoscale magnetic iron biominerals in Alzheimer's disease (AD) tissue. The effects of strong, local magnetic fields generated by nanoscale magnetic iron biominerals on amyloid-beta peptide aggregation rates will be examined using thioflavin-T assay and TEM imaging of peptide aggregates. Aggregation rates will be assessed in control solutions, solutions of peptide with coated magnetic nanoparticles and sham solutions containing the same concentrations of non-magnetic nanoparticles with the same size distribution and surface chemistry. Gla: FOREIGN GRANT: As the PI is a US citizen based at Keele University in the United Kingdom, the project will be administered through a foreign institution - Keele. The PI has considerable and unique experience in the analysis of magnetic iron biominerals in the brain (he has led all of the previous work described in this proposal) and is one of the few people in the wodd working in this field. The proposed project is highly interdisciplinary, incorporating aspects of biophysics, chemistry, neurobiology and biomedical engineering. The PI has a uniquely diverse background related to the proposed research, having worked in physics, chemistry and biomedical engineering departments and the UF Brain Institute since obtaining his PhD in 1991. He has published extensively in nanoscale magnetic iron biomineralization in the brain and his work has been featured by the media in such journals as Science,The Economist, Fact/Switzerland, The Los Angeles Times/Washington Post wire service as well as newspaper, radio and television coverage in six countries. The Pl's combination of skills and experience related to the research proposed here is unique and unavailable in the US. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURAL PROSTHESIS USING POSTERIOR PARIETAL REACH REGION Principal Investigator & Institution: Andersen, Richard A.; Professor of Neuroscience; None; California Institute of Technology Office of Sponsored Research, Mail Code 20115 Pasadena, Ca 91125 Timing: Fiscal Year 2004; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: adapted from applicant's abstract) The purpose of this grant is to develop a neural prosthesis to help paralyzed patients. The prosthesis will be developed in nonhuman primates as a precursor to applying a similar approach in humans. The rationale of the prosthesis is to record from an area of the cerebral cortex that plans reach movements. If these plans can be read-out in real-time, then patients who are paralyzed from spinal cord section, ALS, or other peripheral neuropathies could still think about making movements, and these thoughts could be used to operate external devices. In the experiments, the activity from the parietal reach region (PRR) will be recorded using arrays of electrodes, an area that is responsible for the initial planning of reach movements. Decode algorithms will be developed that will allow these plans to be read out in real time. The output device will be a robot limb whose controller is designed to be instructed by high level signals and to compute many of the lower level aspects of the movement trajectory that are normally computed at levels of the brain closer to the motor output. This hybrid control system represents a new area of robotics research. Additionally, local field potentials will be used to convey similar information to the robotic controller and this should provide a breakthrough for long-term recordings. The specific aims will proceed from the simplest experiment of demonstrating that a monkey can control an animated limb on a computer screen to more complex experiments where

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the experimenters will determine how PRR codes information about reaches in more natural situations. These later experiments will include neurophysiological studies of the coding of sequential movements, curved trajectories, combined hand-eye movements, and visua-motor plasticity. The concurrent engineering studies will develop alogorithms that can reconstruct the intended movements from neural record and develop supervisory control architectures that can move the robotic limb appropriately, all in real-time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROBIOLOGY OF DISEASE -- TEACHING WORKSHOP Principal Investigator & Institution: Kriegstein, Arnold R.; Professor; Society for Neuroscience 11 Dupont Cir Nw, Ste 500 Washington, Dc 20036 Timing: Fiscal Year 2004; Project Start 01-AUG-1983; Project End 31-MAY-2006 Summary: The Society for Neuroscience (SFN) is the major professional organization for scientists who study the nervous system. An important goal of this organization is to encourage scientists in training to undertake research related to diseases of the nervous system. The objective of this grant application is to support teaching workshops that introduce young neuroscientists to current concepts about the etiology and pathogenesis of disorders of the nervous system. For each workshop, about 12 faculty are chosen by the Organizing Committee after eliciting proposals from the Society at large. Clinical presentations provide enrollees with an experience of the human dimension of particular diseases. Lectures cover both clinical research and relevant laboratory work. In addition to lectures, enrollees are given a choice of attending two of four small group workshops that emphasize either specific or methodological issues and encourage lively discussion. Since its inception, 20 workshops have been held, usually on the day prior to the start of the Society for Neuroscience meeting. Topics have included: Infections in the nervous system, epilepsy, Huntington's and Alzheimer's diseases, muscular dystrophy, multiple sclerosis, prion diseases, drug addiction, pain and affective disorders, stroke and excitotoxicity, neuromuscular diseases, amyotrophic lateral sclerosis, schizophrenia, migraine, mental retardation and developmental disorders, Tourette's syndrome and obsessive-compulsive disorder, and the neurobiology of brain tumors. Enrollment generally runs between 100 and 200 attendees. Most enrollees are graduate students or postdoctoral fellows. Current plans are to cover the following topics in the near future: Genes, free radicals, mitochondria and apoptosis in Parkinson's disease, AIDS dementia, peripheral neuropathy, pain, language disorders, and affective disorders. Other topics will be chosen depending on their potential interest to young neuroscientists, their impact on society and the quality of recent research related to that disease area. We are especially interested in covering diseases of the nervous system which are important clinically but which are in need of enhanced basic cellular and molecular understanding. Society members are encouraged to suggest topics in the SFN Newsletter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOGO'S ROLE IN INTRACELLULAR TRAFFICKING Principal Investigator & Institution: Harel, Noam Y.; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2006; Project Start 15-SEP-2006; Project End 31-MAY-2011 Summary: (provided by applicant): Nogo inhibits neurite outgrowth by acting at the myelin surface through a neuronal surface receptor, NgR. Therapies targeting the Nogo-

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NgR pathway show promise in the treatment of spinal cord injury and other central nervous system diseases. However, much remains unknown regarding Nogo's function in uninjured cells. Nogo is a member of the Reticulon family, a conserved set of endoplasmic reticulum (ER)-associated proteins with unclear functions. The bulk of Nogo expression is intracellular rather than surface-associated. Additionally, Nogo is prominently expressed in neurons as well as in oligodendrocytes. These facts argue for other roles played by Nogo besides inhibiting axon growth. We have obtained data suggesting that Nogo isoforms regulate intracellular traffic. Furthermore, Nogo levels affect the specialized neuronal trafficking pathway of axon transport. Nogo may mediate its effects on traffic through small GTPases of the Rab family. Additionally, Nogo may affect trafficking of its own receptor, thereby creating a form of NgR regulation that has not previously been explored. Finally, Nogo may enhance neuronal survival in the context of motor neuron disease. Better understanding of these roles is crucial as therapies are being developed to block the Nogo pathway in the treatment of central nervous system injury. The Aims of this proposal are to further explore the mechanisms of Nogo's involvement in intracellular trafficking using a variety of cell imaging and biochemical techniques. Nogo's effects on the specialized neuronal trafficking pathways of axon transport and synaptic vesicle recycling will be explored with live cell imaging studies in neurons from wild type and Nogo-knockout mice. These studies will be performed under the mentorship of Dr. Stephen M. Strittmatter, a leader in the field of neuroregeneration and axonal signal transduction. He and his extremely well-funded laboratory provide the optimal setting for developing expertise in the techniques required for successful neuroscientific research. Furthermore, Yale's Department of Neurology has committed to fostering the applicant's development by limiting clinical responsibilities to allow at least 85% effort devoted to research, and by keeping open laboratory space available as the applicant transitions to running an independent laboratory during the period of this proposal. The Nogo pathway is intensely studied for its role in blocking injured nerves in the brain and spinal cord from regenerating. However, this proposal shows that Nogo also plays important roles that may help uninjured nerves function. Insight into these roles will shed light on Nogo's involvement in diseases like amyotrophic lateral sclerosis, and will help guide the development of safer therapies to inhibit the Nogo pathway in the context of spinal cord injury and other devastating central nervous system diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NON-VIRAL DELIVERY OF NEUROTROPHIC FACTORS TO THE CNS Principal Investigator & Institution: Francis, Jonathan W.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2005; Project Start 19-APR-1999; Project End 31-DEC-2008 Summary: (provided by applicant): The development of new therapies to treat amyotrophic lateral sclerosis (ALS) is often hindered by the poor bioavailability of candidate drugs to affected motor neurons within the central nervous system (CNS). Thus, while both glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor-1 (IGF-1) have had robust survival promoting effects on injured motor neurons in experimental animals, their success in treating ALS patients appears to have been thwarted by insufficient access to motor neurons in the much larger human CNS. We hypothesize that genetic or chemical fusion of tetanus toxin fragment C (TTC) to either GDNF or IGF-1 will improve growth factor delivery to motor neurons through one or more mechanisms related to the nerve cell binding properties of TTC. The

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primary goal of this project, then, is to assess whether the neuroprotective activity of IGF-1:TTC and GDNF:TTC in an experimental animal model of ALS is superior to that of the respective growth factor alone. Our study has four specific aims: (1) optimize the design, expression, and purification of IGF-1:TTC and GDNF:TTC; (2) characterize the purity, stability, and basic functional activity of these fusion proteins; (3) examine the bioavailability and functional activity of the fusion proteins in rodent CNS following intracerebroventricular or intramuscular administration; and (4) investigate the neuroprotective activity of the fusion proteins in a transgenic rat model of amyotrophic lateral sclerosis (ALS). The experiments in Aim 1 will use recombinant protein expression and purification techniques to generate the fusion proteins, while the studies in Aims 2 and 3 will employ immunocytochemical, Western blot, enzyme immunoassay, and morphometric techniques to assess the functional properties of GDNF:TTC and IGF-1:TTC in cultured ceils and whole animals. Finally, the experiments in Aim 4 will employ transgenic animals in survival and behavioral experiments to assess the neuroprotective effects of GDNF:TTC and/or IGF-1 :TTC in vivo. While the present work may give rise to a new treatment for ALS, the information obtained from our characterization of IGF-1:TTC and GDNF:TTC may lead to the use of these fusion proteins in other neurological disorders as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL CEHC DERIVATIVES FOR NEUROINFLAMMATION Principal Investigator & Institution: Benaksas Schwartz, Pharmaceuticals, Inc. 18085 Gentian Ave Riverside, Ca 92508

Elaine

J.;

Encore

Timing: Fiscal Year 2005; Project Start 30-SEP-2003; Project End 31-JUL-2007 Summary: Experimental studies conducted under an SBIR Phase I (SBIR I) Grant, 1 R43 AG023510, have identified a compound that is a potential treatment for Amyotrophic Lateral Sclerosis (ALS). Encore Pharmaceuticals, Inc. (EncorePharma ) holds a composition of matter patent for the compound. The compound's mode of action in in vitro testing and its activity in preliminary studies in the G93A-SOD1 mouse model of ALS, suggest it may be the first drug candidate to have an overall impact on ALS disease progression. This SBIR Phase II Application (SBIR II) seeks support to further preclinical development of the compound in preparation for submission of an Investigational New Drug (IND) Application to the FDA, allowing initiation of clinical trials with the compound. The important preclinical development work defined in this SBIR II is the first step in commercialization of a potentially important new pharmaceutical agent. The successful scientific/business collaborations with the Oklahoma Medical Research Foundation (OMRF) in SBIR I will be further cultivated in SBIR II. The SBIR II Specific Aims are: to optimize the dose level and route of administration in concert with selecting the active enantiomer using well-defined rodent models of ALS; to conduct chemical process development and small to intermediate scale manufacture of compound (drug substance) according to Good Manufacturing Practices (GMP); to conduct appropriate supporting toxicology and pharmacology studies (including gene toxicity and metabolism) according to Good Laboratory Practices; to evaluate in ALS rodent models the utility of C-tau and other molecules as appropriate, as a biomarker for translation into the clinical setting. With a positive preclinical safety and efficacy profile, an IND will be prepared, filed with FDA and Orphan Drug Designation sought. As the compound may exert an effect against the neuroinflammatory component of ALS and many neurological diseases such as Huntington's, Parkinson's and Alzheimer's, EncorePharma will support, as appropriate, experimental studies with the compound and/or other related compounds in models

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and systems relevant to these diseases. The need to move this potential therapeutic forward for a disease that has very few treatment alternatives cannot be understated. A total of 60,000 to 100,000 individuals are estimated to be affected with ALS worldwide at any given time, and the incidence of the disease is approximately five to nine persons per 100,000. The market potential for a therapeutic hi ALS alone is $100-300 million. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEROXYNITRITE AND SOD IN MOTOR NEURON APOPTOSIS Principal Investigator & Institution: Estevez, Alvaro G.; Director and Associate Professor; Physiology and Biophysics; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2004; Project Start 01-APR-1998; Project End 31-MAR-2006 Summary: (From the Applicant's Abstract): Our long-term goal is to understand how mutations to SOD can increase oxidative stress and cause the death of motor neurons in amyotrophic lateral sclerosis (ALS). We have shown that endogenous formation of the peroxynitrite by the diffusion-limited reaction between superoxide and nitric oxide induces apoptosis in cultured embryonic rat motor neurons deprived of trophic support. Both inhibitors of nitric oxide synthesis as well as Cu, Zn superoxide dismutase (SOD) delivered intracellularly with liposomes protect motor neurons from apoptosis. These data indicate that the interaction between nitric oxide and superoxide has a role in motor neuron apoptosis. Mutations to SOD are implicated in the selective degeneration of motor neurons in ALS and expression of ALS-SOD mutants in transgenic mice produces motor neuron disease. A common phenotype among the ALS-SOD mutations so far investigated is to decrease the affinity for zinc. We have shown that zinc-deficient SOD is both less efficient at scavenging superoxide and a better catalyst of tyrosine nitration. Furthermore, the copper in zinc-deficient SOD can act as a non-specific oneelectron oxidase, robbing electrons from antioxidants like ascorbate and glutathione that can be transferred to oxygen to produce superoxide. In the presence of NO, zincdeficient SOD can catalyze the formation of peroxynitrite. In the previous cycle of funding, we have shown that zinc-deficient SOD induces apoptosis in motor neurons by a nitric oxide-dependent mechanism. For the renewal, our first aim is to further investigate the mechanisms by which zinc-deficient SODs can kill cultured motor neurons and to determine what can protect motor neurons from this toxicity. Our second aim is to characterize the source or sources of superoxide induced in motor neurons by trophic factor is to characterize the source or sources of superoxide induced in motor neurons by trophic factor withdrawal. Our third aim is to test the role of tyrosine nitration by peroxynitrite in the death of motor neurons induced by either trophic factor deprivation or by zinc-deficient SOD. Completion of the specific aims will provide a mechanistic basis for explaining how motor neurons are particularly vulnerable to SOD mutations and establish a link between sporadic and familial SODs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHASE III TRIAL OF MINOCYCLINE IN ALS:I-CLINICAL CENTER Principal Investigator & Institution: Gordon, Paul H.; Neurology; Columbia University Health Sciences Research Administration New York, Ny 100323702 Timing: Fiscal Year 2004; 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

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

Project Title: PHASE III TRIAL OF MINOCYCLINE IN ALS-II DATA CENTER Principal Investigator & Institution: Miller, Robert G.; California Pacific Med Ctr Res Institute 475 Brannan Street, Suite 220 San Francisco, Ca 94107 Timing: Fiscal Year 2004; Project Start 15-AUG-2003; Project End 31-MAY-2007 Summary: (provided by the applicant): This proposal is designed to provide data management and statistical support for the companion application Phase III Trial of Minocycline in ALS: I-Clinical Center (P.I. Paul Gordon, University of New Mexico), which is a multi-center clinical trial of Minocycline in ALS. The clinical trial is a randomized (1:1), double-blind, placebo-controlled trial, which will enroll 400 patients during the first two years. Each patient will be followed monthly for a minimum of 13 months; the first four months without drug or placebo (monitoring phase) to measure rate of decline of a validated functional measure (ALS Functional Rating Scale-Revised, ALSFRS-R), followed by 9 months on drug or placebo (assigned by randomization). The primary test of drug efficacy will be based on comparing changes in slope, i.e., the slope after assignment (based on up to 9 monthly scores), minus the slope before assignment (based on 5 monthly scores), in the drug vs. placebo groups. A linear mixed effects

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model will be used to estimate the average change of slope for patients in each group. The difference in average change, drug vs. placebo, will be tested using a mixed linear effects model. The study has 80% power to detect a change of 15% in slope, which corresponds to 4-5 months of prolonged survival. The companion application, Phase III Trial of Minocycline in ALS: I - Clinical Center (P.I. Paul Gordon, University of New Mexico), describes the details of background, clinical procedures and human subjects. This application describes the specific aims of the Data Management Center, and summarizes results of our previous clinical trials and studies in ALS. We provide data from our previous studies to justify the 4-month lead-in, thereby reducing sample size. We present an analysis of our previous results to support our choice of the primary and secondary efficacy variables. In particular, we demonstrate a close relationship between changes in ALSFRS and survival. We explain the selection of the effect size and development of the sample size in detail, based on analysis of our previous results. The details of data management are described, including the methods for quality control, security and information technology. Finally, the analytic plan is described in full. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROINFLAMMATORY ENZYMES IN AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Przedborski, Serge E.; Professor; Neurology; Columbia University Health Sciences Research Administration New York, Ny 100323702 Timing: Fiscal Year 2004; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: This proposal is submitted to pursue our investigation of the pathogenesis of amyotrophic lateral sclerosis (ALS) using transgenic mice expressing the glycine-93 yields arginine mutant copper/zinc superoxide dismutase (SOD1G93A). Pertinent to this goal, first, we have shown that inducible nitric oxide synthase (iNOS) is upregulated in glial cells in the spinal cords of affected transgenic SOD1G93A mice. To elucidate the role of iNOS in this model of ALS, Specific Aim (SA)-I will determine the effect of iNOS inhibition or ablation on SOD1G93A-mediated neurodegeneration. Second, we have evidence that the production of the highly-reactive tissue damaging species hypochlorous acid is increased in the spinal cords of affected transgenic SOD1G93A mice. To acquire a better understanding the cytotoxic role of hypochlorous acid in this model of ALS, SA-II will quantify spinal cord levels of chlorotyrosine and nitrotyrosine, the two main fingerprints of hypochlorous acid-induced protein oxidative attack, at different disease stages, in different lines of transgenic mice that express either mutant or wild-type SOD1 and, in transgenic SOD1G93A mice after ablation of neuronal NOS (nNOS), iNOS, or myeloperoxidase (MOP), which is the only mammalian enzyme which produced hypochlorous acid. To explore further the role of MPO. SA-III will (1) define spinal cord expression of MPO mRNA and protein, as in SA-II, at different disease stages and transgenic lines; and (2) assess the effect of MPO ablation on SOD1G93A-mediated neurodegeneration. Third, we have observed that cyclooxygenase-2 (Cox-2), a key enzyme in the synthesis of the pro-inflammatory prostaglandin PGE2, is also markedly increased in the spinal cord of affected transgenic SOD1G93A mice. To demonstrate whether Cox-2 upregulation plays a role in SOD1G93A-mediated neurodegeneration, SA-IV will (1) characterize spinal cord Cox-2 mRNA and protein expression, and PGE2 content, as in SA-II, at different disease stages, transgenic lines, and in transgenic SOD1G93A mice after ablation of iNOS; and (2) assess the effects of Cox-2 inhibition or ablation on SOD1G93A-mediated neurodegeneration. This proposal contains a comprehensive set of experiments, which

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should provide insights into the role of iNOS, hypochlorous acid and its synthesizing enzyme MPO, as well as into Cox-2 in transgenic SOD1G93A mice. It should also shed light onto the mechanisms of neurodegeneration in ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROPERTIES OF DYNEIN ISOENZYMES Principal Investigator & Institution: Gibbons, Ian R.; Professor of Biophysics; Molecular and Cell Biology; University of California Berkeley 2150 Shattuck Avenue, Room 313 Berkeley, Ca 947045940 Timing: Fiscal Year 2004; Project Start 01-APR-1982; Project End 31-MAR-2008 Summary: (provided by applicant): Dyneins are motor proteins that move cellular cargos along microtubules toward their minus ends. There are two sub-classes of dynein. Cytoplasmic dynein is a single isoform that is involved in various essential cellular functions, including retrograde vesicle transport in the cytoplasm and in nerve axons, organellar movement, orientation of the mitotic spindle, disassembly of centromeric checkpoint proteins, and nuclear migration. Axonemal dynein occurs as approximately 12 isoforms, encoded by distinct genes, that are responsible for the beating movements of cilia and sperm flagella. In all dyneins the motor unit consists of six AAA protomers disposed in tandem on a single "heavy chain" polypeptide of unusually high molecular mass (>500 kDa). These AAA protomers form a hexameric ring from which the microtubule-binding domain protrudes on a short stalk. Binding and hydrolysis of ATP at certain of the AAA protomers is believed to cause cyclic changes in the angle of the protruding stalk and so translocate the dynein along the microtubule to which it is attached. Sequence analysis suggests that the structure of the AAA protomers in dynein resembles that of other members of the AAA ATPase family, with their closest relationship being to AAA protomers of the recently discovered protein, midasin. The long-term goal of this project is to understand the relationship between structure and function in dynein isoforms. The specific aims are to use techniques of cell and molecular biology: 1) to express individual structural domains of dynein in bacteria or in eukaryote cell cultures in order to obtain relatively low molecular weight forms of these proteins that retain subsets of their functional properties; 2) to use site-directed mutagenesis of the dynein motor to characterize the cooperative ATP-dependent structural changes in the AAA protomers and microtubulebinding stalk that are believed to underlie the ability of dynein to translocate along a microtubule; 3) to use antibodies to define an experimental map of the motor surface and of the changes that occur during the ATPase cycle; 4) to relate the structural and enzymatic properties of the AAA protomers in dynein to those of the AAA protomers in midasin. Defects in dynein underlie many human health problems, including male infertility, bronchiactosis, lissencephaly, primary cilia diskinesia, and defective retrograde transport in nerve axons that can result in amyotrophic lateral sclerosis (ALS). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROSPECTIVE EPIDEMIOLOGICAL STUDY OF ALS Principal Investigator & Institution: Ascherio, Alberto; Associate Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): We propose to study prospectively the relationships between lifestyle factors and risk of amyotrophic lateral sclerosis (ALS) among

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participants in the Cancer Prospective Study II (CPS II) of the American Cancer Society. The original cohort comprised 1,184,622 men and women from all 50 United States, the District of Columbia, and Puerto Rico, aged 30 years and older, who completed a lifestyle and dietary questionnaire in 1982. The proposed investigation will include the 1,098,726 participants who were alive on January 1, 1989, as reliable information on causes of death is only available after this date. During ten years of follow-up, 621 participants in this cohort died of ALS. Specifically, we will examine prospectively the associations between risk of ALS and cigarette smoking, use of antioxidant vitamins, education, occupation, and exposures to agricultural chemicals and solvents. Because of the large number of participants and long follow-up time this cohort provides a unique opportunity to examine prospectively the association between lifestyle variables and the risk of ALS among men and women. A further strength of the proposed investigation is the availability of information on several potential confounders, including past medical history, physical activity, and diet. Identification of the risk factors for ALS will provide clues about the etiology of the disease and contribute to identify those hypotheses that need more intense scrutiny in clinical or laboratory investigations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOIDS AND THE SPECIFICATION OF SPINAL MOTOR NEURONS Principal Investigator & Institution: Sockanathan, Shanthini; Assistant Professor; Neuroscience; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2004; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: The coordinated generation of specialized groups of spinal motor neurons during development of the central nervous system is essential for the assembly of functional neural circuits. Analysis to date hasfocused on the role of the signaling molecule shh in motor neuron specification however increasing evidencesuggests that other inductive molecules may play pivotal roles in their development. The dynamicspatiotemporal expression of RALDH2, the major synthetic enzyme for retinoic acid suggests that retinoidsignaling is required at defined stages in the sequential development of motor neurons. However, loss offunction studies have not been informative due to the early lethality of RALDH2 null embryos. This proposalaims to test the hypothesis that retinoids are required at specific stages of motor neuron development usinggenetic strategies in the mouse to bypass the early lethality of RALDH2 mutants. Tissue specific knockouts of RALDH2 will be constructed and analyzed to first assess the contribution of paraxial mesoderm derived retinoids to motor neuron generation and column induction and second, to determine if motor neuron derived retinoid signaling is necessary for motor column, motor division and motor pool determination. Finally, four prospective target genes for RALDH2 have been isolated using differential screening approaches and experiments outlined here will focus on functional analyses to determine the potential role of two of these genes in motor neuron specification. Taken together, these experiments aim to define the contribution of retinoic acid signaling to motor neuron development with the ultimate aim of assembling a molecular pathway of retinoid dependent events required for their specification during embryogenesis. Understanding the processes by which motor neuron specification occurs may provide insight into the basis of motor neuron degenerative diseases such as amyotrophic lateral sclerosis or the spinal muscular atrophies. This in turn may lead to the design of innovative treatments for these diseases in the future which may incorporate the use of stem cell technology.

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

Project Title: RILUZOLE MOA: TARGETS FOR IMPROVED NEUROPROTECTIVE DRUGS Principal Investigator & Institution: Sluder, Ann E.; Director, Genetics; Cambria Biosciences, Llc 8A Henshaw St Woburn, Ma 01801 Timing: Fiscal Year 2004; Project Start 30-SEP-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disease of motor neurons that results in progressive muscle weakness, paralysis, and ultimately death, usually within five years of disease onset. Late stage ALS patients require extensive supportive care, placing immense emotional and economic burdens on patients and their families. Riluzole, the only drug currently approved for the treatment of ALS, provides only a modest extension of 2 to 3 months in life expectancy for ALS patients, and hepatotoxicity is a significant side effect limiting the drug's use. Biochemical and cellular studies have suggested a wide variety of potential targets for riluzole action, but the precise molecular mechanism of action (MO A) of this drug remains poorly defined. A more complete understanding of riluzole's molecular target(s) would be of great value in guiding the discovery of safer and more effective therapies for ALS. Genetic studies in the model nematode Caenorhabditis elegans have been successfully utilized to identify the targets and mechanistic pathways of a number of human Pharmaceuticals. Preliminary studies have demonstrated a significant effect of riluzole on C. elegans, and multiple independent genetic mutants resistant to the drug have been isolated. This Phase I SBIR project will complete the genetic analysis of these riluzole-resistance alleles in C. elegans, with the goal of characterizing riluzole's MOA and identifying riluzole targets that can be exploited for therapeutic discovery efforts. Two specific aims will be pursued: (1) Genetic mapping of the riluzole-resistance alleles will employ a combination of genetic recombination mapping and single-nucleotide polymorphism analysis. (2) Identification of the riluzole-resistance gene(s). Based on the genetic mapping results, a combination of candidate gene sequencing and, as needed, genetic transformation experiments will be used to identify the specific mutations conferring riluzole resistance. The molecular characterization of the riluzole-resistance gene(s) will identify one or more pathways for riluzole's action in a living model animal with a well-characterized nervous system. Subsequent Phase II efforts will (a) identify and evaluate the function of homologous mammalian genes, and (b) develop and implement new bioassays for the rational discovery of next-generation therapeutics for ALS and other neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISMUTASE

RNAI-MEDIATED

SILENCING

OF

MUTANT

SUPEROXIDE

Principal Investigator & Institution: Maxwell, Michele M.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder resulting from selective death of motor neurons in the brain and spinal cord. In approximately 20% of dominantly-inherited familial ALS cases, the disease is caused by mutations in the gene encoding cytosolic Cu,Zn superoxide dismutase (SOD1). The vast majority of ALS-linked variations in SOD1 are

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point mutations yielding single amino acid substitutions. In cell culture and in rodent models of ALS, mutant SOD1 proteins exhibit dose dependent toxicity; thus, agents that reduce mutant protein expression would be useful therapeutic tools. The overall goal is this project is to evaluate the potential of RNA-mediated interference (RNAi) for silencing expression of mutant SOD1 in vitro and in vivo. Small interfering RNAs (siRNAs) capable of selectively inhibiting expression of mutant SOD1 will be identified. Transgenic mice expressing small hairpin RNAs directed against mutant SOD1 will be generated and crossed to mutant SOD1 transgenic mice; progeny will be monitored for changes in disease onset and progression. In addition, the therapeutic potential of RNAi will be assessed using viral delivery of shRNA to the spinal cords of mutant SOD1 transgenic mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF COPPER CHAPERONE FOR SOD1 IN MODELS OF ALS Principal Investigator & Institution: Wong, Philip C.; Associate Professor; Pathology; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2004; Project Start 10-APR-2000; Project End 31-MAR-2006 Summary: (Verbatim from the Applicant's Abstract) Cu/Zn superoxide dismutase (SOD1) mutations cause about 20 percent of cases of familial amyotrophic lateral sclerosis (FALS). Transgenic mice expressing mutant SOD1 develop a progressive motor neuron disease. A long term goal is to understand the molecular mechanisms by which SOD1 mutants cause selective motor neuron degeneration. Copper, an essential cofactor for SOD1 enzymatic activity, has been proposed to play a critical role in the pathogenesis of SOD1-linked ALS. Because free copper can be toxic in cells, the delivery of copper to specific proteins within various compartments of the cell is tightly regulated by specific copper chaperones like CCS. Previous efforts have demonstrated that CCS is necessary to deliver copper to SOD1, and CCS-deficient mice are viable and show no SOD1 activity. First, to test whether Cu in mutant SOD1 is required to cause motor neuron degeneration, CCS-deficient mice will be crossbred with a series of mutant SOD1 mice. If Cu participates in killing motor neurons, mutant SOD1 mice without CCS will show significant amelioration or rescue of motor neuron disease. Second, because 30 percent of SOD1 is not charged with Cu, transgenic mice overexpressing CCS will be generated to examine whether the level of active SOD1 can be increased in vivo by elevating the level of CCS. Finally, to determine the domains of CCS that are important for Cu delivery, a series of mutant CCS DNA constructs will be transfected into wild-type and CCS-deficient cells to identify CCS mutants that are able to inhibit the CCS Cu trafficking pathway. Taken together, these efforts will test Cubased neurotoxicity mechanisms in vivo. The results will have the potential to identify novel therapeutic targets and may have implications for the design of drug treatments for motor neuron disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF YEAST SEN1P IN RNA MATURATION PATHWAYS Principal Investigator & Institution: Finkel, Jonathan S.; Lab of Molecular Biology; University of Wisconsin Madison Suite 6401 Madison, Wi 537151218 Timing: Fiscal Year 2006; Project Start 01-JAN-2006; Project End 31-DEC-2009 Summary: (provided by applicant): Sen1p in Saccharomyces cerevisiae is a Type I DNA/RNA helicase. Mutations in the helicase domain perturb accumulation of diverse RNA classes, and Sen1p has been implicated in 3' end formation of non- coding RNAs.

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Mutations in the human ortholog of yeast SEN1 (SETX) have been implicated as a cause for the neurological disorders, ataxia-ocular apraxia 2 and Juvenile Amyotrophic Lateral Sclerosis (Lou Gehrig's disease). Speculation about the function of SETX in these diseases derives from work done on the yeast SEN1. Studies of sen1 mutants revealed defects in the processing of small nuclear RNA (snRNA). The aims of this proposal focus on the functional analysis of the interaction between Sen1p and Rnt1p and Sen1p and SmDSp. Rnt1p, which resembles E. coli RNase III, is an endoribonuclease required for RNA maturation. SmDSp is a subunit of the splicing complex. To investigate the potential roles of these interactions in RNA processing, mutations will be created in SEN1 that specifically disrupt the Sen1p-Rnt1p or Sen1p-SmD3p interactions. To assess the purpose of these protein-protein interactions, the non-interacting mutants will be assayed to determine the effects of loss of interaction on processing of the U5 snRNA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROUTE 28 SUMMITS IN NEUROBIOLOGY Principal Investigator & Institution: Palmer, Theo D.; Assistant Professor; Neurosurgery; Stanford University 1215 Welch Road, Mod B Stanford, Ca 943055402 Timing: Fiscal Year 2005; Project Start 01-JUN-2005; Project End 31-MAY-2006 Summary: (provided by applicant): This proposal requests partial funding for the 5th workshop in a series of well optimized and uniquely effective training venues for graduate students and post-graduate fellows. The 2005 Route 28 Summit focuses on the emerging links between injury, inflammation and neurodegeneration in the central nervous system dysfunction. With the help of attending faculty, trainees work in small collaborative groups to competitively produce and present research strategies addressing current issues in multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and spinal cord injury. The workshop involves 45 trainees and formal lectures by 19 attending faculty members. Trainees and teaching faculty are drawn from the international research and clinical communities. The current organizing committee is well experienced and has produced four prior Route 28 Summits in 1999, 2001, 2002, and 2004. The organizers of the Route 28 Summits have made a commitment to attain four Aims: Aim 1. Provide outstanding student access to leading scientists in neurobiology and related disciplines. Aim 2. Promote long-lasting and rewarding crossdisciplinary interactions on the workshop topic. Aim 3. Educate trainees in the process of collaborative thinking and group planning of a competitive research proposal. Aim 4. Provide a cost package that does not discriminate against promising students with a limited travel budget. To our knowledge, the Route 28 Summit workshops provide the only graduate and post-graduate level training venue that purposefully highlights the strengths of collaborative multi-disciplinary research in the biomedical sciences. In addition, the workshop topics and trainee assignments provide a thorough introduction to cutting edge research in disease or injury processes and explore problems facing the translation of basic science into clinical application. These strengths are clearly called out in the newly generated NIH Roadmap and are fundamental to the programmatic goals of the NINDS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOD1/BC1-2 COMPLEX: A ROLE IN REGULATING MOTOR NEURON CELL DEATH Principal Investigator & Institution: Pasinelli, Piera; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114

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Timing: Fiscal Year 2006; Project Start 02-AUG-2006; Project End 31-JAN-2010 Summary: (provided by applicant): In this project we will define a role for copper-zinc superoxide dismutase (SOD1) in the regulation of cell survival and death. While the wild-type (WT) SOD1 is a pro-survival protein, amyotrophic lateral sclerosis (ALS)linked SOD1 mutants are toxic both in vitro and in vivo. We recently found that both WT and mutant SOD1 interact with the anti-apoptotic protein Bcl-2. However, the nature of the mutant SOD1 binding with Bcl-2 differs from WT SOD1. Contrary to WT SOD1, mutant SOD1 specifically localizes to spinal cord mitochondria where it forms SDS-resistant high molecular weight aggregates that bind and entrap Bcl-2. (Pasinelli et al, 2004, Neuron 43: 19-30). These studies suggest a potentially novel function for WT SOD1 in regulating cell survival and death, and a novel, toxic gain-of-function for mutant SOD1. Thus, while WT SOD1 may protect against cell death through its interaction with Bcl-2, mutant SOD1 may become toxic by aberrantly binding to Bcl-2 and converting Bcl-2 into a toxic or non-functional protein. In support of this hypothesis, we now have preliminary data indicating that both WT and mutant SOD1 might require Bcl-2 to exert their anti-and-pro apoptotic function respectively. With the present proposal we intend to characterize the anti and pro-death function of WT and mutant SOD1 and their respective interactions with Bcl-2. The ultimate goal is to understand the mechanism(s) of mutant SOD1-mediated toxicity and to define a potential role for the mitochondrial mutant SOD1/Bcl-2 complex in ALS pathogenesis. The specific aims are: 1) (A) To determine whether WT SOD1 pro-survival activity depends on its binding to Bcl-2, and (B) to determine whether mutant SOD 1-mediated toxicity depends on the aberrant interaction with Bcl-2. 2) (A) To identify the region(s) in SOD1 essential for the binding with Bcl-2, and (B) to study the difference in binding strength between WT SOD1 and Bcl-2 and mutant SOD1 and Bcl-2. 3) (A) To determine whether Bcl-2 undergoes conformational modifications upon binding with mutant SOD1 and.(B) to test the potential benefit of Bcl-2 and SOD1 like-peptides that abolish binding between Bcl-2 and mutant SOD1 on our cell culture model of mutant SOD1-linked ALS. 4) To determine whether Bcl-2 mediates mutant SOD1 mitochondrial translocation. 5) To study the correlation between mutant SOD1/Bcl-2-containing aggregates and ALS using transgenic ALS mice and patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL BIOLOGY OF COPPER HOMEOSTASIS Principal Investigator & Institution: Rosenzweig, Amy C.; Professor; Biochemistry, Molecular Biology and Cell Biology; Northwestern University Evanston, Il 602081110 Timing: Fiscal Year 2004; Project Start 01-FEB-1999; Project End 31-JAN-2008 Summary: (provided by applicant): The long-term goal of this research program is to understand the molecular mechanisms of human copper homeostasis in atomic detail. Copper serves as a cofactor for many key enzymes, but can also facilitate the formation of oxygen radicals, which can damage proteins, DNA, and lipids. The delivery of this essential yet potentially toxic metal ion to distinct cellular locations and particular target proteins is accomplished in part by metallochaperone proteins. Metallochaperones deliver copper ions to target proteins via specific protein-protein interactions. Three classes of eukaryotic copper chaperones have been identified: the Atx1-like chaperones, the copper chaperones for superoxide dismutase, and the copper chaperones for cytochrome c oxidase. The Atx1-like chaperones deliver copper to transport ATPases in the secretory pathway. These ATPases include the human Wilson and Menkes proteins, mutations in which lead to Wilson disease and Menkes syndrome, genetic disorders of copper metabolism. The copper chaperones for superoxide dismutase, known as the

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CCS proteins, provide copper,zinc superoxide dismutase (SOD1) with its catalytic copper ion. Mutations in SOD1 have been linked to familial amyotrophic lateral sclerosis (FALS). The copper chaperones for cytochrome c oxidase, Sco1 and Cox17, help assemble the CuA site in subunit 2 (Cox2). In humans, defects in cytochrome c oxidase lead to fatal cardioencephalomyopathy. The objective of the proposed work is to elucidate on the molecular level how proteins in these pathways bind copper, recognize and dock with physiological partners, and facilitate metal ion transfer. The metal binding properties of the copper chaperones and their target proteins will be studied by biophysical and crystallographic methods. Interactions between chaperones and target proteins will be investigated by biochemical, biophysical, and X-ray crystallographic techniques. In addition, interactions among the multiple metal binding domains of the transport ATPases will be examined. These approaches are expected to reveal molecular details of copper trafficking and provide new insight into the causes and treatments of diseases related to copper metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL INVESTIGATIONS OF METALLOPROTEIN METAL SITES Principal Investigator & Institution: Penner-Hahn, James E.; Professor; Chemistry; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; Project Start 01-APR-1987; Project End 31-MAR-2009 Summary: (provided by applicant): The long term objective of this proposal is to characterize in detail the structural and functional properties of zinc in biological systems. Zinc is the most common metal found in metalloproteins and is the only metal that is known to be required for every major class of enzyme catalysis. Hundreds of zinc proteins have been isolated and thousands of potential zinc binding sites have been identified in protein sequences. Imbalances in the levels of zinc or errors in its transport or regulation can have profound health consequence. Malfunctions in zinc homeostasis have been implicated in a wide range of diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and spongiform encephalopathies; as a modulator of synaptic transmission, zinc has been suggested to play a critical role in the proper functioning of the brain. Despite its importance, there is relatively little information available about biological zinc sites due to the difficulty of studying this spectroscopically "silent" metal. X-ray absorption spectroscopy, one of the few methods able to provide structural information for non-crystalline materials, will be used to determine the structures of zinc in a novel class of zinc-containing alkyl transfer enzymes and to characterize the relative importance of metal stereochemical preference and protein structure in defining the structure of a metal binding site. For the latter work, structures will be compared for a series of spectroscopically silent metal ions (Cu(l), Ag(l), Cd(ll), Hg(ll), Pb(ll), and As(lll), in addition to Zn(ll)). As a complement to "conventional" x-ray spectroscopy, new tools will be developed using high-resolution xray emission spectroscopy and zinc L-edge x-ray spectroscopy. In situ x-ray microprobe imaging and microspectroscopy will be used to characterize metal sites in intact biological tissue, and the newly developed tool of capillary electrophoresis/x-ray fluorescence will be used to determine the metal loading in metalloproteins, with particularly emphasis on the protein superoxide dismutase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURAL STUDIES ON DYNEIN-MICROTUBULE COMPLEX Principal Investigator & Institution: Kikkawa, Masahide; Assistant Profesor; Cell Biology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2006; Project Start 01-JAN-2006; Project End 31-DEC-2010 Summary: (provided by applicant): Microtubule-based motors, dyneins, are nano-meter scale protein machineries and convert chemical energy derived from ATP hydrolysis to mechanical movement. The mechanical movement is employed for various essential intracellular motilities, such as axonal transport, chromosome segregation, and flagellar motility. The importance of dynein functions is underlined by several dynein-related diseases, such as Kartagener's syndrome and amyotrophic lateral sclerosis (ALS). However, little is known about how dynein mutations cause the primary cilia diskinesia or even how dyneins convert chemical energy to mechanical movement. Our long-term goal is to understand the structural basis of energy conversion by dynein and its regulation. To this end we will characterize the structure of dynein-microtubule complexes using cryo-electron microscopy and three-dimensional reconstruction. We have recently obtained two initial structures of dynein-microtubule complexes. One is a low resolution structure of the outer arm dynein-microtubule complex, and another is a medium resolution structure of the microtubule binding domain of dynein, the dynein stalk. Our immediate goals are to refine the structure of the outer arm dyneinmicrotubule complex to 25Angstroms resolution, and to extend the structure of the dynein stalk structure to 10Angstroms resolution. By studying several structures of these complexes in functionally important states, we would like to elucidate conformational changes essential to the energy conversion, motility and regulation of dynein. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TARGETED MOTOR NEURON GENE DELIVERY FOR SPASTICITY Principal Investigator & Institution: Boulis, Nicholas M.; Assistant Professor; Neurosurgery; Cleveland Clinic Lerner Col/Med-Cwru 9500 Euclid Avenue Cleveland, Oh 44195 Timing: Fiscal Year 2004; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Technological advancements have provided neurosurgery with new paradigms for the restoration of neural function. The dual emergence of accurate stereotaxis and deep brain stimulation (DBS) have generated a revolution in the application of targeted neuromodulation applied to movement disorders, epilepsy, eating disorders, obsessive compulsive disease, and pain (Appendix C). Nonetheless, because DBS depends on the focused delivery of electric current, it is incapable of pharmacological specificity. Rather than delivering electric current, viral vectors can alter synaptic function with molecular specificity. Further, vector tropism can be modified, creating the potential for system specific neuronal gene delivery. The experiments outlined in this proposal attempt to develop a vector capable of both neural tropism and neuromodulation. To test these concepts, we propose to develop a recombinant adeno-associated virus (rAAV) capable of synaptic inhibition and motor neuron tropism. We have chosen the spinal reflex arc as a simple mammalian functional system amenable to neuromodulation. In addition, the functional disorder, spasticity, provides a target for the study of applied neuromodulation. We hypothesize that an rAAV vector capable of specific motor neuron inhibition will have therapeutic efficacy in animal models of spasticity. In addition to providing a novel approach to spasticity, data from these studies will permit the rational design of rAAV vector(s) for application

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to motor neuron disease (ALS) and stereotactic neuromodulation. There are 3 Aims: 1) Construct novel vectors capable of focused synaptic inhibition, 2) develop strategies for targeted gene delivery to motor neurons with rAAV, 3) apply targeted rAAV capable of synaptic inhibition in models of spasticity. The applicant has developed a focused interest in the neural basis for behavior in both normal and pathological states. His early training in simple systems neurophysiology, and later training in biochemistry and molecular biology have prepared him for a career in the study of focused gene-based neuromodulation. His appointment to the Cleveland Clinic Foundation will give him access to one of the most active programs in Functional Neurosurgery, and create opportunities for clinical application of his work. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ALS LOCKED-IN COMMUNICATOR Principal Investigator & Institution: Schmidt, Robert N.; Scientist; Cleveland Medical Devices, Inc. Cleveland, Oh 44103 Timing: Fiscal Year 2006; Project Start 01-SEP-2006; Project End 31-JAN-2008 Summary: (provided by applicant): Standard Assistive Technology (AT) solutions do not help people with locked-in syndrome because most AT input devices depend on some form of small but reliable muscle movement, such as pressing a button, eye movements, or blinking. This program will provide a simple device to take standard AT technology to the next level with Biometric Interfaces. This program will develop a fourmode communication aid for disabled individuals. Since a large share of its market will be advanced stage Amyotrophic Lateral Sclerosis (Lou Gehrigs Disease, or ALS) patients and other locked-in patients, it will be referred to "The ALS Locked-ln COmmunicatoR, or TALCOR (pronounced "TALKER"). The goal of this program is to develop and validate a new device that allows severely disable individuals who cannot communicate to do so. TALCOR will provide four different methods of non-traditional communications: 1. Brain Computer Interface (BCI) using EEG; 2. Galvanic Skin Response (GSR). 3. pH changes in the mouth; and 4. Amplified and filtered muscle movement, EMG: In Phase I, we will build a prototype TALCOR that will demonstrate all four modes on the lab bench and with healthy volunteers, and at least one of these methods (or modes) of communication with a patient that currently does not have the ability to communicate. In Phase II, we will upgrade the selected communication modes, harden the device, improve the software, enhance the design toward manufacturing and commercialization, and test the device on patients in the modes selected in Phase I to show its utility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE HISTIDYL IMIDAZOLE LIGAND IN METALLOPROTEINS Principal Investigator & Institution: Valentine, Joan S.; Professor; Chemistry and Biochemistry; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2004; Project Start 01-JAN-1980; Project End 31-MAR-2006 Summary: (provided by applicant): Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) is a progressive, fatal neurodegenerative disease that is characterized by degeneration of motor neurons in the cortex, brainstem, and spinal cord, leading to paralysis and eventual death. In approximately 10 percent of ALS cases, the disease is inherited; approximately one-fifth of these familial cases are associated with mutations in sod1, the gene that encodes the human antioxidant enzyme copper-zinc superoxide

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dismutase (CuZnSOD). These mutations are the only known cause of ALS and therefore represent the strongest clues available in investigating what causes ALS, whether inherited or sporadic. Over 90 individual mutations in CuZnSOD are known to cause ALS, and it is widely accepted that they exert their toxic effects by a gain of function mechanism. Several plausible mechanisms have been suggested to explain the nature of the toxic function gained by CuZnSOD as a consequence of the ALS mutations. The proposed mechanisms include a new chemical reactivity for CuZnSOD, formation of CuZnSOD aggregates, co-aggregation of other unknown components with CuZnSOD, and disruption of metal ion homeostasis due to binding or release from CuZnSOD. Each of these mechanisms would appear to be dependent on a change in structure or on a change in conformational stability or flexibility of the mutant protein relative to the extremely stable wild-type protein. It is therefore important to determine the physical properties of the mutant enzymes, particularly with respect to structure, stability, dynamics, and metal binding and to assay new and potentially toxic chemical reactivities. The primary objective of this project is to discover how mutations in CuZnSOD cause ALS and to explore the possibility that CuZnSOD is also linked to sporadic, i.e., non inherited forms, of ALS. The specific aims are as follows: to expand numbers of isolated, properly metallated and N-acetylated ALS-mutant CuZnSOD proteins for structural and mechanistic characterization, to determine the thermal stabilities and thermodynamics of metal ion binding of wild type and ALS-mutant CuZnSOD, to compare the dynamic properties of wild type and ALS-mutant CuZnSOD, to isolate and characterize mixed dimers consisting of one subunit each of ALS-mutant and wild type CuZnSOD (analogous to the mixed dimers that are expected to occur in ALS patients), to prepare chemically modified wild type CuZnSODs for comparison of properties with ALS-mutant CuZnSOD as possible models for sporadic ALS, to study reactions of ALS-mutant CuZnSOD with ascorbate and with hydrogen peroxide, to continue whole cell studies of yeast strains expressing wild type and ALS mutant CuZnSODs as their only CuZnSODs, and to develop in vivo inhibitors of wild type and ALS-mutant CuZnSODs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF IDUNA IN NEUROPROTECTION Principal Investigator & Institution: Dawson, Valina L.; Professor; Clinical Research Center; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2006; Project Start 15-AUG-2006; Project End 31-JAN-2011 Summary: (provided by applicant): There are approximately 250 neurological - brain and nervous system - disorders. Combined, neurologic disorders are the leading cause of death, disability and loss of quality of life worldwide according to the World Health Organization. The incidence of these disorders ranges from stroke, epilepsy and Alzheimer's, which affect millions, to rare diseases such as amyotrophic lateral sclerosis and ataxia's. To address the problem of brain and nervous system disorders investigators have focused attention on describing cell injury mechanisms. However, discovery of cell survival strategies could have profound impact on the treatment of neurologic disorders and disease and is an area that has not yet been rigorously investigated. Recently we developed a strategy to discover neuroprotective genes from preconditioned neural tissue. Some of the first genes we have begun to characterize provide protection not only against ischemic and excitotoxic injury but are protective against classic apoptotic injury triggered by staurosporin or serum withdrawal. This is very exciting, suggesting that it might be possible to find molecules that are broadly

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protective and therefore might provide treatment for stroke and perhaps even for other neurologic disorders such as Parkinson's disease, Huntington's disease or ALS. From this screen we identified a protein of unknown function that is potently neuroprotective that we have named Iduna and proposed the following aims to explore the biologic function of Iduna. Aim 1: What is the anatomical and cellular localization of Iduna in control and preconditioned tissues? Aim 2: What are the death programs against which Iduna protects neurons? Aim 3: Is Iduna neuroprotective in vivo? Aim 4: What is the neuroprotective network of Iduna? On completion of these studies we will have identified the biologic actions of Iduna and the survival pathways it mediates, as well as, identified potential disease targets that might benefit from expression of Iduna. Our long-term goal is to understand novel enodgenous survival pathways so that these pathways can be exploited for the treatment of neurologic injury and disease. The goal is to understand the function of Iduna so that translational therapy can be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THIRD INTERNATIONAL BCI MEETING Principal Investigator & Institution: Vaughan, Theresa M.; Wadsworth Center One University Pl Rensselaer, Ny 12144 Timing: Fiscal Year 2005; Project Start 01-JUN-2005; Project End 31-MAY-2007 Summary: (provided by applicant): Brain-computer interface (BCI) research seeks to give people with severe motor disabilities (e.g. amyotrophic lateral sclerosis, brainstem stroke, cerebral palsy, and spinal cord injury) communication and control technology that does not depend on neuromuscular output. BCI can provide people who are severely disabled with non-muscular methods for controlling cursor movements, selecting letters or icons, or even operating neuro-prostheses. Facilitated and encouraged by new understanding of brain function, by the advent of powerful low-cost computers, and by appreciation of the needs and potentials of people with disabilities, BCI research has grown rapidly through the past decade and its growth has greatly accelerated in the past two years. Effective BCI research requires interdisciplinary interactions involving neuroscience, psychology, engineering, mathematics, computer science, and clinical rehabilitation. No standard venue brings these groups together, in recognition of this, and of the growth in BCI research, the NIH sponsored and the Wadsworth Center organized in 1999 and 2002 the first two international BCI meetings. These meetings brought together researchers from all over the world and included all relevant disciplines. Foundation support allowed many graduate students and postdoctoral fellows to participate. The meetings were extremely successful. The first was reported in 18 peer-reviewed papers in a special section of IEEE Trans. Rehab. Eng, and the second in 28 peer-reviewed papers in a dedicated issue of IEEE Trans Neur. Syst. Rehab. Eng. In large part due to the interdisciplinary interactions fostered by these meetings, BCI research continues to grow even more rapidly. This proposal seeks core funding for the Third International BCI Meeting, June 14-19, 2005. The mornings of the first three days will provide concise updates from about 50 BCI laboratories, and the afternoons will be devoted to four parallel workshops addressing the four critical areas of BCI research: signals and recording methods; signal processing; clinical issues and applications; and software and hardware. The fourth day will be a plenary session comprised of summary presentations from each workshop. Evenings will offer a keynote address, poster sessions, and BCI demonstrations. Foundation support contingent on the success of this proposal will fund students and fellows. Proceedings will be published as a dedicated issue of IEEE Trans Neur. Syst. Rehab. Eng. By bringing together essentially all active BCI research groups, by focusing on the most important

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issues, by involving students and fellows, and by producing a comprehensive state-ofthe-art set of papers, this Third International BCI Meeting should greatly encourage and facilitate continued BCI research and development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TROPHIC FACTOR SIGNALING AND MOTOR NEURON DEATH Principal Investigator & Institution: Kalb, Robert G.; Associate Professor; Children's Hospital of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318 Timing: Fiscal Year 2006; Project Start 15-FEB-2006; Project End 31-JAN-2011 Summary: (provided by applicant): The central pathologic event in Amyotrophic Lateral Sclerosis (ALS) is the selective degeneration of motor neurons. While most cases (-90%) are sporadic, the familial cases are due to mutations in a variety of different genes such as SOD1 and p150glued. Excessive activation of glutamate receptors (excitotoxicity) is an early triggering event. The death of motor neurons from excitotoxic insult or mutant gene expression can be studied in cell culture using dissociated rodent embryonic spinal cord tissue. Our previous in vitro work demonstrates that excitotoxic motor neuron death only occurs if Brain-derived neuronotrophic factor (BDNF) signaling via TrkB is intact. The phosphatidylinositol 3' kinase (PI3'K) signaling cascade is activated by TrkB and PI3'K signaling is necessary and sufficient for BDNF-induced excitotoxic death of motor neuron. Pharmacological manipulations that inhibit Trk activation can also protect motor neurons from the toxic effects of mutant SOD1 and p150glued. This can be accomplished using proprietary derivatives of K252a (made by Cephalon Pharmaceuticals) or by inhibiting the activation of adenosine A2A receptors. In specific aim #1 we will examine the alterations in intracellular signaling cascades that follow from administration of these agents. The potential interplay between mutant SOD1 and p150glued and Trk signaling events will also be studied. In specific aim #2, we will study the in vivo pharmacodynamics of these agents on Trk activation and signaling. This is a prelude to future studies in which we hope to examine the efficacy of these agents in animal models of ALS. In specific aim #3 we will study the signaling cascades downstream of activated PIS'K (two serine-theonine kinases (PDK1, Akt) and small monomeric GTP'ases of the RhoA and Arf families) to see which is needed to evoke excitotoxic sensitivity of motor neurons. This will define susceptibility-to-toxicity intracellular signaling pathways in motor neurons. Relevance: The proposed work attempts to translate basic science observations into new treatments for ALS. The development of new drug targets for ALS could guide the way for novel therapies for other, more prevalent, neuro-degenerative disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: UNDERSTANDING MECHANISM AND THERAPY OF ALS USING RNAI Principal Investigator & Institution: Xu, Zuoshang; Associate Professor; Biochemistry and Molecular Pharmacology; Univ of Massachusetts Med Sch Worcester 55 Lake Avenue North Worcester, Ma 01655 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Diseases caused by dominant, gain-of-function mutations develop in people bearing one mutant and one wild-type copy of the gene. Some of the best known examples of this class are neurodegenerative diseases, including Huntington's, a subset of amyotrophic lateral sclerosis (ALS), Alzheimer's and Parkinson's diseases. In all these diseases, the exact pathways whereby the mutant

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proteins cause cell degeneration are not entirely clear, but the origin of the cellular toxicity is known to be the mutant protein. Thus, selectively lowering or eliminating the mutant protein is a key step in developing effective therapies. Until recently, it was not clear how specific down-regulation of a wide variety of mutant proteins could be achieved. But now, new advances in RNA interference (RNAi) raise the possibility that RNAi can be developed and eventually applied as a therapeutic means for these neurodegenerative diseases. RNAi can mediate sequence-selective suppression of gene expression in a wide variety of eukaryotes by introducing short RNA duplexes (called small interfering RNAs or siRNAs) with sequence homologies to the target gene. Recent experiments indicate that small hairpin RNAs (shRNAs) transcribed in vivo can trigger degradation of corresponding mRNAs similar to siRNA. These developments raise the possibility that siRNA duplexes or vectors expressing shRNAs may be used to block the expression of a toxic mutant gene. This proposal investigates in vivo efficacy of RNAi therapy using transgenic technology in a mouse model for ALS that is caused by mutations in Cu, Zn superoxide dismutase (SOD1). To determine the potential of RNAi therapy, we will express shRNAs targeting specifically the mutant mRNAs in transgenic mice. We will test how effective and how specific these shRNAs are in suppressing the mutant protein expression and alleviating the disease. To determine in which cell types the suppression of the mutant expression is most crucial, we will express shRNAs in selected cell types using Cre-lox recombination system, We will determine in which cell type suppression of mutant SOD1 expression has the largest impact in alleviating disease. To determine the optimal time for therapy, we will use the Tamoxifeninducible Cre recombinant system to determine at what stage of the disease induction of shRNA to suppress mutant SOD1expresion is most effective. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen 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 amyotrophic lateral sclerosis: •

"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 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

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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. •

"Health Hazard Evaluation Report: University of Kentucky College of Pharmacy, Lexington, Kentucky," published in November 2000. Sponsored by: National Inst. for Occupational Safety and Health, Cincinnati, OH. Written by: C. K. Cook, H. Daftarian and V. Mortimer. Abstract: In June 1999, the National Institute for Occupational Safety and Health (NIOSH) received a request from management at the University of Kentucky Medical Center to conduct a health hazard evaluation (HHE) at the College of Pharmacy building. The request stated that two College of Pharmacy faculty personnel had been diagnosed with chronic neurological conditions (multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS)), and that there were concerns that the development of these conditions may be work-related. Since the building was first occupied in 1985, faculty personnel often reported smelling chemical odors from research labs on the 4th floor. NIOSH investigators reviewed the facility's Chemical Hygiene Plan, chemical inventory lists, ventilation blueprints, and floor plans. A tracer gas evaluation of the building's ventilation system was conducted to evaluate potential pollutant pathways and airflow patterns on the 4th floor. The tracer gas study demonstrated how chemical odors generated in labs can enter each floor's common return-air plenum, then disperse to other areas in the building, and how air contaminants released from fume hood exhaust stacks and a plumbing vent could reenter the building's ventilation system. Some research labs were under positive pressure, which may allow chemical odors to disperse to areas outside the lab.

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"New trace element determinations in the fingernails of ALS patients," published in 1996. Sponsored by: Oak Ridge National Lab., TN.; Department of Energy, Washington, DC. Written by: D. J. Van Dalsem, L. Robinson and W. D. Ehmann. Abstract: ORNL's High Flux Isotope Reactor was used in a neutron activation analysis experiment to determine selected elemental composition of fingernails from patients afflicted with Amyotrophic lateral sclerosis (ALS). While no statistical difference were found in aluminium, a significant difference was observed for copper concentrations.

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"Public Health Assessment for Petitioned Public Health Assessment Great Lakes Chemical Corporation, El Dorado, Union County, Arkansas, Region 6. CERCLIS No. ARD043195429. - Final rept," published in June 2000. Abstract: The Great Lakes Chemical Company (GLCC) manufactures elemental bromine and brominated compounds from salt brines extracted from deep wells. Community members are concerned that emissions from Great Lakes Chemical Company are causing an increased incidence of motor neuron disease (in particular, Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease). Environmental sampling data before 1987 are not available to evaluate the potential health impact of Great Lakes Chemical Company emissions. However, a review of available environmental sampling data show that the on-site soil and groundwater are contaminated with brominated compounds. Human exposure to these media is limited because public access to the site is restricted and on-site groundwater is not being used for drinking water. No chemical contaminants detected in the nearest residence at levels of health concern. A review of blood samples showed no evidence of a correlation between blood bromide levels of nearby residents and adverse health effects. ATSDR also found no association between

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environmental contamination from any source (including GLCC) and motor neuron disease mortality in El Dorado, Arkansas. The Agency for Toxic Substances and Disease Registry has classified this site as No Apparent Public Health Hazard based on the levels of contaminants found around Great Lakes Chemical Company.

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

A case of amyotrophic lateral sclerosis and breast cancer. Author(s): Kijima Y, Yoshinaka H, Higuchi I, Owaki T, Aikou T. Source: Breast Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15657525&query_hl=10&itool=pubmed_docsum

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Advances in clinical trials for amyotrophic lateral sclerosis. Author(s): Gordon PH. Source: Curr Neurol Neurosci Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15676108&query_hl=10&itool=pubmed_docsum

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AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Author(s): Kim K, Moore DH, Makriyannis A, Abood ME. Source: European Journal of Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16781706&query_hl=10&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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Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. Author(s): Lai C, Xie C, McCormack SG, Chiang HC, Michalak MK, Lin X, Chandran J, Shim H, Shimoji M, Cookson MR, Huganir RL, Rothstein JD, Price DL, Wong PC, Martin LJ, Zhu JJ, Cai H. 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=17093100&query_hl=10&itool=pubmed_docsum

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Amyotrophic lateral sclerosis and gene therapy. Author(s): Miller TM, Smith RA, Cleveland DW. Source: Nat Clin Pract Neurol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16932606&query_hl=10&itool=pubmed_docsum

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Amyotrophic lateral sclerosis and sports: a case-control study. Author(s): Valenti M, Pontieri FE, Conti F, Altobelli E, Manzoni T, Frati L. 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=15693813&query_hl=10&itool=pubmed_docsum

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Amyotrophic lateral sclerosis mutations have the greatest destabilizing effect on the apo- and reduced form of SOD1, leading to unfolding and oxidative aggregation. Author(s): Furukawa Y, O'Halloran TV. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15691826&query_hl=10&itool=pubmed_docsum

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Amyotrophic lateral sclerosis: contemporary concepts in etiopathogenesis and pharmacotherapy. Author(s): Strong MJ. Source: Expert Opinion on Investigational Drugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15566317&query_hl=10&itool=pubmed_docsum

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Amyotrophic lateral sclerosis: possible role of environmental influences. Author(s): Wicklund MP. Source: Neurologic Clinics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15757793&query_hl=10&itool=pubmed_docsum

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An RNAi strategy for treatment of amyotrophic lateral sclerosis caused by mutant Cu,Zn superoxide dismutase. Author(s): Xia XG, Zhou H, Zhou S, Yu Y, Wu R, Xu Z. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15663483&query_hl=10&itool=pubmed_docsum

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Analysis of factors that modify susceptibility and rate of progression in amyotrophic lateral sclerosis (ALS). Author(s): Qureshi MM, Hayden D, Urbinelli L, Ferrante K, Newhall K, Myers D, Hilgenberg S, Smart R, Brown RH, Cudkowicz ME. Source: Amyotroph Lateral Scler. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16963407&query_hl=10&itool=pubmed_docsum

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Another angiogenic gene linked to amyotrophic lateral sclerosis. Author(s): Lambrechts D, Lafuste P, Carmeliet P, Conway EM. Source: Trends in Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16843725&query_hl=10&itool=pubmed_docsum

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Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease. Author(s): Orrell RW, Lane RJ, Ross M. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15674899&query_hl=10&itool=pubmed_docsum

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Apolipoprotein E is associated with age at onset of amyotrophic lateral sclerosis. Author(s): Li YJ, Pericak-Vance MA, Haines JL, Siddique N, McKenna-Yasek D, Hung WY, Sapp P, Allen CI, Chen W, Hosler B, Saunders AM, Dellefave LM, Brown RH, Siddique T. Source: Neurogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15657798&query_hl=10&itool=pubmed_docsum

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Are there causal relationships between the development of the inflammatory diseases amyotrophic lateral sclerosis and asthma? Author(s): Menendez A, Kuffler D. Source: P R Health Sci J. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16883679&query_hl=10&itool=pubmed_docsum

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Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis. Author(s): van Kan HJ, Groeneveld GJ, Kalmijn S, Spieksma M, van den Berg LH, Guchelaar HJ. Source: British Journal of Clinical Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15752377&query_hl=10&itool=pubmed_docsum

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Attitudes toward and desire for assisted suicide among persons with amyotrophic lateral sclerosis. Author(s): Achille MA, Ogloff JR. Source: Omega. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15688543&query_hl=10&itool=pubmed_docsum

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Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis. Author(s): Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Boccaletti R, Testa L, Livigni S, Fagioli F. Source: Neurological Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16808883&query_hl=10&itool=pubmed_docsum

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Baroreflex stimulation shows impaired cardiovagal and preserved vasomotor function in early-stage amyotrophic lateral sclerosis. Author(s): Hilz MJ, Hecht MJ, Mittelhamm F, Neundorfer B, Brown CM. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12495575&query_hl=10&itool=pubmed_docsum

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Basic and clinical research on amyotrophic lateral sclerosis and other motor neuron disorders in Italy: recent findings and achievements from a network of laboratories. Author(s): Beghi E, Mennini T; Italian Network for the Study of Motor Neuron Disease. 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=15197603&query_hl=10&itool=pubmed_docsum

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Basic fibroblast growth factor does not prolong survival in a transgenic model of familial amyotrophic lateral sclerosis. Author(s): Upton-Rice MN, Cudkowicz ME, Warren L, Mathew RK, Ren JM, Finklestein SP, Brown RH Jr. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10589551&query_hl=10&itool=pubmed_docsum

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Basophilic cytoplasmic inclusions in a case of sporadic juvenile amyotrophic lateral sclerosis. Author(s): Aizawa H, Kimura T, Hashimoto K, Yahara O, Okamoto K, Kikuchi K. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10930592&query_hl=10&itool=pubmed_docsum

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Behavioural and anatomical effects of systemically administered leukemia inhibitory factor in the SOD1(G93A G1H) mouse model of familial amyotrophic lateral sclerosis. Author(s): Azari MF, Lopes EC, Stubna C, Turner BJ, Zang D, Nicola NA, Kurek JB, Cheema SS. Source: Brain Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12915243&query_hl=10&itool=pubmed_docsum

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Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis. Author(s): Nagano I, Shiote M, Murakami T, Kamada H, Hamakawa Y, Matsubara E, Yokoyama M, Moritaz K, Shoji M, Abe K. Source: Neurological Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16197815&query_hl=10&itool=pubmed_docsum

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Beta-amyloid 42 accumulation in the lumbar spinal cord motor neurons of amyotrophic lateral sclerosis patients. Author(s): Calingasan NY, Chen J, Kiaei M, Beal MF. Source: Neurobiology of Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15837590&query_hl=10&itool=pubmed_docsum

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Bilirubin and amyotrophic lateral sclerosis. Author(s): Iwasaki Y, Igarashi O, Iwasa Y, Hirano K, Satoh R, Iwamoto K, Kawase Y, Aoyagi J, Ichikawa Y, Kawabe K, Ikeda K. Source: Clinical Neurology and Neurosurgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15708236&query_hl=10&itool=pubmed_docsum

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Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Author(s): Di Matteo V, Esposito E. Source: Curr Drug Targets Cns Neurol Disord. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12769802&query_hl=10&itool=pubmed_docsum

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Biochemical and ultrastructural study of neurofibrillary tangles in amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula of Japan. Author(s): Itoh N, Ishiguro K, Arai H, Kokubo Y, Sasaki R, Narita Y, Kuzuhara S. 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=12901704&query_hl=10&itool=pubmed_docsum

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Biochemical characterization of plasma in amyotrophic lateral sclerosis: amino acid and protein composition. Author(s): Palma A, de Carvalho M, Barata N, Evangelista T, Chicau P, Regalla M, Costa J. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16036434&query_hl=10&itool=pubmed_docsum

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Amyotrophic Lateral Sclerosis

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Biomarkers for amyotrophic lateral sclerosis. Author(s): Bowser R, Cudkowicz M, Kaddurah-Daouk R. Source: Expert Review of Molecular Diagnostics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16706741&query_hl=10&itool=pubmed_docsum

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Biotransformation of nitric oxide in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Author(s): Kokic AN, Stevic Z, Stojanovic S, Blagojevic DP, Jones DR, Pavlovic S, Niketic V, Apostolski S, Spasic MB. Source: Redox Report : Communications in Free Radical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16354415&query_hl=10&itool=pubmed_docsum

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Blood oxidative stress in amyotrophic lateral sclerosis. Author(s): Bonnefont-Rousselot D, Lacomblez L, Jaudon M, Lepage S, Salachas F, Bensimon G, Bizard C, Doppler V, Delattre J, Meininger V. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11018250&query_hl=10&itool=pubmed_docsum

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Blood transfusion in motor neurone disease (amyotrophic lateral sclerosis) Author(s): Burnett IB. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10399875&query_hl=10&itool=pubmed_docsum

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Botulinum toxin improves sialorrhea and quality of living in bulbar amyotrophic lateral sclerosis. Author(s): Verma A, Steele J. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16583370&query_hl=10&itool=pubmed_docsum

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Brain-derived neurotrophic factor is not altered in the serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients. Author(s): Ilzecka J, Stelmasiak Z. 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=11976981&query_hl=10&itool=pubmed_docsum

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Breaking the news in amyotrophic lateral sclerosis. Author(s): Chio A, Borasio GD. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15799546&query_hl=10&itool=pubmed_docsum

Studies

85

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Bulbar-onset amyotrophic lateral sclerosis in a patient with Chiari I malformation. Author(s): Lo Coco D, Militello A, Piccoli F, La Bella V. Source: Acta Neurologica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11589655&query_hl=10&itool=pubmed_docsum

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Calcium signaling pathways mediating synaptic potentiation triggered by amyotrophic lateral sclerosis IgG in motor nerve terminals. Author(s): Pagani MR, Reisin RC, Uchitel OD. 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=16525045&query_hl=10&itool=pubmed_docsum

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Calorimetric analysis of thermodynamic stability and aggregation for apo and holo amyotrophic lateral sclerosis-associated Gly-93 mutants of superoxide dismutase. Author(s): Stathopulos PB, Rumfeldt JA, Karbassi F, Siddall CA, Lepock JR, Meiering EM. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16407238&query_hl=10&itool=pubmed_docsum

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Can selection of rapidly progressing patients shorten clinical trials in amyotrophic lateral sclerosis? Author(s): de Carvalho M, Swash M. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16606769&query_hl=10&itool=pubmed_docsum

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Cerebral degeneration predicts survival in amyotrophic lateral sclerosis. Author(s): Kalra S, Vitale A, Cashman NR, Genge A, Arnold DL. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16835288&query_hl=10&itool=pubmed_docsum

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Changes in motor cortex excitability during muscle fatigue in amyotrophic lateral sclerosis. Author(s): Nardone R, Buffone E, Florio I, Tezzon F. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15716542&query_hl=10&itool=pubmed_docsum

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Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicleassociated membrane protein-associated protein B (VAPB/ALS8). Author(s): Kanekura K, Nishimoto I, Aiso S, Matsuoka M. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16891305&query_hl=10&itool=pubmed_docsum

86

Amyotrophic Lateral Sclerosis

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Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Author(s): Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R, Julien JP. Source: Nature Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16369483&query_hl=10&itool=pubmed_docsum

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Chronological changes of sympathetic outflow to muscles in amyotrophic lateral sclerosis. Author(s): Shindo K, Shimokawa C, Watanabe H, Iida H, Ohashi K, Nitta K, Nagasaka T, Tsunoda S, Shiozawa Z. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15546595&query_hl=10&itool=pubmed_docsum

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Circulating antibodies to cysteinyl catecholamines in amyotrophic lateral sclerosis and Parkinson's disease patients. Author(s): Salauze L, van der Velden C, Lagroye I, Veyret B, Geffard M. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16319026&query_hl=10&itool=pubmed_docsum

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Classification of amyotrophic lateral sclerosis cases at presentation in epidemiological studies. Author(s): Zoccolella S, Beghi E, Serlenga L, Logroscino G. 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=16388367&query_hl=10&itool=pubmed_docsum

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Clinical trials in amyotrophic lateral sclerosis: the tenuous past and the promising future. Author(s): Choudry RB, Cudkowicz ME. Source: Journal of Clinical Pharmacology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16291708&query_hl=10&itool=pubmed_docsum

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Cognitive function in bulbar- and spinal-onset amyotrophic lateral sclerosis. A longitudinal study in 52 patients. Author(s): Schreiber H, Gaigalat T, Wiedemuth-Catrinescu U, Graf M, Uttner I, Muche R, Ludolph AC. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15742104&query_hl=10&itool=pubmed_docsum

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Cognitive functioning in sporadic amyotrophic lateral sclerosis: a six month longitudinal study. Author(s): Robinson KM, Lacey SC, Grugan P, Glosser G, Grossman M, McCluskey LF. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16614030&query_hl=10&itool=pubmed_docsum

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Commentary on: Return of the cycad hypothesis--does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health? Author(s): Wilson J, Shaw CA. Source: Neuropathology and Applied Neurobiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16640652&query_hl=10&itool=pubmed_docsum

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Common dynamical signatures of familial amyotrophic lateral sclerosis-associated structurally diverse Cu, Zn superoxide dismutase mutants. Author(s): Khare SD, Dokholyan NV. 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=16488975&query_hl=10&itool=pubmed_docsum

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Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson's disease. Author(s): Goldknopf IL, Sheta EA, Bryson J, Folsom B, Wilson C, Duty J, Yen AA, Appel SH. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16516157&query_hl=10&itool=pubmed_docsum

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Complexity of astrocyte-motor neuron interactions in amyotrophic lateral sclerosis. Author(s): Pehar M, Vargas MR, Cassina P, Barbeito AG, Beckman JS, Barbeito L. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16909019&query_hl=10&itool=pubmed_docsum

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Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Author(s): Deng HX, Shi Y, Furukawa Y, Zhai H, Fu R, Liu E, Gorrie GH, Khan MS, Hung WY, Bigio EH, Lukas T, Dal Canto MC, O'Halloran TV, Siddique T. 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=16636275&query_hl=10&itool=pubmed_docsum

88

Amyotrophic Lateral Sclerosis

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COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. Author(s): Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P. Source: Bmc Neurology [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16512913&query_hl=10&itool=pubmed_docsum

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Decreased galectin-1 immunoreactivity of the skin in amyotrophic lateral sclerosis. Author(s): Wada M, Ono S, Kadoya T, Kawanami T, Kurita K, Kato T. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12639727&query_hl=10&itool=pubmed_docsum

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Decrement in surface-recorded motor unit potentials in amyotrophic lateral sclerosis. Author(s): Henderson RD, Daube JR. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15534253&query_hl=10&itool=pubmed_docsum

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Degradation of amyotrophic lateral sclerosis-linked mutant Cu,Zn-superoxide dismutase proteins by macroautophagy and the proteasome. Author(s): Kabuta T, Suzuki Y, Wada K. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16920710&query_hl=10&itool=pubmed_docsum

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Deletions causing spinal muscular atrophy do not predispose to amyotrophic lateral sclerosis. Author(s): Parboosingh JS, Meininger V, McKenna-Yasek D, Brown RH Jr, Rouleau GA. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10369311&query_hl=10&itool=pubmed_docsum

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Depression and bulbar involvement in amyotrophic lateral sclerosis. Author(s): Hillemacher T, Grassel E, Tigges S, Bleich S, Neundorfer B, Kornhuber J, Hecht MJ. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15799555&query_hl=10&itool=pubmed_docsum

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Descriptive epidemiology of amyotrophic lateral sclerosis in Japan, 1995-2001. Author(s): Okamoto K, Kobashi G, Washio M, Sasaki S, Yokoyama T, Miyake Y, Sakamoto N, Tanaka H, Inaba Y. Source: J Epidemiol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15678922&query_hl=10&itool=pubmed_docsum

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Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy. Author(s): Kalra S, Hanstock CC, Martin WR, Allen PS, Johnston WS. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16908742&query_hl=10&itool=pubmed_docsum

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Development and implementation of the Dutch protocol for rehabilitative management in amyotrophic lateral sclerosis. Author(s): van den Berg JP, de Groot IJ, Joha BC, van Haelst JM, van Gorcom P, Kalmijn S. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15799551&query_hl=10&itool=pubmed_docsum

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Development of a rat model of amyotrophic lateral sclerosis expressing a human SOD1 transgene. Author(s): Aoki M, Kato S, Nagai M, Itoyama Y. Source: Neuropathology : Official Journal of the Japanese Society of Neuropathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16382787&query_hl=10&itool=pubmed_docsum

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Different immunoreactivity against monoclonal antibodies between wild-type and mutant copper/zinc superoxide dismutase linked to amyotrophic lateral sclerosis. Author(s): Fujiwara N, Miyamoto Y, Ogasahara K, Takahashi M, Ikegami T, Takamiya R, Suzuki K, Taniguchi N. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15522870&query_hl=10&itool=pubmed_docsum

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Diffusion tensor imaging in amyotrophic lateral sclerosis: volumetric analysis of the corticospinal tract. Author(s): Wang S, Poptani H, Bilello M, Wu X, Woo JH, Elman LB, McCluskey LF, Krejza J, Melhem ER. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16775271&query_hl=10&itool=pubmed_docsum

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Diffusion tensor MRI as a diagnostic tool of upper motor neuron involvement in amyotrophic lateral sclerosis. Author(s): Hong YH, Lee KW, Sung JJ, Chang KH, Song IC. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15546594&query_hl=10&itool=pubmed_docsum

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Amyotrophic Lateral Sclerosis

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Diffusion-tensor MR imaging of corticospinal tract in amyotrophic lateral sclerosis and progressive muscular atrophy. Author(s): Cosottini M, Giannelli M, Siciliano G, Lazzarotti G, Michelassi MC, Del Corona A, Bartolozzi C, Murri L. Source: Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16183935&query_hl=10&itool=pubmed_docsum

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Dissociated small hand muscle involvement in amyotrophic lateral sclerosis detected by motor unit number estimates. Author(s): Kuwabara S, Mizobuchi K, Ogawara K, Hattori T. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10398204&query_hl=10&itool=pubmed_docsum

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Distal excitability changes in motor axons in amyotrophic lateral sclerosis. Author(s): Nakata M, Kuwabara S, Kanai K, Misawa S, Tamura N, Sawai S, Hattori T, Bostock H. 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=16765084&query_hl=10&itool=pubmed_docsum

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Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models. Author(s): Jonsson PA, Graffmo KS, Andersen PM, Brannstrom T, Lindberg M, Oliveberg M, Marklund SL. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16330499&query_hl=10&itool=pubmed_docsum

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Does apoptosis occur in amyotrophic lateral sclerosis? TUNEL experience from human amyotrophic lateral sclerosis (ALS) tissues. Author(s): Tomik B, Adamek D, Pierzchalski P, Banares S, Duda A, Partyka D, Pawlik W, Kaluza J, Krajewski S, Szczudlik A. Source: Folia Neuropathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16012908&query_hl=10&itool=pubmed_docsum

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Does VEGF represent a potential treatment for amyotrophic lateral sclerosis? Author(s): Ilzecka J. Source: Curr Opin Investig Drugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16425672&query_hl=10&itool=pubmed_docsum

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Dopamine transporter immunoreactivity in peripheral blood mononuclear cells in amyotrophic lateral sclerosis. Author(s): Buttarelli FR, Circella A, Pellicano C, Pontieri FE. 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=16643322&query_hl=10&itool=pubmed_docsum

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Dysregulation of stathmin, a microtubule-destabilizing protein, and up-regulation of Hsp25, Hsp27, and the antioxidant peroxiredoxin 6 in a mouse model of familial amyotrophic lateral sclerosis. Author(s): Strey CW, Spellman D, Stieber A, Gonatas JO, Wang X, Lambris JD, Gonatas NK. Source: American Journal of Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15509539&query_hl=10&itool=pubmed_docsum

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Early abnormalities in transgenic mouse models of amyotrophic lateral sclerosis. Author(s): Durand J, Amendola J, Bories C, Lamotte d'Incamps B. Source: Journal of Physiology, Paris. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16448809&query_hl=10&itool=pubmed_docsum

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Early or late appearance of "dropped head syndrome" in amyotrophic lateral sclerosis. Author(s): Gourie-Devi M, Nalini A, Sandhya S. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12700323&query_hl=10&itool=pubmed_docsum

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Effect of ubiquitin expression on neuropathogenesis in a mouse model of familial amyotrophic lateral sclerosis. Author(s): Gilchrist CA, Gray DA, Stieber A, Gonatas NK, Kopito RR. Source: Neuropathology and Applied Neurobiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15634228&query_hl=10&itool=pubmed_docsum

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Effects of lumbar sympathetic ganglion block for a patient with amyotrophic lateral sclerosis (ALS). Author(s): Kitoh T, Kobayashi K, Ina H, Ofusa Y, Otagiri T, Tanaka S, Ono K. Source: Journal of Anesthesia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16633768&query_hl=10&itool=pubmed_docsum

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Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Author(s): Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Source: Lancet. Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16426990&query_hl=10&itool=pubmed_docsum

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EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives. Author(s): Andersen PM, Borasio GD, Dengler R, Hardiman O, Kollewe K, Leigh PN, Pradat PF, Silani V, Tomik B; EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis. 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=16324086&query_hl=10&itool=pubmed_docsum

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Electromechanical coupling and synchronous firing of single wrist extensor motor units in sporadic amyotrophic lateral sclerosis. Author(s): Schmied A, Pouget J, Vedel JP. 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=10400212&query_hl=10&itool=pubmed_docsum

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Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease. Author(s): Koistinen H, Prinjha R, Soden P, Harper A, Banner SJ, Pradat PF, Loeffler JP, Dingwall C. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16856153&query_hl=10&itool=pubmed_docsum

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Emotional responding in amyotrophic lateral sclerosis. Author(s): Lule D, Kurt A, Jurgens R, Kassubek J, Diekmann V, Kraft E, Neumann N, Ludolph AC, Birbaumer N, Anders S. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15977000&query_hl=10&itool=pubmed_docsum

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Estimating the occurrence of amyotrophic lateral sclerosis among Gulf War (19901991) veterans using capture-recapture methods. Author(s): Coffman CJ, Horner RD, Grambow SC, Lindquist J; VA Cooperative Studies Program Project #500. Source: Neuroepidemiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15650320&query_hl=10&itool=pubmed_docsum

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Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). Author(s): Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Hadlock K, Jin X, Reis J, Narvaez A, McGrath MS. Source: Journal of Neuroimmunology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15652422&query_hl=10&itool=pubmed_docsum

Studies

93

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Evidence-based care in amyotrophic lateral sclerosis. Author(s): Piepers S, van den Berg LH. Source: Lancet. Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16426982&query_hl=10&itool=pubmed_docsum

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Excitotoxicity and amyotrophic lateral sclerosis. Author(s): Van Damme P, Dewil M, Robberecht W, Van Den Bosch L. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16909020&query_hl=10&itool=pubmed_docsum

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Experimental therapies hold promise for treating amyotrophic lateral sclerosis. Author(s): Friedrich MJ. 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=15741517&query_hl=10&itool=pubmed_docsum

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Expression of a familial amyotrophic lateral sclerosis-associated mutant human superoxide dismutase in yeast leads to decreased mitochondrial electron transport. Author(s): Gunther MR, Vangilder R, Fang J, Beattie DS. Source: Archives of Biochemistry and Biophysics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15488469&query_hl=10&itool=pubmed_docsum

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Expression of leukaemia inhibitory factor in skin of patients with amyotrophic lateral sclerosis. Author(s): Hu J, Imai T, Shimizu N, Nakagawa H, Ono S. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10382701&query_hl=10&itool=pubmed_docsum

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Expression of N19S-SOD1, an SOD1 mutant found in sporadic amyotrophic lateral sclerosis patients, induces low-grade motoneuronal toxicity. Author(s): Obata Y, Niikura T, Kanekura K, Hashimoto Y, Kawasumi M, Kita Y, Aiso S, Matsuoka M, Nishimoto I. Source: Journal of Neuroscience Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16035108&query_hl=10&itool=pubmed_docsum

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Expression of ubiquitin and proteasome in motorneurons and astrocytes of spinal cords from patients with amyotrophic lateral sclerosis. Author(s): Mendonca DM, Chimelli L, Martinez AM. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16806703&query_hl=10&itool=pubmed_docsum

94

Amyotrophic Lateral Sclerosis

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Expression of vascular endothelial growth factor and its receptors in the central nervous system in amyotrophic lateral sclerosis. Author(s): Brockington A, Wharton SB, Fernando M, Gelsthorpe CH, Baxter L, Ince PG, Lewis CE, Shaw PJ. 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=16410746&query_hl=10&itool=pubmed_docsum

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Extensive exercise is not harmful in amyotrophic lateral sclerosis. Author(s): Liebetanz D, Hagemann K, von Lewinski F, Kahler E, Paulus W. Source: The European Journal of Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15579165&query_hl=10&itool=pubmed_docsum

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F wave study in amyotrophic lateral sclerosis: assessment of balance between upper and lower motor neuron involvement. Author(s): Argyriou AA, Polychronopoulos P, Talelli P, Chroni E. 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=16678483&query_hl=10&itool=pubmed_docsum

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Factors which predict physical and mental health status in patients with amyotrophic lateral sclerosis over time. Author(s): Norquist JM, Jenkinson C, Fitzpatrick R, Swash M; ALS-HPS Steering Group. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14506943&query_hl=10&itool=pubmed_docsum

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Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex-tauopathy without mutations in the tau gene? Author(s): Kowalska A, Konagaya M, Sakai M, Hashizume Y, Tabira T. Source: Folia Neuropathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12899197&query_hl=10&itool=pubmed_docsum

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Familial amyotrophic lateral sclerosis mutants of copper/zinc superoxide dismutase are susceptible to disulfide reduction. Author(s): Tiwari A, Hayward LJ. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12458194&query_hl=10&itool=pubmed_docsum

Studies

95

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Familial amyotrophic lateral sclerosis with a point mutation (G37R) of the superoxide dismutase 1 gene: a clinicopathological study. Author(s): Inoue K, Fujimura H, Ogawa Y, Satoh T, Shimada K, Sakoda S. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12710516&query_hl=10&itool=pubmed_docsum

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Familial amyotrophic lateral sclerosis with bulbar onset and a novel Asp101Tyr Cu/Zn superoxide dismutase gene mutation. Author(s): Tan CF, Piao YS, Hayashi S, Obata H, Umeda Y, Sato M, Fukushima T, Nakano R, Tsuji S, Takahashi H. Source: Acta Neuropathologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15235802&query_hl=10&itool=pubmed_docsum

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Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Author(s): Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T, Schelhaas HJ, Kusters B, Troost D, Baas F, de Jong V, Shaw CE. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16495328&query_hl=10&itool=pubmed_docsum

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Familial amyotrophic lateral sclerosis with His46Arg mutation in Cu/Zn superoxide dismutase presenting characteristic clinical features and Lewy body-like hyaline inclusions. Author(s): Ohi T, Nabeshima K, Kato S, Yazawa S, Takechi S. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15465081&query_hl=10&itool=pubmed_docsum

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Familial amyotrophic lateral sclerosis: first report from India. Author(s): Nalini A, Yeshraj G, Veerendrakumar M. Source: Neurology India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16936397&query_hl=10&itool=pubmed_docsum

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Flail arm syndrome: a clinical variant of amyotrophic lateral sclerosis. Author(s): Czaplinski A, Steck AJ, Andersen PM, Weber M. 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=15272904&query_hl=10&itool=pubmed_docsum

96

Amyotrophic Lateral Sclerosis

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Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis. Author(s): Tomiyama M, Rodriguez-Puertas R, Cortes R, Pazos A, Palacios JM, Mengod G. Source: Synapse (New York, N.Y.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12125045&query_hl=10&itool=pubmed_docsum

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Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis. Author(s): Kabashi E, Agar JN, Taylor DM, Minotti S, Durham HD. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15189335&query_hl=10&itool=pubmed_docsum

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Folding of Cu, Zn superoxide dismutase and familial amyotrophic lateral sclerosis. Author(s): Khare SD, Ding F, Dokholyan NV. Source: Journal of Molecular Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14623191&query_hl=10&itool=pubmed_docsum

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Free insulin-like growth factor (IGF)-I and IGF binding proteins 2, 5, and 6 in spinal motor neurons in amyotrophic lateral sclerosis. Author(s): Wilczak N, de Vos RA, De Keyser J. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12660059&query_hl=10&itool=pubmed_docsum

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Frequency of a tau genotype in amyotrophic lateral sclerosis. Author(s): Munch C, Prechter F, Xu R, Linke P, Prudlo J, Kuzma M, Kwiecinski H, Ludolph AC, Meyer T. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16005901&query_hl=10&itool=pubmed_docsum

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Frequency, timing and outcome of gastrostomy tubes for amyotrophic lateral sclerosis/motor neurone disease--a record linkage study from the Scottish Motor Neurone Disease Register. Author(s): Forbes RB, Colville S, Swingler RJ; Scottish Motor Neurone Disease Research Group. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15258782&query_hl=10&itool=pubmed_docsum

Studies

97

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Frontotemporal white matter changes in amyotrophic lateral sclerosis. Author(s): Abrahams S, Goldstein LH, Suckling J, Ng V, Simmons A, Chitnis X, Atkins L, Williams SC, Leigh PN. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15739047&query_hl=10&itool=pubmed_docsum

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Functional motor compensation in amyotrophic lateral sclerosis. Author(s): Schoenfeld MA, Tempelmann C, Gaul C, Kuhnel GR, Duzel E, Hopf JM, Feistner H, Zierz S, Heinze HJ, Vielhaber S. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15750701&query_hl=10&itool=pubmed_docsum

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F-Waves and the corticospinal lesion in amyotrophic lateral sclerosis. Author(s): de Carvalho M, Scotto M, Lopes A, Swash M. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12495574&query_hl=10&itool=pubmed_docsum

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Gabapentin for the treatment of spasticity in patients with amyotrophic lateral sclerosis. Author(s): de Carvalho M. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11465933&query_hl=10&itool=pubmed_docsum

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Gabapentin therapy for amyotrophic lateral sclerosis: lack of improvement in neuronal integrity shown by MR spectroscopy. Author(s): Kalra S, Cashman NR, Caramanos Z, Genge A, Arnold DL. Source: Ajnr. American Journal of Neuroradiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12637300&query_hl=10&itool=pubmed_docsum

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Galectin-1 as a potential therapeutic agent for amyotrophic lateral sclerosis. Author(s): Kato T, Ren CH, Wada M, Kawanami T. Source: Current Drug Targets. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16026259&query_hl=10&itool=pubmed_docsum

98

Amyotrophic Lateral Sclerosis

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Galectin-1 is a component of neurofilamentous lesions in sporadic and familial amyotrophic lateral sclerosis. Author(s): Kato T, Kurita K, Seino T, Kadoya T, Horie H, Wada M, Kawanami T, Daimon M, Hirano A. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11263987&query_hl=10&itool=pubmed_docsum

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Gastrointestinal dysfunction in amyotrophic lateral sclerosis. Author(s): Toepfer M, Folwaczny C, Klauser A, Riepl RL, Muller-Felber W, Pongratz D. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12365061&query_hl=10&itool=pubmed_docsum

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Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis. Author(s): Jiang YM, Yamamoto M, Kobayashi Y, Yoshihara T, Liang Y, Terao S, Takeuchi H, Ishigaki S, Katsuno M, Adachi H, Niwa J, Tanaka F, Doyu M, Yoshida M, Hashizume Y, Sobue G. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15668976&query_hl=10&itool=pubmed_docsum

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Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases. Author(s): Alisky JM, Davidson BL. Source: Human Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11096437&query_hl=10&itool=pubmed_docsum

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Genetic aspects of amyotrophic lateral sclerosis. Author(s): Siddique T, Lalani I. Source: Adv Neurol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11908227&query_hl=10&itool=pubmed_docsum

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Genetic epidemiology of amyotrophic lateral sclerosis. Author(s): Majoor-Krakauer D, Willems PJ, Hofman A. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12630951&query_hl=10&itool=pubmed_docsum

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Genetics of amyotrophic lateral sclerosis. Author(s): Robberecht W. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11200702&query_hl=10&itool=pubmed_docsum

Studies

99

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Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis. Author(s): Panas M, Karadima G, Kalfakis N, Psarrou O, Floroskoufi P, Kladi A, Petersen MB, Vassilopoulos D. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11200686&query_hl=10&itool=pubmed_docsum

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Geographical distribution of amyotrophic lateral sclerosis with neurofibrillary tangles in the Kii Peninsula of Japan. Author(s): Kokubo Y, Kuzuhara S, Narita Y. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11151416&query_hl=10&itool=pubmed_docsum

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Glial cell line-derived neurotrophic factor protein prevents motor neuron loss of transgenic model mice for amyotrophic lateral sclerosis. Author(s): Manabe Y, Nagano I, Gazi MS, Murakami T, Shiote M, Shoji M, Kitagawa H, Abe K. Source: Neurological Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12635522&query_hl=10&itool=pubmed_docsum

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Glial cells of the spinal cord and subcortical white matter up-regulate neuronal nitric oxide synthase in sporadic amyotrophic lateral sclerosis. Author(s): Anneser JM, Cookson MR, Ince PG, Shaw PJ, Borasio GD. Source: Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11573993&query_hl=10&itool=pubmed_docsum

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Glial proliferation and metabotropic glutamate receptor expression in amyotrophic lateral sclerosis. Author(s): Anneser JM, Chahli C, Ince PG, Borasio GD, Shaw PJ. 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=15330338&query_hl=10&itool=pubmed_docsum

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Global loss of Na,K-ATPase and its nitric oxide-mediated regulation in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Ellis DZ, Rabe J, Sweadner KJ. 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=12514200&query_hl=10&itool=pubmed_docsum

100

Amyotrophic Lateral Sclerosis

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Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. Author(s): Spreux-Varoquaux O, Bensimon G, Lacomblez L, Salachas F, Pradat PF, Le Forestier N, Marouan A, Dib M, Meininger V. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11790386&query_hl=10&itool=pubmed_docsum

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Glutamate release induced by activation of glycine and GABA transporters in spinal cord is enhanced in a mouse model of amyotrophic lateral sclerosis. Author(s): Raiteri L, Zappettini S, Stigliani S, Paluzzi S, Raiteri M, Bonanno G. Source: Neurotoxicology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15885796&query_hl=10&itool=pubmed_docsum

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Glycation proceeds faster in mutated Cu, Zn-superoxide dismutases related to familial amyotrophic lateral sclerosis. Author(s): Takamiya R, Takahashi M, Myint T, Park YS, Miyazawa N, Endo T, Fujiwara N, Sakiyama H, Misonou Y, Miyamoto Y, Fujii J, Taniguchi N. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12626432&query_hl=10&itool=pubmed_docsum

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Golgi apparatus of the motor neurons in patients with amyotrophic lateral sclerosis and in mice models of amyotrophic lateral sclerosis. Author(s): Fujita Y, Okamoto K. Source: Neuropathology : Official Journal of the Japanese Society of Neuropathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16382790&query_hl=10&itool=pubmed_docsum

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Health-related quality of life in amyotrophic lateral sclerosis: determining a meaningful deterioration. Author(s): Norquist JM, Fitzpatrick R, Jenkinson C. Source: Quality of Life Research : an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15503836&query_hl=10&itool=pubmed_docsum

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Heterogeneous distribution of amyotrophic lateral sclerosis patients with SOD-1 gene mutations: preliminary data on an Italian survey. Author(s): Malaspina A, Zaman R, Mazzini L, Camana C, Poloni E, Curti D, Ceroni M. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10202988&query_hl=10&itool=pubmed_docsum

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101

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Hexosaminidase A deficiency is an uncommon cause of a syndrome mimicking amyotrophic lateral sclerosis. Author(s): Drory VE, Birnbaum M, Peleg L, Goldman B, Korczyn AD. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12811781&query_hl=10&itool=pubmed_docsum

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High frequency of systemic mycoplasmal infections in Gulf War veterans and civilians with Amyotrophic Lateral Sclerosis (ALS). Author(s): Nicolson GL, Nasralla MY, Haier J, Pomfret J. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12383408&query_hl=10&itool=pubmed_docsum

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Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Author(s): Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD. Source: Neurobiology of Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11741389&query_hl=10&itool=pubmed_docsum

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Histological recovery of the hepatocytes is based on the redox system upregulation in the animal models of mutant superoxide dismutase (SOD)1-linked amyotrophic lateral sclerosis. Author(s): Kato M, Kato S, Abe Y, Nishino T, Ohama E, Aoki M, Itoyama Y. Source: Histology and Histopathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16598672&query_hl=10&itool=pubmed_docsum

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Hoarseness due to bilateral vocal cord paralysis as an initial manifestation of familial amyotrophic lateral sclerosis. Author(s): Fukae J, Kubo S, Hattori N, Komatsu K, Kato M, Aoki M, Mizuno Y. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16036438&query_hl=10&itool=pubmed_docsum

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Home mechanical ventilation in amyotrophic lateral sclerosis patients is not always a problem. Author(s): Servera E, Gomez-Merino E, Perez D, Marin J. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10713039&query_hl=10&itool=pubmed_docsum

102

Amyotrophic Lateral Sclerosis

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Homozygosity for Asn86Ser mutation in the CuZn-superoxide dismutase gene produces a severe clinical phenotype in a juvenile onset case of familial amyotrophic lateral sclerosis. Author(s): Hayward C, Brock DJ, Minns RA, Swingler RJ. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9556377&query_hl=10&itool=pubmed_docsum

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Hospitalization in amyotrophic lateral sclerosis: causes, costs, and outcomes. Author(s): Lechtzin N, Wiener CM, Clawson L, Chaudhry V, Diette GB. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11274310&query_hl=10&itool=pubmed_docsum

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How amyotrophic lateral sclerosis got its name: the clinical-pathologic genius of JeanMartin Charcot. Author(s): Rowland LP. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11255459&query_hl=10&itool=pubmed_docsum

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How beneficial is noninvasive ventilation in patients with amyotrophic lateral sclerosis? Author(s): Lechtzin N. Source: Nat Clin Pract Neurol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16932582&query_hl=10&itool=pubmed_docsum

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HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) with amyotrophic lateral sclerosis-like manifestations. Author(s): Matsuzaki T, Nakagawa M, Nagai M, Nobuhara Y, Usuku K, Higuchi I, Takahashi K, Moritoyo T, Arimura K, Izumo S, Akiba S, Osame M. Source: Journal of Neurovirology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11175327&query_hl=10&itool=pubmed_docsum

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Human CCS gene: genomic organization and exclusion as a candidate for amyotrophic lateral sclerosis (ALS). Author(s): Silahtaroglu AN, Brondum-Nielsen K, Gredal O, Werdelin L, Panas M, Petersen MB, Tommerup N, Tumer Z. Source: Bmc Genetics [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11991808&query_hl=10&itool=pubmed_docsum

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103

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Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Author(s): Jaarsma D, Haasdijk ED, Grashorn JA, Hawkins R, van Duijn W, Verspaget HW, London J, Holstege JC. Source: Neurobiology of Disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11114261&query_hl=10&itool=pubmed_docsum

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Human intrathecal transplantation of peripheral blood stem cells in amyotrophic lateral sclerosis. Author(s): Janson CG, Ramesh TM, During MJ, Leone P, Heywood J. Source: Journal of Hematotherapy & Stem Cell Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11798518&query_hl=10&itool=pubmed_docsum

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Human skeletal muscle atrophy in amyotrophic lateral sclerosis reveals a reduction in Akt and an increase in atrogin-1. Author(s): Leger B, Vergani L, Soraru G, Hespel P, Derave W, Gobelet C, D'Ascenzio C, Angelini C, Russell AP. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16507768&query_hl=10&itool=pubmed_docsum

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Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis). Author(s): Ende N, Weinstein F, Chen R, Ende M. Source: Life Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10896029&query_hl=10&itool=pubmed_docsum

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Humanin and colivelin: neuronal-death-suppressing peptides for Alzheimer's disease and amyotrophic lateral sclerosis. Author(s): Matsuoka M, Hashimoto Y, Aiso S, Nishimoto I. Source: Cns Drug Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16958985&query_hl=10&itool=pubmed_docsum

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Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. Author(s): Turner BJ, Atkin JD, Farg MA, Zang DW, Rembach A, Lopes EC, Patch JD, Hill AF, Cheema SS. 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=15634772&query_hl=10&itool=pubmed_docsum

104

Amyotrophic Lateral Sclerosis

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Impairment of glutamate transport and increased vulnerability to oxidative stress in neuroblastoma SH-SY5Y cells expressing a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis. Author(s): Sala G, Beretta S, Ceresa C, Mattavelli L, Zoia C, Tremolizzo L, Ferri A, Carri MT, Ferrarese C. Source: Neurochemistry International. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15670639&query_hl=10&itool=pubmed_docsum

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Implementation of X-ray fluorescence microscopy for investigation of elemental abnormalities in amyotrophic lateral sclerosis. Author(s): Tomik B, Chwiej J, Szczerbowska-Boruchowska M, Lankosz M, Wojcik S, Adamek D, Falkenberg G, Bohic S, Simionovici A, Stegowski Z, Szczudlik A. Source: Neurochemical Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16733809&query_hl=10&itool=pubmed_docsum

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Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis. Author(s): Guillemin GJ, Meininger V, Brew BJ. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16909022&query_hl=10&itool=pubmed_docsum

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Inappropriate surgeries resulting from misdiagnosis of early amyotrophic lateral sclerosis. Author(s): Srinivasan J, Scala S, Jones HR, Saleh F, Russell JA. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16609978&query_hl=10&itool=pubmed_docsum

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Increasing peak expiratory flow time in amyotrophic lateral sclerosis. Author(s): Wilson SR, Quantz MA, Strong MJ, Ahmad D. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15653977&query_hl=10&itool=pubmed_docsum

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Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. Author(s): Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16847061&query_hl=10&itool=pubmed_docsum

Studies

105

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Informatics-assisted protein profiling in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Lukas TJ, Luo WW, Mao H, Cole N, Siddique T. Source: Molecular & Cellular Proteomics : Mcp. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16571896&query_hl=10&itool=pubmed_docsum

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Inhibition of chaperone activity is a shared property of several Cu,Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosis. Author(s): Tummala H, Jung C, Tiwari A, Higgins CM, Hayward LJ, Xu Z. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15753080&query_hl=10&itool=pubmed_docsum

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Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. Author(s): Basso M, Massignan T, Samengo G, Cheroni C, De Biasi S, Salmona M, Bendotti C, Bonetto V. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16943203&query_hl=10&itool=pubmed_docsum

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Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogenactivated protein kinase. Author(s): Bendotti C, Bao Cutrona M, Cheroni C, Grignaschi G, Lo Coco D, Peviani M, Tortarolo M, Veglianese P, Zennaro E. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16909017&query_hl=10&itool=pubmed_docsum

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Intrathecal upregulation of granulocyte colony stimulating factor and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis. Author(s): Tanaka M, Kikuchi H, Ishizu T, Minohara M, Osoegawa M, Motomura K, Tateishi T, Ohyagi Y, Kira J. 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=16896315&query_hl=10&itool=pubmed_docsum

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Is motoneuronal cell death in amyotrophic lateral sclerosis apoptosis? Author(s): Yamazaki M, Esumi E, Nakano I. Source: Neuropathology : Official Journal of the Japanese Society of Neuropathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16382789&query_hl=10&itool=pubmed_docsum

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Is pentoxifylline safe and effective in patients with amyotrophic lateral sclerosis? Author(s): Lindhorst S, Cudkowicz M. Source: Nat Clin Pract Neurol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16932586&query_hl=10&itool=pubmed_docsum

106

Amyotrophic Lateral Sclerosis

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Is TNFalpha really a good therapeutic target in motoneuronal degeneration? A case of amyotrophic lateral sclerosis in a patient with RA receiving infliximab. Author(s): Dziadzio M, Reddy V, Rahman S, Mummery C, Keat A. Source: Rheumatology (Oxford, England). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16877458&query_hl=10&itool=pubmed_docsum

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Japanese familial amyotrophic lateral sclerosis family with a two-base deletion in the superoxide dismutase-1 gene. Author(s): Watanabe Y, Adachi Y, Nakashima K. Source: Neuropathology : Official Journal of the Japanese Society of Neuropathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11304044&query_hl=10&itool=pubmed_docsum

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Juvenile amyotrophic lateral sclerosis with unusual presentation: a case report. Author(s): Panagariya A, Garg A, Sharma B. Source: Neurology India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14652459&query_hl=10&itool=pubmed_docsum

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Juvenile amyotrophic lateral sclerosis. Author(s): Aggarwal A, Shashiraj. Source: Indian J Pediatr. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16567917&query_hl=10&itool=pubmed_docsum

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Juvenile familial amyotrophic lateral sclerosis: four cases with long survival. Author(s): Otero Siliceo E, Arriada-Mendicoa N, Balderrama J. Source: Developmental Medicine and Child Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9652786&query_hl=10&itool=pubmed_docsum

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Juvenile familial amyotrophic lateral sclerosis: two siblings. Author(s): Ozge A, Kaleagas H, Tataroglu C, Unal O. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12495579&query_hl=10&itool=pubmed_docsum

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Kif1Bbeta isoform is enriched in motor neurons but does not change in a mouse model of amyotrophic lateral sclerosis. Author(s): Conforti L, Dell'Agnello C, Calvaresi N, Tortarolo M, Giorgini A, Coleman MP, Bendotti C. Source: Journal of Neuroscience Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12584731&query_hl=10&itool=pubmed_docsum

Studies

107

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Lactate stress testing in sporadic amyotrophic lateral sclerosis. Author(s): Finsterer J. Source: The International Journal of Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15809220&query_hl=10&itool=pubmed_docsum

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L-carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis. Author(s): Kira Y, Nishikawa M, Ochi A, Sato E, Inoue M. Source: Brain Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16412993&query_hl=10&itool=pubmed_docsum

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Lead exposure and amyotrophic lateral sclerosis. Author(s): Kamel F, Umbach DM, Munsat TL, Shefner JM, Hu H, Sandler DP. Source: Epidemiology (Cambridge, Mass.). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11964933&query_hl=10&itool=pubmed_docsum

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Lead exposure as a risk factor for amyotrophic lateral sclerosis. Author(s): Kamel F, Umbach DM, Hu H, Munsat TL, Shefner JM, Taylor JA, Sandler DP. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16909025&query_hl=10&itool=pubmed_docsum

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Limitations of inferences from observational databases in amyotrophic lateral sclerosis: all that glitters is not gold. Author(s): Armon C, Guiloff RJ, Bedlack R. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12495570&query_hl=10&itool=pubmed_docsum

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Longitudinal analysis of progression of dysphagia in amyotrophic lateral sclerosis. Author(s): Higo R, Tayama N, Nito T. Source: Auris, Nasus, Larynx. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15364359&query_hl=10&itool=pubmed_docsum

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Longitudinal effects of noninvasive positive-pressure ventilation in patients with amyotrophic lateral sclerosis. Author(s): Butz M, Wollinsky KH, Wiedemuth-Catrinescu U, Sperfeld A, Winter S, Mehrkens HH, Ludolph AC, Schreiber H. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12872016&query_hl=10&itool=pubmed_docsum

108

Amyotrophic Lateral Sclerosis

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Long-term safety of riluzole in amyotrophic lateral sclerosis. Author(s): Lacomblez L, Bensimon G, Leigh PN, Debove C, Bejuit R, Truffinet P, Meininger V; ALS Study Groups I and II. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12061945&query_hl=10&itool=pubmed_docsum

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Loss of metabotropic glutamate receptor-mediated regulation of glutamate transport in chemically activated astrocytes in a rat model of amyotrophic lateral sclerosis. Author(s): Vermeiren C, Hemptinne I, Vanhoutte N, Tilleux S, Maloteaux JM, Hermans E. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16371010&query_hl=10&itool=pubmed_docsum

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Low concentrations of glutamate induce apoptosis in cultured neurons: implications for amyotrophic lateral sclerosis. Author(s): Cid C, Alvarez-Cermeno JC, Regidor I, Salinas M, Alcazar A. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12480091&query_hl=10&itool=pubmed_docsum

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Measurement of decline of functioning in persons with amyotrophic lateral sclerosis: responsiveness and possible applications of the Functional Independence Measure, Barthel Index, Rehabilitation Activities Profile and Frenchay Activities Index. Author(s): De Groot IJ, Post MW, Van Heuveln T, Van Den Berg LH, Lindeman E. Source: Amyotroph Lateral Scler. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16963406&query_hl=10&itool=pubmed_docsum

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Measures and markers in amyotrophic lateral sclerosis. Author(s): Cudkowicz M, Qureshi M, Shefner J. Source: Neurorx. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15717028&query_hl=10&itool=pubmed_docsum

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Mitochondria in amyotrophic lateral sclerosis: a trigger and a target. Author(s): Dupuis L, Gonzalez de Aguilar JL, Oudart H, de Tapia M, Barbeito L, Loeffler JP. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16908975&query_hl=10&itool=pubmed_docsum

Studies

109

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Modafinil to treat fatigue in amyotrophic lateral sclerosis: an open label pilot study. Author(s): Carter GT, Weiss MD, Lou JS, Jensen MP, Abresch RT, Martin TK, Hecht TW, Han JJ, Weydt P, Kraft GH. Source: Am J Hosp Palliat Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15736608&query_hl=10&itool=pubmed_docsum

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Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Author(s): Pasinelli P, Brown RH. Source: Nature Reviews. Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16924260&query_hl=10&itool=pubmed_docsum

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Motor neuron protection in amyotrophic lateral sclerosis. Author(s): Carmichael G. Source: Lancet. Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15709223&query_hl=10&itool=pubmed_docsum

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Motor unit number estimation predicts disease onset and survival in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Shefner JM, Cudkowicz M, Brown RH Jr. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16892429&query_hl=10&itool=pubmed_docsum

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MR imaging of upper motor neuron compromise in amyotrophic lateral sclerosis. Author(s): da Rocha AJ, Maia AC Jr, Fonseca RB. Source: Radiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16990687&query_hl=10&itool=pubmed_docsum

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Mutant SOD1 instability: implications for toxicity in amyotrophic lateral sclerosis. Author(s): Tiwari A, Hayward LJ. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16909016&query_hl=10&itool=pubmed_docsum

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Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. Author(s): Vijayvergiya C, Beal MF, Buck J, Manfredi G. 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=15758154&query_hl=10&itool=pubmed_docsum

110

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Neuroinflammation in the pathogenesis of amyotrophic lateral sclerosis. Author(s): Weydt P, Moller T. Source: Neuroreport. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15812300&query_hl=10&itool=pubmed_docsum

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Neurophysiological measures in amyotrophic lateral sclerosis: markers of progression in clinical trials. Author(s): de Carvalho M, Chio A, Dengler R, Hecht M, Weber M, Swash M. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16036422&query_hl=10&itool=pubmed_docsum

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Neuroprotective effect of oxidized galectin-1 in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Chang-Hong R, Wada M, Koyama S, Kimura H, Arawaka S, Kawanami T, Kurita K, Kadoya T, Aoki M, Itoyama Y, Kato T. Source: Experimental Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15899257&query_hl=10&itool=pubmed_docsum

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Neurotrophic factors and amyotrophic lateral sclerosis. Author(s): Ekestern E. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16908980&query_hl=10&itool=pubmed_docsum

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No evidence of linkage to chromosome 9q21-22 in a Swedish family with frontotemporal dementia and amyotrophic lateral sclerosis. Author(s): Ostojic J, Axelman K, Lannfelt L, Froelich-Fabre S. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12672552&query_hl=10&itool=pubmed_docsum

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Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity. Author(s): Jokic N, Gonzalez de Aguilar JL, Pradat PF, Dupuis L, Echaniz-Laguna A, Muller A, Dubourg O, Seilhean D, Hauw JJ, Loeffler JP, Meininger V. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15786457&query_hl=10&itool=pubmed_docsum

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Non-invasive ventilation in amyotrophic lateral sclerosis. Author(s): Servera E, Sancho J. Source: Lancet. Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16545744&query_hl=10&itool=pubmed_docsum

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Normal chest radiograph in terminal respiratory failure due to amyotrophic lateral sclerosis. Author(s): Won C, Banerjee D, Stark P, Kuschner WG. Source: Southern Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16711329&query_hl=10&itool=pubmed_docsum

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Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Author(s): Kress JA, Kuhnlein P, Winter P, Ludolph AC, Kassubek J, Muller U, Sperfeld AD. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16240357&query_hl=10&itool=pubmed_docsum

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Objective tests for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS). Author(s): Di Lazzaro V, Oliviero A, Saturno E, Pilato F, Dileone M, Tonali PA. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15557544&query_hl=10&itool=pubmed_docsum

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O-glycosylation of the tail domain of neurofilament protein M in human neurons and in spinal cord tissue of a rat model of amyotrophic lateral sclerosis (ALS). Author(s): Ludemann N, Clement A, Hans VH, Leschik J, Behl C, Brandt R. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16006557&query_hl=10&itool=pubmed_docsum

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Only subtle cognitive deficits in non-bulbar amyotrophic lateral sclerosis patients. Author(s): Rottig D, Leplow B, Eger K, Ludolph AC, Graf M, Zierz S. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16208524&query_hl=10&itool=pubmed_docsum

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Origin and distribution of bone marrow-derived cells in the central nervous system in a mouse model of amyotrophic lateral sclerosis. Author(s): Solomon JN, Lewis CA, Ajami B, Corbel SY, Rossi FM, Krieger C. Source: Glia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16518833&query_hl=10&itool=pubmed_docsum

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Oropharyngeal dysphagia in amyotrophic lateral sclerosis: neurological and dysphagia specific rating scales. Author(s): Kidney D, Alexander M, Corr B, O'toole O, Hardiman O. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15512903&query_hl=10&itool=pubmed_docsum

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Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models. Author(s): Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM, Brannstrom T, Rehnmark A, Marklund SL. 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=16624935&query_hl=10&itool=pubmed_docsum

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Oxidative damage to proteins in the spinal cord in amyotrophic lateral sclerosis (ALS). Author(s): Niebroj-Dobosz I, Dziewulska D, Kwiecinski H. Source: Folia Neuropathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15535033&query_hl=10&itool=pubmed_docsum

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Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation. Author(s): Ihara Y, Nobukuni K, Takata H, Hayabara T. Source: Neurological Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15829169&query_hl=10&itool=pubmed_docsum

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Oximetry and indications for tracheotomy for amyotrophic lateral sclerosis. Author(s): Bach JR, Bianchi C, Aufiero E. Source: Chest. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15539719&query_hl=10&itool=pubmed_docsum

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Paraoxonase-1 Q192R polymorphism and risk of sporadic amyotrophic lateral sclerosis. Author(s): Slowik A, Tomik B, Partyka D, Turaj W, Pera J, Dziedzic T, Szermer P, Figlewicz DA, Szczudlik A. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16630171&query_hl=10&itool=pubmed_docsum

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Pharmacologic approaches to the treatment of amyotrophic lateral sclerosis. Author(s): McGeer EG, McGeer PL. Source: Biodrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15691215&query_hl=10&itool=pubmed_docsum

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Positive effects of tertiary centres for amyotrophic lateral sclerosis on outcome and use of hospital facilities. Author(s): Chio A, Bottacchi E, Buffa C, Mutani R, Mora G; PARALS. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16614011&query_hl=10&itool=pubmed_docsum

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113

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Predictors of psychological distress in carers of people with amyotrophic lateral sclerosis: a longitudinal study. Author(s): Goldstein LH, Atkins L, Landau S, Brown R, Leigh PN. Source: Psychological Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16490122&query_hl=10&itool=pubmed_docsum

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Probabilistic diffusion tractography: a potential tool to assess the rate of disease progression in amyotrophic lateral sclerosis. Author(s): Ciccarelli O, Behrens TE, Altmann DR, Orrell RW, Howard RS, JohansenBerg H, Miller DH, Matthews PM, Thompson AJ. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16672290&query_hl=10&itool=pubmed_docsum

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Prospective study of occupation and amyotrophic lateral sclerosis mortality. Author(s): Weisskopf MG, McCullough ML, Morozova N, Calle EE, Thun MJ, Ascherio A. Source: American Journal of Epidemiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16269579&query_hl=10&itool=pubmed_docsum

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Protective effect of metabotropic glutamate receptor inhibition on amyotrophic lateral sclerosis-cerebrospinal fluid toxicity in vitro. Author(s): Anneser JM, Chahli C, Borasio GD. Source: Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16820266&query_hl=10&itool=pubmed_docsum

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Proteomic profiling of cerebrospinal fluid identifies biomarkers for amyotrophic lateral sclerosis. Author(s): Ranganathan S, Williams E, Ganchev P, Gopalakrishnan V, Lacomis D, Urbinelli L, Newhall K, Cudkowicz ME, Brown RH Jr, Bowser R. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16313519&query_hl=10&itool=pubmed_docsum

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Psychopathology in amyotrophic lateral sclerosis: a preliminary study with 27 ALS patients. Author(s): Bungener C, Piquard A, Pradat PF, Salachas F, Meininger V, Lacomblez L. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16319025&query_hl=10&itool=pubmed_docsum

114

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Pulmonary predictors of survival in amyotrophic lateral sclerosis: use in clinical trial design. Author(s): Schmidt EP, Drachman DB, Wiener CM, Clawson L, Kimball R, Lechtzin N. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16258948&query_hl=10&itool=pubmed_docsum

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Quality of life and psychosocial issues in ventilated patients with amyotrophic lateral sclerosis and their caregivers. Author(s): Kaub-Wittemer D, Steinbuchel N, Wasner M, Laier-Groeneveld G, Borasio GD. Source: Journal of Pain and Symptom Management. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14527757&query_hl=10&itool=pubmed_docsum

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Quality of life in patients with amyotrophic lateral sclerosis: perceptions, coping resources, and illness characteristics. Author(s): Nelson ND, Trail M, Van JN, Appel SH, Lai EC. Source: Journal of Palliative Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14509487&query_hl=10&itool=pubmed_docsum

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Quantification of hyperreflexia in amyotrophic lateral sclerosis (ALS) by the soleus stretch reflex. Author(s): Christensen PB, Nielsen JF, Sinkjaer T. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14506942&query_hl=10&itool=pubmed_docsum

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Quantification of upper motor neuron loss in amyotrophic lateral sclerosis. Author(s): Rosler KM, Truffert A, Hess CW, Magistris MR. 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=11090774&query_hl=10&itool=pubmed_docsum

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Quantitative assessment of motor fatigue in amyotrophic lateral sclerosis. Author(s): Sanjak M, Brinkmann J, Belden DS, Roelke K, Waclawik A, Neville HE, Ringel SP, Murphy JR, Brooks BR. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11676992&query_hl=10&itool=pubmed_docsum

Studies

115

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Quantitative EEG analysis for assessment to 'plan' a task in amyotrophic lateral sclerosis patients: a study of executive functions (planning) in ALS patients. Author(s): Santhosh J, Bhatia M, Sahu S, Anand S. Source: Brain Research. Cognitive Brain Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15561501&query_hl=10&itool=pubmed_docsum

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Quantitative evaluation of the pyramidal tract segmented by diffusion tensor tractography: feasibility study in patients with amyotrophic lateral sclerosis. Author(s): Aoki S, Iwata NK, Masutani Y, Yoshida M, Abe O, Ugawa Y, Masumoto T, Mori H, Hayashi N, Kabasawa H, Kwak S, Takahashi S, Tsuji S, Ohtomo K. Source: Radiat Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15940067&query_hl=10&itool=pubmed_docsum

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Quantitative evidence for neurofilament heavy subunit aggregation in motor neurons of spinal cords of patients with amyotrophic lateral sclerosis. Author(s): Mendonca DM, Chimelli L, Martinez AM. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15933787&query_hl=10&itool=pubmed_docsum

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Quantitative thermal sensory testing in patients with amyotrophic lateral sclerosis using reaction time exclusive method of levels (MLE). Author(s): Deepika J, Manvir B, Sumit S, Vinay G, Trilochan S, Garima S, Padma MV, Madhuri B. Source: Electromyogr Clin Neurophysiol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16918198&query_hl=10&itool=pubmed_docsum

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Quantitative voice analysis in the assessment of bulbar involvement in amyotrophic lateral sclerosis. Author(s): Robert D, Pouget J, Giovanni A, Azulay JP, Triglia JM. Source: Acta Oto-Laryngologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10587009&query_hl=10&itool=pubmed_docsum

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Radio-sensitivity of the cells from amyotrophic lateral sclerosis model mice transfected with human mutant SOD1. Author(s): Wate R, Takahashi S, Ito H, Kusaka H, Kubota Y, Suetomi K, Sato H, Okayasu R. Source: Journal of Radiation Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15802861&query_hl=10&itool=pubmed_docsum

116

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Rapid improvement in cortical neuronal integrity in amyotrophic lateral sclerosis detected by proton magnetic resonance spectroscopic imaging. Author(s): Kalra S, Tai P, Genge A, Arnold DL. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16609809&query_hl=10&itool=pubmed_docsum

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Rapid progression of amyotrophic lateral sclerosis presenting during pregnancy: a case report. Author(s): Leveck DE, Davies GA. Source: J Obstet Gynaecol Can. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15937610&query_hl=10&itool=pubmed_docsum

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Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. Author(s): Talbot K, Ansorge O. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16987882&query_hl=10&itool=pubmed_docsum

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Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)mutated familial ALS, and SOD1-mutated ALS animal models. Author(s): Kato S, Kato M, Abe Y, Matsumura T, Nishino T, Aoki M, Itoyama Y, Asayama K, Awaya A, Hirano A, Ohama E. Source: Acta Neuropathologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15983830&query_hl=10&itool=pubmed_docsum

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Reply to 'Mitochondrial changes in skeletal muscle in amyotrophic lateral sclerosis and other neurogenic atrophies--a comment'. Author(s): Krasnianski A, Deschauer M, Krasnianski M, Zierz S. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16477084&query_hl=10&itool=pubmed_docsum

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Research advances in amyotrophic lateral sclerosis (ALS): a personal view. Author(s): Rowland LP. Source: Neurol Neurochir Pol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15735983&query_hl=10&itool=pubmed_docsum

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Respiratory effects of amyotrophic lateral sclerosis: problems and solutions. Author(s): Lechtzin N. Source: Respiratory Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16867198&query_hl=10&itool=pubmed_docsum

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Reticulons as markers of neurological diseases: focus on amyotrophic lateral sclerosis. Author(s): Fergani A, Dupuis L, Jokic N, Larmet Y, de Tapia M, Rene F, Loeffler JP, Gonzalez de Aguilar JL. Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16909024&query_hl=10&itool=pubmed_docsum

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Return of the cycad hypothesis - does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health? Author(s): Ince PG, Codd GA. Source: Neuropathology and Applied Neurobiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16008818&query_hl=10&itool=pubmed_docsum

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Screening of the regulatory and coding regions of vascular endothelial growth factor in amyotrophic lateral sclerosis. Author(s): Brockington A, Kirby J, Eggitt D, Schofield E, Morris C, Lewis CE, Ince PG, Shaw PJ. Source: Neurogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15776280&query_hl=10&itool=pubmed_docsum

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Sensory testing in the assessment of laryngeal sensation in patients with amyotrophic lateral sclerosis. Author(s): Amin MR, Harris D, Cassel SG, Grimes E, Heiman-Patterson T. Source: The Annals of Otology, Rhinology, and Laryngology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16900807&query_hl=10&itool=pubmed_docsum

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Serotonergic mechanisms in amyotrophic lateral sclerosis. Author(s): Sandyk R. Source: The International Journal of Neuroscience. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16861147&query_hl=10&itool=pubmed_docsum

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Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Author(s): Chio A, Benzi G, Dossena M, Mutani R, Mora G. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15634730&query_hl=10&itool=pubmed_docsum

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Signs and symptoms at diagnosis of amyotrophic lateral sclerosis: a population-based study in southern Italy. Author(s): Zoccolella S, Beghi E, Palagano G, Fraddosio A, Samarelli V, Lamberti P, Lepore V, Serlenga L, Logroscino G; SLAP registry. 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=16834713&query_hl=10&itool=pubmed_docsum

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Single fiber electromyography in 78 patients with amyotrophic lateral sclerosis. Author(s): Cui LY, Liu MS, Tang XF. Source: Chinese Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15603713&query_hl=10&itool=pubmed_docsum

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Slower disease progression and prolonged survival in contemporary patients with amyotrophic lateral sclerosis: is the natural history of amyotrophic lateral sclerosis changing? Author(s): Czaplinski A, Yen AA, Simpson EP, Appel SH. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16908741&query_hl=10&itool=pubmed_docsum

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Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosislinked superoxide dismutase mutants against unfolding and aggregation. Author(s): Ray SS, Nowak RJ, Brown RH Jr, Lansbury PT Jr. 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=15738401&query_hl=10&itool=pubmed_docsum

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Standard equations are not accurate in assessing resting energy expenditure in patients with amyotrophic lateral sclerosis. Author(s): Sherman MS, Pillai A, Jackson A, Heiman-Patterson T. Source: Jpen. Journal of Parenteral and Enteral Nutrition. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15568293&query_hl=10&itool=pubmed_docsum

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Stem-cell therapy in amyotrophic lateral sclerosis. Author(s): Mazzini L, Fagioli F, Boccaletti R. Source: Lancet. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15567004&query_hl=10&itool=pubmed_docsum

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Tau protein concentrations in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Author(s): Jimenez-Jimenez FJ, Hernanz A, Medina-Acebron S, de Bustos F, Zurdo JM, Alonso H, Puertas I, Barcenilla B, Sayed Y, Cabrera-Valdivia F. Source: Acta Neurologica Scandinavica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15644071&query_hl=10&itool=pubmed_docsum

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The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Author(s): Wu DC, Re DB, Nagai M, Ischiropoulos H, Przedborski S. 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=16877542&query_hl=10&itool=pubmed_docsum

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The pro and the active form of matrix metalloproteinase-9 is increased in serum of patients with amyotrophic lateral sclerosis. Author(s): Demestre M, Parkin-Smith G, Petzold A, Pullen AH. Source: Journal of Neuroimmunology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15652414&query_hl=10&itool=pubmed_docsum

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The relationship between amyotrophic lateral sclerosis and frontotemporal dementia. Author(s): Ringholz GM, Greene SR. Source: Curr Neurol Neurosci Rep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16928348&query_hl=10&itool=pubmed_docsum

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Trial of celecoxib in amyotrophic lateral sclerosis. Author(s): Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, Drachman DB. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16802291&query_hl=10&itool=pubmed_docsum

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Trouble on the pitch: are professional football players at increased risk of developing amyotrophic lateral sclerosis? Author(s): Al-Chalabi A, Leigh PN. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15713848&query_hl=10&itool=pubmed_docsum

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Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Author(s): Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17023659&query_hl=10&itool=pubmed_docsum

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Ultrastructural change of synapses of Betz cells in patients with amyotrophic lateral sclerosis. Author(s): Sasaki S, Iwata M. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10400070&query_hl=10&itool=pubmed_docsum

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Ultrastructural changes of mitochondria in the skeletal muscle of patients with amyotrophic lateral sclerosis. Author(s): Chung MJ, Suh YL. Source: Ultrastructural Pathology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12028652&query_hl=10&itool=pubmed_docsum

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Unexpected decline in survival from amyotrophic lateral sclerosis/motor neurone disease. Author(s): Forbes RB, Colville S, Cran GW, Swingler RJ; Scottish Motor Neurone Disease Register. Source: Journal of Neurology, Neurosurgery, and Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15548498&query_hl=10&itool=pubmed_docsum

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Unsaturated fatty acids induce cytotoxic aggregate formation of amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutants. Author(s): Kim YJ, Nakatomi R, Akagi T, Hashikawa T, Takahashi R. Source: The Journal of Biological Chemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15799963&query_hl=10&itool=pubmed_docsum

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Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Author(s): Heath PR, Shaw PJ. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12362409&query_hl=10&itool=pubmed_docsum

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121

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Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. Author(s): Dupuis L, di Scala F, Rene F, de Tapia M, Oudart H, Pradat PF, Meininger V, Loeffler JP. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14500553&query_hl=10&itool=pubmed_docsum

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Use of noninvasive ventilation in patients with amyotrophic lateral sclerosis. Author(s): Lechtzin N, Wiener CM, Clawson L, Davidson MC, Anderson F, Gowda N, Diette GB; ALS CARE Study Group. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15204018&query_hl=10&itool=pubmed_docsum

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Use of Sniff nasal-inspiratory force to predict survival in amyotrophic lateral sclerosis. Author(s): Morgan RK, McNally S, Alexander M, Conroy R, Hardiman O, Costello RW. Source: American Journal of Respiratory and Critical Care Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15516537&query_hl=10&itool=pubmed_docsum

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Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds. Author(s): Ratovitski T, Corson LB, Strain J, Wong P, Cleveland DW, Culotta VC, Borchelt DR. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10400992&query_hl=10&itool=pubmed_docsum

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Vascular endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative diseases. Author(s): Bogaert E, Van Damme P, Van Den Bosch L, Robberecht W. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16856151&query_hl=10&itool=pubmed_docsum

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VEGF C2578A polymorphism does not contribute to amyotrophic lateral sclerosis susceptibility in sporadic Chinese patients. Author(s): Zhang Y, Zhang H, Fu Y, Song H, Wang L, Zhang J, Fan D. Source: Amyotroph Lateral Scler. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16753977&query_hl=10&itool=pubmed_docsum

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VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Author(s): Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12847526&query_hl=10&itool=pubmed_docsum

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VEGF promoter haplotype and amyotrophic lateral sclerosis (ALS). Author(s): Terry PD, Kamel F, Umbach DM, Lehman TA, Hu H, Sandler DP, Taylor JA. Source: Journal of Neurogenetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15763997&query_hl=10&itool=pubmed_docsum

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Ventilator dependence and expressions of need: a study of patients with amyotrophic lateral sclerosis in Japan. Author(s): Hirano YM, Yamazaki Y, Shimizu J, Togari T, Bryce TJ. Source: Social Science & Medicine (1982). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16263201&query_hl=10&itool=pubmed_docsum

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Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. Author(s): Miller TM, Kaspar BK, Kops GJ, Yamanaka K, Christian LJ, Gage FH, Cleveland DW. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15852369&query_hl=10&itool=pubmed_docsum

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Visualization of defective mitochondrial function in skeletal muscle fibers of patients with sporadic amyotrophic lateral sclerosis. Author(s): Vielhaber S, Winkler K, Kirches E, Kunz D, Buchner M, Feistner H, Elger CE, Ludolph AC, Riepe MW, Kunz WS. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10540022&query_hl=10&itool=pubmed_docsum

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What's in a name? Amyotrophic lateral sclerosis, motor neuron disease, and allelic heterogeneity. Author(s): Rowland LP. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9629837&query_hl=10&itool=pubmed_docsum

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Wheelchair economy class syndrome in amyotrophic lateral sclerosis. Author(s): Kimura F, Ishida S, Furutama D, Hirata Y, Sato T, Hosokawa T, Hanafusa T. Source: Neuromuscular Disorders : Nmd. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16487707&query_hl=10&itool=pubmed_docsum

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Wheelchair use by patients with amyotrophic lateral sclerosis: a survey of user characteristics and selection preferences. Author(s): Trail M, Nelson N, Van JN, Appel SH, Lai EC. 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=11239293&query_hl=10&itool=pubmed_docsum

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When motor execution is selectively impaired: control of manipulative finger forces in amyotrophic lateral sclerosis. Author(s): Nowak DA, Hermsdorfer J, Topka H. Source: Motor Control. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12893960&query_hl=10&itool=pubmed_docsum

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Widespread sensorimotor and frontal cortical atrophy in Amyotrophic Lateral Sclerosis. Author(s): Grosskreutz J, Kaufmann J, Fradrich J, Dengler R, Heinze HJ, Peschel T. Source: Bmc Neurology [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16638121&query_hl=10&itool=pubmed_docsum

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Withdrawing ventilator support for a home-based amyotrophic lateral sclerosis patient: a case study. Author(s): Schwarz JK, Del Bene ML. Source: J Clin Ethics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15630871&query_hl=10&itool=pubmed_docsum

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Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Author(s): Abrahams S, Goldstein LH, Simmons A, Brammer M, Williams SC, Giampietro V, Leigh PN. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15163610&query_hl=10&itool=pubmed_docsum

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Xaliproden in amyotrophic lateral sclerosis: early clinical trials. Author(s): Lacomblez L, Bensimon G, Douillet P, Doppler V, Salachas F, Meininger V. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15204011&query_hl=10&itool=pubmed_docsum

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Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Groeneveld GJ, de Leeuw van Weenen J, van Muiswinkel FL, Veldman H, Veldink JH, Wokke JH, Bar PR, van den Berg LH. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14625013&query_hl=10&itool=pubmed_docsum

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Zinc and copper in the pathogenesis of amyotrophic lateral sclerosis. Author(s): Elliott JL. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11474839&query_hl=10&itool=pubmed_docsum

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CHAPTER 2. ALTERNATIVE MEDICINE AND AMYOTROPHIC LATERAL SCLEROSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis 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 amyotrophic lateral sclerosis (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 amyotrophic lateral sclerosis: •

A clinical trial of therapeutic electrical stimulation for amyotrophic lateral sclerosis. Author(s): Handa I, Matsushita N, Ihashi K, Yagi R, Mochizuki R, Mochizuki H, Abe Y, Shiga Y, Hoshimiya N, Itoyama Y, et al. Source: The Tohoku Journal of Experimental Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7597693&query_hl=1&itool=pubmed_docsum

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A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. Author(s): Zhao Z, Lange DJ, Voustianiouk A, MacGrogan D, Ho L, Suh J, Humala N, Thiyagarajan M, Wang J, Pasinetti GM. Source: Bmc Neuroscience [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16584562&query_hl=1&itool=pubmed_docsum

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A Phase I safety study of hyperbaric oxygen therapy for amyotrophic lateral sclerosis. Author(s): Steele J, Matos LA, Lopez EA, Perez-Pinzon MA, Prado R, Busto R, Arheart KL, Bradley WG. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15799556&query_hl=1&itool=pubmed_docsum

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A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Author(s): Barbeito LH, Pehar M, Cassina P, Vargas MR, Peluffo H, Viera L, Estevez AG, Beckman JS. Source: Brain Research. Brain Research Reviews. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15572176&query_hl=1&itool=pubmed_docsum

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A specific inhibitor of janus kinase-3 increases survival in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Trieu VN, Liu R, Liu XP, Uckun FM. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10623568&query_hl=1&itool=pubmed_docsum

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A sporadic case of juvenile amyotrophic lateral sclerosis; semi-quantitative and histoenzymatical study of the denervated muscles. Author(s): Cognazzo A, Martin L. Source: European Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4314073&query_hl=1&itool=pubmed_docsum

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A therapeutic trial of thymic factor in amyotrophic lateral sclerosis (ALS). Author(s): Provinciali L, Giovagnoli AR, Di Bella P, Baroni M, Dellantonio R. Source: Advances in Experimental Medicine and Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3577920&query_hl=1&itool=pubmed_docsum

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Abnormal excitability of the corticospinal pathway in patients with amyotrophic lateral sclerosis: a single motor unit study using transcranial magnetic stimulation. Author(s): Kohara N, Kaji R, Kojima Y, Mills KR, Fujii H, Hamano T, Kimura J, Takamatsu N, Uchiyama T. Source: Electroencephalography and Clinical Neurophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8625875&query_hl=1&itool=pubmed_docsum

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Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment. Author(s): Goodall EF, Morrison KE.

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Source: Expert Reviews in Molecular Medicine [electronic Resource]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16723044&query_hl=1&itool=pubmed_docsum •

Amyotrophic lateral sclerosis and hopelessness: psychosocial factors. Author(s): Plahuta JM, McCulloch BJ, Kasarskis EJ, Ross MA, Walter RA, McDonald ER. Source: Social Science & Medicine (1982). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12409126&query_hl=1&itool=pubmed_docsum

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Amyotrophic lateral sclerosis in an Italian professional soccer player. Author(s): Vanacore N, Binazzi A, Bottazzi M, Belli S. Source: Parkinsonism & Related Disorders. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16459125&query_hl=1&itool=pubmed_docsum

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Amyotrophic lateral sclerosis versus cervical spondylotic myelopathy: a study using transcranial magnetic stimulation with recordings from the trapezius and limb muscles. Author(s): Truffert A, Rosler KM, Magistris MR. 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=10825710&query_hl=1&itool=pubmed_docsum

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Amyotrophic lateral sclerosis. Clinicopathological studies of a family. Author(s): Metcalf CW, Hirano A. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=5089897&query_hl=1&itool=pubmed_docsum

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Amyotrophic lateral sclerosis: a challenge for constant adaptation. Author(s): Stone N. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2956338&query_hl=1&itool=pubmed_docsum

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Amyotrophic lateral sclerosis: integrating care for patients and their families. Author(s): Thompson B. Source: Am J Hosp Palliat Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2361109&query_hl=1&itool=pubmed_docsum

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Amyotrophic lateral sclerosis: new developments in diagnostic markers. Author(s): Dengler R, von Neuhoff N, Bufler J, Krampfl K, Peschel T, Grosskreutz J.

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Source: Neurodegener Dis. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16909023&query_hl=1&itool=pubmed_docsum •

Amyotrophic lateral sclerosis: recent advances and future therapies. Author(s): Nirmalananthan N, Greensmith L. Source: Current Opinion in Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16280684&query_hl=1&itool=pubmed_docsum

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Astrocyte activation by fibroblast growth factor-1 and motor neuron apoptosis: implications for amyotrophic lateral sclerosis. Author(s): Cassina P, Pehar M, Vargas MR, Castellanos R, Barbeito AG, Estevez AG, Thompson JA, Beckman JS, Barbeito L. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15773903&query_hl=1&itool=pubmed_docsum

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Burden of care in amyotrophic lateral sclerosis. Author(s): Hecht MJ, Graesel E, Tigges S, Hillemacher T, Winterholler M, Hilz MJ, Heuss D, Neundorfer B. Source: Palliative Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12822849&query_hl=1&itool=pubmed_docsum

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Calcitonin gene-related peptide immunoreactivity in familial amyotrophic lateral sclerosis. Author(s): Kato T, Hirano A, Manaka H, Sasaki H, Katagiri T, Kawanami T, Shikama Y, Seino T, Sasaki H. Source: Neuroscience Letters. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=1667811&query_hl=1&itool=pubmed_docsum

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Characterization of three yeast copper-zinc superoxide dismutase mutants analogous to those coded for in familial amyotrophic lateral sclerosis. Author(s): Nishida CR, Gralla EB, Valentine JS. 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=7937915&query_hl=1&itool=pubmed_docsum

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Controversies about amyotrophic lateral sclerosis. Author(s): Rowland LP. Source: Neurologia (Barcelona, Spain). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9011143&query_hl=1&itool=pubmed_docsum

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Cortical versus spinal dysfunction in amyotrophic lateral sclerosis. Author(s): Attarian S, Vedel JP, Pouget J, Schmied A. Source: Muscle & Nerve. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16506152&query_hl=1&itool=pubmed_docsum

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Corticobulbar tract involvement in amyotrophic lateral sclerosis. A transcranial magnetic stimulation study. Author(s): Urban PP, Vogt T, Hopf HC. Source: Brain; a Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9648545&query_hl=1&itool=pubmed_docsum

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Decreased electroencephalogram alpha band [8-13 Hz] power in amyotrophic lateral sclerosis patients: a study of alpha activity in an awake relaxed state. Author(s): Santhosh J, Bhatia M, Sahu S, Anand S. Source: Neurology India. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15805665&query_hl=1&itool=pubmed_docsum

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Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. Author(s): Mazzini L, Balzarini C, Colombo R, Mora G, Pastore I, De Ambrogio R, Caligari M. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11677005&query_hl=1&itool=pubmed_docsum

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Ethical aspects of unproved therapies in multiple sclerosis, amyotrophic lateral sclerosis, and other neurologic diseases. Author(s): van den Noort S. Source: Seminars in Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11649670&query_hl=1&itool=pubmed_docsum

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Evoked cardiac response components in cognitive processing: differential effects of amyotrophic lateral sclerosis. Author(s): Kaiser J, Wronka E, Barry RJ, Szczudlik A. Source: Acta Neurobiol Exp (Wars). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10645638&query_hl=1&itool=pubmed_docsum

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Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. Author(s): Cochrane Database Syst Rev. 2006;(1):CD004156

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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=16437474&itool=pubmed_docsum •

Factors supporting quality of life over time for individuals with amyotrophic lateral sclerosis: the role of positive self-perception and religiosity. Author(s): Bremer BA, Simone AL, Walsh S, Simmons Z, Felgoise SH. Source: Annals of Behavioral Medicine : a Publication of the Society of Behavioral Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15454359&query_hl=1&itool=pubmed_docsum

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Genistein is neuroprotective in murine models of familial amyotrophic lateral sclerosis and stroke. Author(s): Trieu VN, Uckun FM. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10329446&query_hl=1&itool=pubmed_docsum

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Glutathione peroxidase in amyotrophic lateral sclerosis: the effects of selenium supplementation. Author(s): Apostolski S, Marinkovic Z, Nikolic A, Blagojevic D, Spasic MB, Michelson AM. Source: Journal of Environmental Pathology, Toxicology and Oncology : Official Organ of the International Society for Environmental Toxicology and Cancer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9726810&query_hl=1&itool=pubmed_docsum

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High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. Author(s): Graf M, Ecker D, Horowski R, Kramer B, Riederer P, Gerlach M, Hager C, Ludolph AC, Becker G, Osterhage J, Jost WH, Schrank B, Stein C, Kostopulos P, Lubik S, Wekwerth K, Dengler R, Troeger M, Wuerz A, Hoge A, Schrader C, Schimke N, Krampfl K, Petri S, Zierz S, Eger K, Neudecker S, Traufeller K, Sievert M, Neundorfer B, Hecht M; German vitamin E/ALS Study Group. Source: Journal of Neural Transmission (Vienna, Austria : 1996). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15517433&query_hl=1&itool=pubmed_docsum

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Histochemical and X-ray microanalytical localization of aluminum in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Author(s): Piccardo P, Yanagihara R, Garruto RM, Gibbs CJ Jr, Gajdusek DC. Source: Acta Neuropathologica. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=2467502&query_hl=1&itool=pubmed_docsum

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Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Author(s): Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W. Source: Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9371911&query_hl=1&itool=pubmed_docsum

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Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. Author(s): Andreassen OA, Jenkins BG, Dedeoglu A, Ferrante KL, Bogdanov MB, Kaddurah-Daouk R, Beal MF. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11299300&query_hl=1&itool=pubmed_docsum

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Individual and health-related quality of life assessment in amyotrophic lateral sclerosis patients and their caregivers. Author(s): Lo Coco G, Lo Coco D, Cicero V, Oliveri A, Lo Verso G, Piccoli F, La Bella V. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16109426&query_hl=1&itool=pubmed_docsum

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Integrating manual and movement therapy with philosophical counseling for treatment of a patient with amyotrophic lateral sclerosis: a case study that explores the principles of holistic intervention. Author(s): Cottingham JT, Maitland J. Source: Alternative Therapies in Health and Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10710808&query_hl=1&itool=pubmed_docsum

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Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. Author(s): Garbuzova-Davis S, Willing AE, Zigova T, Saporta S, Justen EB, Lane JC, Hudson JE, Chen N, Davis CD, Sanberg PR. Source: Journal of Hematotherapy & Stem Cell Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12857367&query_hl=1&itool=pubmed_docsum

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Lead content of neuromuscular tissue in amyotrophic lateral sclerosis: case report and other considerations. Author(s): Petkau A, Sawatzky A, Hillier CR, Hoogstraten J. Source: Br J Ind Med. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4214550&query_hl=1&itool=pubmed_docsum

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Magnetoencephalographic evidence of abnormal auditory processing in amyotrophic lateral sclerosis with bulbar signs. Author(s): Pekkonen E, Osipova D, Laaksovirta H.

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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=14744570&query_hl=1&itool=pubmed_docsum •

Major stressors facing patients with amyotrophic lateral sclerosis (ALS): a survey to identify their concerns and to compare with those of their caregivers. Author(s): Trail M, Nelson N, Van JN, Appel SH, Lai EC. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15204023&query_hl=1&itool=pubmed_docsum

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Management of amyotrophic lateral sclerosis with riluzole. Author(s): Neatherlin JS. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9791781&query_hl=1&itool=pubmed_docsum

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Management strategies for patients with amyotrophic lateral sclerosis from diagnosis through death. Author(s): Simmons Z. Source: The Neurologist. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16148733&query_hl=1&itool=pubmed_docsum

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Marijuana in the management of amyotrophic lateral sclerosis. Author(s): Carter GT, Rosen BS. Source: Am J Hosp Palliat Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11467101&query_hl=1&itool=pubmed_docsum

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Motor cortex stimulation for amyotrophic lateral sclerosis. Time for a therapeutic trial? Author(s): Di Lazzaro V, Oliviero A, Saturno E, Pilato F, Dileone M, Sabatelli M, Tonali PA. 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=15134719&query_hl=1&itool=pubmed_docsum

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My journey with amyotrophic lateral sclerosis. Author(s): Nowotny ML.

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Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9604825&query_hl=1&itool=pubmed_docsum •

Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis. Author(s): Rizzardini M, Lupi M, Mangolini A, Babetto E, Ubezio P, Cantoni L. Source: Brain Research Bulletin. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16624679&query_hl=1&itool=pubmed_docsum

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Neurophysiological features of fasciculation potentials evoked by transcranial magnetic stimulation in amyotrophic lateral sclerosis. Author(s): de Carvalho M, Miranda PC, Lourdes Sales Luis M, Ducla-Soares E. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10787113&query_hl=1&itool=pubmed_docsum

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Nutritional issues and supplements in amyotrophic lateral sclerosis and other neurodegenerative disorders. Author(s): Cameron A, Rosenfeld J. Source: Current Opinion in Clinical Nutrition and Metabolic Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12394638&query_hl=1&itool=pubmed_docsum

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Nutritional management in amyotrophic lateral sclerosis: a worldwide perspective. Author(s): Silani V, Kasarskis EJ, Yanagisawa N. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9747929&query_hl=1&itool=pubmed_docsum

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Optimising the detection of upper motor neuron function dysfunction in amyotrophic lateral sclerosis--a transcranial magnetic stimulation study. Author(s): Osei-Lah AD, Mills KR. Source: Journal of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15592732&query_hl=1&itool=pubmed_docsum

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Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease? Author(s): Belli S, Vanacore N. Source: European Journal of Epidemiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15921041&query_hl=1&itool=pubmed_docsum

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Psychological function in individuals with amyotrophic lateral sclerosis (ALS). Author(s): Brown WA, Mueller PS.

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Source: Psychosomatic Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=4392415&query_hl=1&itool=pubmed_docsum •

Reduced creatine kinase activity in transgenic amyotrophic lateral sclerosis mice. Author(s): Wendt S, Dedeoglu A, Speer O, Wallimann T, Beal MF, Andreassen OA. Source: Free Radical Biology & Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11978494&query_hl=1&itool=pubmed_docsum

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Resilience and distress among amyotrophic lateral sclerosis patients and caregivers. Author(s): Rabkin JG, Wagner GJ, Del Bene M. Source: Psychosomatic Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10772408&query_hl=1&itool=pubmed_docsum

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Responses of masseter muscles to transcranial magnetic stimulation in patients with amyotrophic lateral sclerosis. Author(s): Trompetto C, Caponnetto C, Buccolieri A, Marchese R, Abbruzzese G. Source: Electroencephalography and Clinical Neurophysiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9751293&query_hl=1&itool=pubmed_docsum

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Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. Author(s): Ryu H, Smith K, Camelo SI, Carreras I, Lee J, Iglesias AH, Dangond F, Cormier KA, Cudkowicz ME, Brown RH Jr, Ferrante RJ. Source: Journal of Neurochemistry. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15934930&query_hl=1&itool=pubmed_docsum

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Spiritual well-being of the individual with amyotrophic lateral sclerosis. Author(s): Dal Bello-Haas V, Andrews-Hinders D, Bocian J, Mascha E, Wheeler T, Mitsumoto H. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11464852&query_hl=1&itool=pubmed_docsum

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Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Author(s): Mazzini L, Fagioli F, Boccaletti R, Mareschi K, Oliveri G, Olivieri C, Pastore I, Marasso R, Madon E.

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Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=13129802&query_hl=1&itool=pubmed_docsum •

Stem cells in the treatment of amyotrophic lateral sclerosis (ALS). Author(s): Silani V, Fogh I, Ratti A, Sassone J, Ciammola A, Cova L. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12710505&query_hl=1&itool=pubmed_docsum

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Survey of cannabis use in patients with amyotrophic lateral sclerosis. Author(s): Amtmann D, Weydt P, Johnson KL, Jensen MP, Carter GT. Source: Am J Hosp Palliat Care. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15055508&query_hl=1&itool=pubmed_docsum

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Survival in amyotrophic lateral sclerosis. The role of psychological factors. Author(s): McDonald ER, Wiedenfeld SA, Hillel A, Carpenter CL, Walter RA. Source: Archives of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8274106&query_hl=1&itool=pubmed_docsum

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Symptomatic care of patients with amyotrophic lateral sclerosis. Author(s): Smith RA, Norris FH 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=52730&query_hl=1&itool=pubmed_docsum

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The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain. Author(s): Liu Z, Martin LJ. Source: The Journal of Comparative Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16736475&query_hl=1&itool=pubmed_docsum

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The amyotrophic lateral sclerosis (ALS) support network of Kentucky: an informational support group using interactive video. Author(s): Kasarkis EJ, Elza TA, Bishop NG, Spears AC. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9419062&query_hl=1&itool=pubmed_docsum

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The cortico-diaphragmatic pathway involvement in amyotrophic lateral sclerosis: Neurophysiological, respiratory and clinical considerations. Author(s): Miscio G, Gukov B, Pisano F, Mazzini L, Baudo S, Salvadori A, Mauro A. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17078971&query_hl=1&itool=pubmed_docsum

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The family support group in the treatment of amyotrophic lateral sclerosis. Author(s): Finger S. Source: Neurologic Clinics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3561383&query_hl=1&itool=pubmed_docsum

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The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders. Author(s): Ellis AC, Rosenfeld J. Source: Cns Drugs. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15584767&query_hl=1&itool=pubmed_docsum

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The role of the amyotrophic lateral sclerosis and motor neurone disease community in health-care resourcing. Author(s): Levvy G. Source: Int J Clin Pract Suppl. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9691245&query_hl=1&itool=pubmed_docsum

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The serotonin precursor 5-hydroxytryptophan delays neuromuscular disease in murine familial amyotrophic lateral sclerosis. Author(s): Turner BJ, Lopes EC, Cheema SS. Source: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14527871&query_hl=1&itool=pubmed_docsum

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The use of alternative medicine by patients with amyotrophic lateral sclerosis. Author(s): Wasner M, Klier H, Borasio GD. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11677007&query_hl=1&itool=pubmed_docsum

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The use of herbal supplements and alternative therapies by patients with amyotrophic lateral sclerosis (ALS). Author(s): Vardeny O, Bromberg MB. Source: J Herb Pharmacother. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16520295&query_hl=1&itool=pubmed_docsum

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Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Ferrante RJ, Klein AM, Dedeoglu A, Beal MF. Source: Journal of Molecular Neuroscience : Mn. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11665866&query_hl=1&itool=pubmed_docsum

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Transcranial magnetic stimulation and BDNF plasma levels in amyotrophic lateral sclerosis. Author(s): Angelucci F, Oliviero A, Pilato F, Saturno E, Dileone M, Versace V, Musumeci G, Batocchi AP, Tonali PA, Di Lazzaro V. Source: Neuroreport. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15094483&query_hl=1&itool=pubmed_docsum

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Transcranial magnetic stimulation compared with upper motor neuron signs in patients with amyotrophic lateral sclerosis. Author(s): Schulte-Mattler WJ, Muller T, Zierz S. Source: Journal of the Neurological Sciences. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10540036&query_hl=1&itool=pubmed_docsum

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Transcranial magnetic stimulation for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS). Author(s): Mitsumoto H, Floyd A, Tang MX, Kaufmann P, Battista V, Hristova A, Pullman SL. Source: Suppl Clin Neurophysiol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16893129&query_hl=1&itool=pubmed_docsum

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Transgenic models of amyotrophic lateral sclerosis. Author(s): Grieb P. Source: Folia Neuropathol. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15679043&query_hl=1&itool=pubmed_docsum

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Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease. Author(s): Ashworth NL, Satkunam LE, Deforge D. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16437474&query_hl=1&itool=pubmed_docsum

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Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease. Author(s): Ashworth NL, Satkunam LE, Deforge D. Source: Cochrane Database Syst Rev. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14974059&query_hl=1&itool=pubmed_docsum

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Use of fiberoptic endoscopic evaluation of swallowing (FEES) in patients with amyotrophic lateral sclerosis. Author(s): Leder SB, Novella S, Patwa H. Source: Dysphagia. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15383947&query_hl=1&itool=pubmed_docsum

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Vitamin E intake and quality of life in amyotrophic lateral sclerosis patients: a follow-up case series study. Author(s): Galbussera A, Tremolizzo L, Brighina L, Testa D, Lovati R, Ferrarese C, Cavaletti G, Filippini G. 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=16897634&query_hl=1&itool=pubmed_docsum

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Vitamin E intake and risk of amyotrophic lateral sclerosis. Author(s): Ascherio A, Weisskopf MG, O'reilly EJ, Jacobs EJ, McCullough ML, Calle EE, Cudkowicz M, Thun MJ. Source: Annals of Neurology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15529299&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/

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The following is a specific Web list relating to amyotrophic lateral sclerosis; 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: •

Herbs and Supplements BCAAs Source: Prima Communications, Inc.www.personalhealthzone.com Branched-Chain Amino Acids Source: Healthnotes, Inc.; www.healthnotes.com Glutamic Acid Source: Healthnotes, Inc.; www.healthnotes.com Melatonin 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 AMYOTROPHIC LATERAL SCLEROSIS 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.13 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 “amyotrophic lateral sclerosis“ (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on amyotrophic lateral sclerosis, we have not necessarily excluded non-medical patents in this bibliography.

Patent Applications on Amyotrophic Lateral Sclerosis As of December 2000, U.S. patent applications are open to public viewing.14 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 amyotrophic lateral sclerosis: 13Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm. 14 This has been a common practice outside the United States prior to December 2000.

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Biomarkers for amyotrophic lateral sclerosis Inventor(s): Bowser, Robert P.; (Cranberry Township, PA), Ranganathan, Srikanth; (Pittsburgh, PA) Correspondence: Leydig Voit & Mayer, Ltd; Two Prudential Plaza, Suite 4900; 180 North Stetson Avenue; Chicago; IL; 60601-6780; US Patent Application Number: 20050148026 Date filed: October 25, 2004 Abstract: The invention provides a method for diagnosing amyotrophic lateral sclerosis (ALS) in a subject, a method for assessing the effectiveness of a drug in treating ALS, and a method for determining the site of onset of ALS in a subject. Each method comprises (a) obtaining a sample from the subject, (b) analyzing the proteins in the sample by mass spectroscopy, and (c) determining a mass spectral profile for the sample. In some embodiments, the method comprises comparing the mass spectral profile of the sample to the mass spectral profile of a positive or a negative standard. Excerpt(s): This patent application claims the benefit of U.S. Provisional Patent Application No. 60/513,930, filed Oct. 23, 2003. This invention pertains to biomarkers of amyotrophic lateral sclerosis and methods of using same. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease or motor neuron disease (MND), is one of several neurodegenerative diseases of the central nervous system. ALS is the most common adult onset motor neuron disease, affecting one in every 20,000 individuals, with an average age of onset of 50-55 years. ALS is characterized by rapidly progressive degeneration of motor neurons in the brain, brainstem, and spinal cord (Cleveland et al., Nat. Rev. Neurosci., 2, 806-19 (2001)). The median survival of patients from time of diagnosis is five years. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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METHOD TO TREAT PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS AND THE LIKE Inventor(s): Rooney, Roberta Nora Malone; (North Olmsted, OH) Correspondence: Roberta N. Rooney; 6787 Warrington Drive; North Olmsted; OH; 44070; US Patent Application Number: 20040176344 Date filed: April 6, 2004 Abstract: The hepatically produced isomers, URO I and URO III, are neuroprotectors capable of halting or mitigating the nervous system destruction in common neurological disorders. URO I protects neurons of the central nervous system from damage that would otherwise ensue from the neurotoxicity associated with the hepatic heme porphyrin precursors, delta-aminolevulinic acid and porphobilinogen. A method is disclosed to increase URO I to treat amyotrophic lateral sclerosis (ALS), stroke, encephalitis, meningitis, spinal cord injury and hereditary biochemical multiple sclerosis. Increases of URO III are also used to protect neurons in the peripheral nervous system in disorders including acute immunodeficiency syndrome (AIDS) related neuropathy, Guillaine-Barre syndrome and diabetic neuropathy.

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Excerpt(s): This invention relates generally to the treatment of central nervous system (CNS) and peripheral nervous system (PNS) neuropathies, especially amyotrophic lateral sclerosis (ALS), wherein the neurotoxicity associated with the porphyrin precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), is a contributing factor, and more particularly, to the use of a uroporphyrin isomer, uroporphyrin I (URO I) or uroporphyrin III (URO III) or any of their substrates as such treatment. The hepatic porphyrias are usually caused by inborn shortages of one or more of the enzymes/catalysts that facilitate heme synthesis (Nordmann Y; Puy H. 2002, Clin Chim Acta, 325(1-2):17-37), though some porphyrias, notably porphyria cutanea tarda (PCT) and porphyria turcica (Dean G. 1981, Arch Dermatol, (6):318), may be acquired. The acute (neurotoxic) porphyrias cause CNS and PNS damage, elevations of porphyrins and may cause dementia. Most cause cutaneous photosensitivity as well. (Lip G Y. et al. 1993, Br J Clin Pract 47(1):38-43). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of substances with immunomodulating activity for the treatment of amyotrophic lateral sclerosis Inventor(s): Schubert, Walter; (Biederitz, DE) Correspondence: Weingarten, Schurgin, Gagnebin & Hayes Llp; Ten Post Office Square; Boston; MA; 02109; US Patent Application Number: 20010009898 Date filed: March 8, 2001 Abstract: It has been discovered that, in the case of amyotrophic lateral sclerosis, usually a lethal motoneuron disease, a large number of the immune system cells expressing receptors (Fc receptors) of immunoglobulins (IgC), preferably immunoglobulins of classes 1 and 3 (Fc.gamma.RIII receptors for IgG1 and IgG3) can be found in the blood stream. Selective destruction or functional obstruction of these cells can be achieved in order to treat amyotrophic lateral sclerosis (ALS) with the following substances, or their preparations (in the form of intravenous applications or preparations), individually or in combination: a) antibodies, preferably monoclonal antibodies, which bind to Fc.gamma.RIII receptors, inactivate said receptors or individual species of this receptor family or cause the destruction of cellular forms containing said receptors, and/or are coupled to other cytotoxic substances, b) soluble Fc.gamma. receptors, preferably soluble Fc.gamma.RIII receptors, which bind to immunoglobulins, preferably G immunoglobulins of under-class 1 (IgG1) and/or 3 (IgG3), c) the protein V which binds to immunoglobulin G, obtained from Gardnerella vaginalis, and d) antisense RNA molecules which bind specifically to MRNA sequences of Fc.gamma. receptors, preferably to those of Fc.gamma.RIII receptors. Excerpt(s): The invention relates to the use of substances having a well-directed, i.e. selective, effect on a certain receptor family (Fc.gamma.R) or on those immune system cells with defined surface characteristics which express said receptor and whose presence--in examinations performed by the applicant--has been found to be specific, or its number specifically increased, in the case of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (in the following referred to as ALS, its abbreviation) is a neurodegenerative disease of the human motoneuron system which usually takes a lethal course within 3 to 5 years, whose causes have not been determined etiologically and for which there is no, or no significant, therapy as yet. The progressive decay of

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nerve cells of the first and second motor neurons are the cause of an increasing paralysis of the voluntary muscles, eventually leading to a total walking inability and the increasing paralysis of the respiratory musculature. It has largely been proven that cellular and humoral (antibody-mediated) immunological processes play an important role, if yet unexplained in the individual case, in the pathogenesis of ALS. Worldwide, the prevalence of this disease is 4 in 100,000 and its incidence is 1 in 100,000 inhabitants. Numerous examination results seem to imply that immunological mechanisms are at play in the pathogenesis of amyotrophic lateral sclerosis. The following findings substantiate this assumption: Cytotoxic serum activity of ALS patients in neuronal cell cultures; serum immunoglobulin G (IgG) toxicity against spinal and cortical neurons as well as voltage-dependent calcium channel proteins; cytotoxicity of the cerebrospinal fluid of ALS patients against glutamate receptors; changes of the serum concentration of IgG isotypes; immune response of peripheral blood lymphocytes of ALS patients to isolated cell membranes; detection of invasive immune system cells in the motoneuron system of ALS patients Here, these cells seem to be involved in the motoneuron damaging mechanisms (the quotations of the individual above data can be found in: Westarp, M. E. et al., Neurosci. Lett. 173, 124-126, 1994). 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 amyotrophic lateral sclerosis, 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 amyotrophic lateral sclerosis (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 amyotrophic lateral sclerosis. You can also use this procedure to view pending patent applications concerning amyotrophic lateral sclerosis. 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 AMYOTROPHIC LATERAL SCLEROSIS Overview This chapter provides bibliographic book references relating to amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis at online booksellers’ Web sites, you may discover non-medical books that use the generic term “amyotrophic lateral sclerosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for amyotrophic lateral sclerosis (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

21st Century Complete Medical Guide to Amyotrophic Lateral Sclerosis (ALS), Lou Gehrig's Disease, Authoritative CDC, NIH, and FDA Documents, Clinical References,. for Patients and Physicians (CD-ROM) PM Medical Health News (2004); ISBN: 1592486738; http://www.amazon.com/exec/obidos/ASIN/1592486738/icongroupinterna

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Amyotrophic lateral sclerosis: Proceedings of the International Symposium on Amyotrophic Lateral Sclerosis held February 2 and 3, 1978 (Publication - Japan Medical Research Foundation; no. 8) (1979); ISBN: 0839114222; http://www.amazon.com/exec/obidos/ASIN/0839114222/icongroupinterna

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Brain Disorders Sourcebook: Basic Consumer Health Information About Strokes, Epilepsy, Amyotrophic Lateral Sclerosis (Als/Lou Ge Karen Bellenir (1999); ISBN:

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B000LZK3TW; http://www.amazon.com/exec/obidos/ASIN/B000LZK3TW/icongroupinterna •

Brain Disorders Sourcebook: Basic Consumer Health Information About Strokes, Epilepsy, Amyotrophic Lateral Sclerosis (Als/Lou Gehrig's Disease) Parkinson's. Brain Tumors (Health Reference Series) Sandra J. Judd (2005); ISBN: 0780807448; http://www.amazon.com/exec/obidos/ASIN/0780807448/icongroupinterna

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Cognition impaired in 30% with ALS: a small study of patients with classic amyotrophic lateral sclerosis found cognitive impairment in 30% of the patients. ): An article from: Clinical Psychiatry News Mary Ann Moon (2006); ISBN: B000I0SC8Y; http://www.amazon.com/exec/obidos/ASIN/B000I0SC8Y/icongroupinterna

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Go Not Gently: Letters from a Patient With Amyotrophic Lateral Sclerosis (Continuing series on thanatology) Frances McGill (1980); ISBN: 0405126433; http://www.amazon.com/exec/obidos/ASIN/0405126433/icongroupinterna

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Handbook of Amyotrophic Lateral Sclerosis (Neurological Disease and Therapy) Richard Smith (1992); ISBN: 0824786106; http://www.amazon.com/exec/obidos/ASIN/0824786106/icongroupinterna

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Management of amyotrophic lateral sclerosis with Riluzole.: An article from: Journal of Neuroscience Nursing Jacquelin S. Neatherlin (1998); ISBN: B00098BIS6; http://www.amazon.com/exec/obidos/ASIN/B00098BIS6/icongroupinterna

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Motor neurone disease deaths (ICD 335.2) and amyotrophic lateral sclerosis for the United States, Wisconsin by county, Milwaukee City and other selected. & analysis of health data working papers) Raymond D Nashold (1988); ISBN: B00071J440; http://www.amazon.com/exec/obidos/ASIN/B00071J440/icongroupinterna

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Palliative Care in Amyotrophic Lateral Sclerosis (Motor Neuron Disease) David Oliver, Gian Domenico Borasio, and Declan Walsh (2000); ISBN: 0192631667; http://www.amazon.com/exec/obidos/ASIN/0192631667/icongroupinterna

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Search for the cause of amyotrophic lateral sclerosis and parkinsonism-dementia of Guam: Deposition of heavy metals and essential minerals in the central nervous system Ralph M Garruto (1985); ISBN: B00070R9RU; http://www.amazon.com/exec/obidos/ASIN/B00070R9RU/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select LocatorPlus. Once you are in the search area, simply type amyotrophic lateral sclerosis (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Books. From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine15: 15

In addition to LocatorPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a Books button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the

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Amyotrophic lateral sclerosis: proceedings of the International Symposium on Amyotrophic Lateral Sclerosis held February 2 and 3, 1978 Author: Tsubaki, Tadao,; Year: 1979; Baltimore: University Park Press, c1979; ISBN: 9780839114 http://www.amazon.com/exec/obidos/ASIN/9780839114/icongroupinterna

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Amyotrophic lateral sclerosis in Asia and Oceania: proceedings of the Sixth Asian and Oceanian Congress of Neurology Amyotrophic Lateral Sclerosis Workshop, Taipei, Taiwan, Republic of China, November 14, 1983 Author: Chen, K. M. (KwangMing); Year: 1984; Taipei]: Shyan-Fu Chou, National Taiwan University, [1984]

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Bibliography of amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam Author: Garruto, Ralph M.; Year: 1983; Bethesda, Md.: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, 1983

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Brain disorders sourcebook: basic consumer health information about strokes, epilepsy, amyotrophic lateral sclerosis (ALS Author: Bellenir, Karen.; Year: 1999; Detroit, MI: Omnigraphics, c1999; ISBN: 9780780802 http://www.amazon.com/exec/obidos/ASIN/9780780802/icongroupinterna

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Handbook of amyotrophic lateral sclerosis Author: Smith, Richard Alan,; Year: 1992; New York: Dekker, c1992; ISBN: 9780824786 http://www.amazon.com/exec/obidos/ASIN/9780824786/icongroupinterna

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Molecular mechanism and therapeutics of amyotrophic lateral sclerosis: proceedings of the International Symposium on Molecular Mechanism and Therapeutics of Amyotrophic Lateral Sclerosis, Japan, 22-24 September 2000 Author: Abe, Kōji.; Year: 2001; Amsterdam; New York: Elsevier, 2001; ISBN: 9780444506 http://www.amazon.com/exec/obidos/ASIN/9780444506/icongroupinterna

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Normal aging: a neurochemical, neurophysiological, and neuropsychological study with special reference to Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis Author: Hartikainen, Päivi.; Year: 1994; Kuopio: Dept. of Neurology, University of Kuopio, 1994; ISBN: 9789517809 http://www.amazon.com/exec/obidos/ASIN/9789517809/icongroupinterna

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Palliative care in amyotrophic lateral sclerosis (motor neurone disease) Author: Oliver, David,; Year: 2000; Oxford; New York: Oxford University Press, 2000; ISBN: 9780192631 http://www.amazon.com/exec/obidos/ASIN/9780192631/icongroupinterna

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Pathogenesis and therapy of amyotrophic lateral sclerosis Author: Serratrice, Georges.; Year: 1995; Philadelphia: Lippincott-Raven, c1995; ISBN: 9780781703 http://www.amazon.com/exec/obidos/ASIN/9780781703/icongroupinterna

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Riluzole for the treatment of amyotrophic lateral sclerosis: an assessment of clinical efficacy and safety Author: Garces, Kirsten.; Year: 2003; Ottawa: Canadian Coordinating Office for Health Technology Assessment, [2003]; ISBN: 9781894620 http://www.amazon.com/exec/obidos/ASIN/9781894620/icongroupinterna

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The Diagnosis and treatment of amyotrophic lateral sclerosis Author: Mulder, Donald W.,; Year: 1980; Boston: Houghton Mifflin, Medical Division, 1980; ISBN: 9780892894 http://www.amazon.com/exec/obidos/ASIN/9780892894/icongroupinterna

books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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CHAPTER 5. MULTIMEDIA ON AMYOTROPHIC LATERAL SCLEROSIS Overview In this chapter, we show you how to find bibliographic information related to multimedia sources of information on amyotrophic lateral sclerosis.

Bibliography: Multimedia on Amyotrophic Lateral Sclerosis The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select LocatorPlus. Once you are in the search area, simply type amyotrophic lateral sclerosis (or synonyms) into the search box, and select the Quick Limit Option for Keyword, Title, or Journal Title Search: Audiovisuals and Computer Files. From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on amyotrophic lateral sclerosis: •

Augmentative and alternative communication intervention in individuals with amyotrophic lateral sclerosis [videorecording] Source: produced by National Center for Neurogenic Communication Disorders of the University of Arizona; Year: 2000; Format: Videorecording; Tucson, AZ: Arizona Board of Regents, c2000

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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.16

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.

16 This appendix is an excerpt from the National Library of Medicine’s handbook, Help Me Understand Genetics. For the full text of the Help Me Understand Genetics handbook, see http://ghr.nlm.nih.gov/handbook.

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Mitochondria: Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.

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Nucleus: The nucleus serves as the cell’s command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.

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Plasma membrane: The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.

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Ribosomes: Ribosomes are organelles that process the cell’s genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum. What Is DNA?

DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.

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DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone. What Is Mitochondrial DNA? Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of

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DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins. What Is a Gene? A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.

Genes are made up of DNA. Each chromosome contains many genes. What Is a Chromosome? In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are not visible in the cell’s nucleus—not even under a microscope—when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know about chromosomes was learned by observing chromosomes during cell division. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.

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DNA and histone proteins are packaged into structures called chromosomes. How Many Chromosomes Do People Have? In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twentytwo of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.

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The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype. How Do Geneticists Indicate the Location of a Gene? Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene’s position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome. Cytogenetic Location Geneticists use a standardized way of describing a gene’s cytogenetic location. In most cases, the location describes the position of a particular band on a stained chromosome: 17q12 It can also be written as a range of bands, if less is known about the exact location: 17q12-q21 The combination of numbers and letters provide a gene’s “address” on a chromosome. This address is made up of several parts: •

The chromosome on which the gene can be found. The first number or letter used to describe a gene’s location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.

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The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene’s address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.

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The position of the gene on the p or q arm. The position of a gene is based on a distinctive pattern of light and dark bands that appear when the chromosome is stained in a certain way. The position is usually designated by two digits (representing a region and a band), which are sometimes followed by a decimal point and one or more additional digits (representing sub-bands within a light or dark area). The number indicating the gene position increases with distance from the centromere. For example: 14q21 represents position 21 on the long arm of chromosome 14. 14q21 is closer to the centromere than 14q22.

Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene’s cytogenetic location. “Cen” indicates that the gene is very close to the centromere. For example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter” stands for terminus, which indicates that the gene is very close to the end of the p or q arm. For example, 14qter refers to the tip of the long arm of chromosome 14. (“Tel” is also sometimes used to describe a gene’s location. “Tel” stands for telomeres, which are at the ends of each chromosome. The abbreviations “tel” and “ter” refer to the same location.)

The CFTR gene is located on the long arm of chromosome 7 at position 7q31.2.

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Molecular Location The Human Genome Project, an international research effort completed in 2003, determined the sequence of base pairs for each human chromosome. This sequence information allows researchers to provide a more specific address than the cytogenetic location for many genes. A gene’s molecular address pinpoints the location of that gene in terms of base pairs. For example, the molecular location of the APOE gene on chromosome 19 begins with base pair 50,100,901 and ends with base pair 50,104,488. This range describes the gene’s precise position on chromosome 19 and indicates the size of the gene (3,588 base pairs). Knowing a gene’s molecular location also allows researchers to determine exactly how far the gene is from other genes on the same chromosome. Different groups of researchers often present slightly different values for a gene’s molecular location. Researchers interpret the sequence of the human genome using a variety of methods, which can result in small differences in a gene’s molecular address. For example, the National Center for Biotechnology Information (NCBI) identifies the molecular location of the APOE gene as base pair 50,100,901 to base pair 50,104,488 on chromosome 19. The Ensembl database identifies the location of this gene as base pair 50,100,879 to base pair 50,104,489 on chromosome 19. Neither of these addresses is incorrect; they represent different interpretations of the same data. For consistency, Genetics Home Reference presents data from NCBI for the molecular location of genes. What Are Proteins and What Do They Do? Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique 3-dimensional structure and its specific function.

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Examples of Protein Functions Proteins can be described according to their large range of functions in the body, listed in alphabetical order: Function Antibody

Description Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.

Example Immunoglobulin G (IgG)

Enzyme

Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.

Phenylalanine hydroxylase

Messenger

Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.

Growth hormone

Structural component

These proteins provide structure and support for cells. On a larger scale, they also allow the body to move. These proteins bind and carry atoms and small molecules within cells and throughout the body.

Actin

Transport/storage

Ferritin

How Does a Gene Make a Protein? Most genes contain the information needed to make functional molecules called proteins. (A few genes produce other molecules that help the cell assemble proteins.) The journey from gene to protein is complex and tightly controlled within each cell. It consists of two major steps: transcription and translation. Together, transcription and translation are known as gene expression. During the process of transcription, the information stored in a gene’s DNA is transferred to a similar molecule called RNA (ribonucleic acid) in the cell nucleus. Both RNA and DNA are made up of a chain of nucleotide bases, but they have slightly different chemical properties. The type of RNA that contains the information for making a protein is called messenger RNA (mRNA) because it carries the information, or message, from the DNA out of the nucleus into the cytoplasm. Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which “reads” the sequence of mRNA bases. Each sequence of three bases, called a codon, usually codes for

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one particular amino acid. (Amino acids are the building blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three bases that does not code for an amino acid). The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the “central dogma.”

Through the processes of transcription and translation, information from genes is used to make proteins.

Can Genes Be Turned On and Off in Cells? Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood. Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is transferred to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.

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How Do Cells Divide? There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells. Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by a number of genes. When mitosis is not regulated correctly, health problems such as cancer can result. The other type of cell division, meiosis, ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of DNA shuffling while the cells are dividing.

Mitosis and meiosis, the two types of cell division. How Do Genes Control the Growth and Division of Cells? A variety of genes are involved in the control of cell growth and division. The cell cycle is the cell’s way of replicating itself in an organized, step-by-step fashion. Tight regulation of this process ensures that a dividing cell’s DNA is copied properly, any errors in the DNA are repaired, and each daughter cell receives a full set of chromosomes. The cycle has checkpoints (also called restriction points), which allow certain genes to check for mistakes and halt the cycle for repairs if something goes wrong.

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If a cell has an error in its DNA that cannot be repaired, it may undergo programmed cell death (apoptosis). Apoptosis is a common process throughout life that helps the body get rid of cells it doesn’t need. Cells that undergo apoptosis break apart and are recycled by a type of white blood cell called a macrophage. Apoptosis protects the body by removing genetically damaged cells that could lead to cancer, and it plays an important role in the development of the embryo and the maintenance of adult tissues. Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor.

Genetic Mutations and Health This section presents basic information about gene mutations, chromosomal changes, and conditions that run in families.17 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 17

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.

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

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

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One or more major signs or symptoms of the disorder (for example, sickle cell anemia)

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

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•

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

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

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The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after a famous baseball player who had the condition).

Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer’s disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine. Genetics Home Reference uses the nonpossessive form of eponyms. Genetics Home Reference consults with experts in the field of medical genetics to provide the current, most accurate name for each disorder. Alternate names are included as synonyms. Naming genes The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome. During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature. Genetics Home Reference describes genes using the HGNC’s official gene names and gene symbols. Genetics Home Reference frequently presents the symbol and name separated with a colon (for example, FGFR4: Fibroblast growth factor receptor 4).

Inheriting Genetic Conditions This section gives you information on inheritance patterns and understanding risk. What Does It Mean If a Disorder Seems to Run in My Family? A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not inherited. Instead, environmental factors

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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.

•

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.

•

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.

•

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute18: •

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

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

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

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

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

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

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

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

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

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These publications are typically written by one or more of the various NIH Institutes.

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•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

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

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

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

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

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

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

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

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

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

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

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

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

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

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

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.19 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic

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Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html).

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citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine20: •

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

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

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The NLM Gateway21 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.22 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type amyotrophic lateral sclerosis (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 9280 151 72 6 3 9512

HSTAT23 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.24 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.25 Simply search by amyotrophic lateral sclerosis (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists26 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. 21

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

22

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). 23 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 24 25

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. 26 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.27 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.28 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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

•

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

•

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

The Genome Project and Amyotrophic Lateral Sclerosis In the following section, we will discuss databases and references which relate to the Genome Project and amyotrophic lateral sclerosis. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).29 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type amyotrophic lateral sclerosis (or synonyms) into the search box, and click Go. If too many results appear, you can narrow the search by adding the word clinical. Each report will

27

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. 28 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. 29 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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have additional links to related research and databases. The following is an example of the results you can obtain from the OMIM for amyotrophic lateral sclerosis: •

AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=105400

•

AMYOTROPHIC LATERAL SCLEROSIS with FRONTOTEMPORAL DEMENTIA Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=105550

•

AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE; ALS2 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=205100

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AMYOTROPHIC LATERAL SCLEROSIS with POLYGLUCOSAN BODIES Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=205250

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AMYOTROPHIC LATERAL SCLEROSIS 5; ALS5 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602099

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AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE; ALS4 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602433

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AMYOTROPHIC LATERAL SCLEROSIS 3; ALS3 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606640

•

AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE, CHROMOSOME REGION GENE 2; ALS2CR2 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607333

•

AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE, CHROMOSOME REGION GENE 3; ALS2CR3 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607334

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AMYOTROPHIC LATERAL SCLEROSIS 2 CHROMOSOME CANDIDATE 8; ALS2CR8 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607586

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AMYOTROPHIC LATERAL SCLEROSIS 6 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608030

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AMYOTROPHIC LATERAL SCLEROSIS 7 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608031

•

AMYOTROPHIC LATERAL SCLEROSIS 8; ALS8 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608627

REGION,

Genes and Disease (NCBI - Map) The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras

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oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html •

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

•

Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

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•

GEO DataSets: Curated gene expression and molecular abundance data sets assembled from the Gene Expression Omnibus (GEO) repository, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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GEO Profiles: Individual gene expression and molecular abundance profiles assembled from the Gene Expression Omnibus (GEO) repository, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi, and then select the database that you would like to search. Or, to search across databases, you can enter amyotrophic lateral sclerosis (or synonyms) into the search box and click Go. Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database30 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html.

30

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html.

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The Genome Database31 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the GDB Human Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search All Biological Data by Name/GDB ID. Type amyotrophic lateral sclerosis (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word and or or (using or might be useful when using synonyms).

31

Adapted from the Genome Database: http://www.gdb.org/gdb/aboutGDB.html#mission.

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APPENDIX C. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called Fact Sheets or Guidelines. They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on amyotrophic lateral sclerosis can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources This section directs you to sources which either publish fact sheets or can help you find additional guidelines on topics related to amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis:

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Amyotrophic Lateral Sclerosis http://www.nlm.nih.gov/medlineplus/amyotrophiclateralsclerosis.html Charcot-Marie-Tooth Disease http://www.nlm.nih.gov/medlineplus/charcotmarietoothdisease.html Degenerative Nerve Diseases http://www.nlm.nih.gov/medlineplus/degenerativenervediseases.html Metabolic Disorders http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html Muscle Disorders http://www.nlm.nih.gov/medlineplus/muscledisorders.html Neurologic Diseases http://www.nlm.nih.gov/medlineplus/neurologicdiseases.html Neuromuscular Disorders http://www.nlm.nih.gov/medlineplus/neuromusculardisorders.html Spinal Muscular Atrophy http://www.nlm.nih.gov/medlineplus/spinalmuscularatrophy.html

Within the health topic page dedicated to amyotrophic lateral sclerosis, the following was listed: •

Diagnosis/Symptoms Creatine Kinase Test Source: Muscular Dystrophy Association http://www.mda.org/publications/Quest/q71ss-cktest.html Electromyography and Nerve Conduction Velocities Source: Muscular Dystrophy Association http://www.mda.org/publications/Quest/q75ss.html

•

Coping Reasons for Living with ALS Source: ALS Association http://www.alsa.org/patient/living.cfm?CFID=12809

•

Children Lou Gehrig's Disease (ALS) Source: Nemours Foundation http://kidshealth.org/kid/grownup/conditions/als.html

•

From the National Institutes of Health Amyotrophic Lateral Sclerosis Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotro phiclateralsclerosis.htm

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Amyotrophic Lateral Sclerosis (ALS) Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/amyotrophiclat eralsclerosis.htm •

Latest News Abnormal Protein Linked to Two Neurological Diseases Source: 10/05/2006, HealthDay http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_39619 .html Studies Suggest Military Service Increases Risk for ALS Source: 11/10/2006, HealthDay http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_41181 .html

•

Organizations ALS Association http://www.alsa.org/ Muscular Dystrophy Association http://www.mda.org/ National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/ Society for Neuroscience http://web.sfn.org/

•

Research Can Computers Read Your Mind? Source: 05/24/2005, American Academy of Neurology http://www.neurology.org/cgi/content/full/64/10/E30 What's Old is New Again - Antibiotic Protects Nerves by Removing Excess Glutamate Source: 02/07/2005, National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/news_and_events/news_articles/news_article_ALS_ce ftriaxone.htm

•

Statistics Who Gets ALS Source: ALS Association http://www.alsa.org/als/who.cfm?CFID=12809

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

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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: •

ALS MND Alliance Summary: Amyotrophic Lateral Sclerosis (ALS), Progressive Muscular Atrophy (PMA. Palsy (PBP),Primary Lateral Sclerosis (PLS) are. of cases are familial (inherited) with. Source: www.alsmndalliance.org http://www.alsmndalliance.org/whatis.html

•

Amyotrophic Lateral Sclerosis Fact Sheet Summary: Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, is arapidly progressive. The familial form of ALS usually results from a pattern of. Source: www.ninds.nih.gov http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophic lateralsclerosis.htm

•

Diaphragm Training (DT) in Amyotrophic Lateral Sclerosis Summary: Diaphragm Training (DT) in Amyotrophic Lateral Sclerosis Rachel Nardin, MD andElizabeth. respiratory decline and improve survival in this progressive disease. Source: www.alsa.org http://www.alsa.org/patient/grant.cfm?id=750

•

Experts Suggest Promising Drugs for ALS Clinical Trials Summary: compounds that show promise for treating amyotrophic lateral sclerosis (ALS, also.of the biology of the motor neuron, the cell that dies in the disease. Source: www.alsa.org http://www.alsa.org/patient/article.cfm?id=987

•

Huntington's Disease Press Releases Summary: 18, 2003. A new study reveals for the first time how gene mutations lead to the inherited form of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. Source: www.ninds.nih.gov http://www.ninds.nih.gov/disorders/huntington/press_huntington.htm

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Job Accommodation Network Summary: Accommodation Ideas. Amyotrophic Lateral Sclerosis (ALS)/Lou Gehrig's Disease. Amyotrophic lateral sclerosis (ALS), often referred. Source: www.jan.wvu.edu http://www.jan.wvu.edu/soar/other/als.html

•

MDA / Quest 3-3 / Research Updates Summary: Researchers at Massachusetts General Hospital in Boston are recruiting patientswith familial amyotrophic lateral sclerosis for a trial of the drug. Source: www.mdausa.org http://www.mdausa.org/publications/Quest/q33resup.html

•

National Registry of Veterans with Amyotrophic Lateral Sclerosis. Summary: Title: National Registry of Veterans with Amyotrophic Lateral Sclerosis. ALS is adisease of high priority to the VA, particularly due to ongoing concerns about. Source: www.alsa.org http://www.alsa.org/patient/drug.cfm?id=628 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 amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis (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

•

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

•

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

•

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

•

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

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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 amyotrophic lateral sclerosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis. 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 amyotrophic lateral sclerosis (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 amyotrophic lateral sclerosis (or a synonym) into the search box, and click Submit Query.

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Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families32: •

Genetic Alliance: http://geneticalliance.org

•

Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html

•

Madisons Foundation: http://www.madisonsfoundation.org/

•

March of Dimes: http://www.marchofdimes.com

•

National Organization for Rare Disorders (NORD): http://www.rarediseases.org/ For More Information on Genetics

The following publications offer detailed information for patients about the science of genetics: •

What Is a Genome?: http://www.ncbi.nlm.nih.gov/About/primer/genetics_genome.html

•

A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html

•

Genetic Mapping: http://www.genome.gov/10000715

32

Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/archive//20040831/nichsr/ta101/ta10108.html

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on amyotrophic lateral sclerosis: •

Basic Guidelines for Amyotrophic Lateral Sclerosis ALS Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000688.htm Amyotrophic lateral sclerosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000688.htm Spinal stenosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000441.htm

•

Signs & Symptoms for Amyotrophic Lateral Sclerosis Ankle, feet, and leg swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003104.htm Apnea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003069.htm

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Clumsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003198.htm Difficulty breathing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Difficulty swallowing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003115.htm Hoarseness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003054.htm Incontinence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003142.htm Leg swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003104.htm Loss of bladder control Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003142.htm Muscle Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003193.htm Muscle atrophy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003188.htm Muscle contractions Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003193.htm Muscle cramps Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003193.htm Muscle weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm Paralysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003190.htm Spasms Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003193.htm Spasticity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003297.htm Speech impairment Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003204.htm Swelling Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm

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Ulcers Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003228.htm Urinary frequency/urgency, increased Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003140.htm Wasting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003188.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm •

Diagnostics and Tests for Amyotrophic Lateral Sclerosis AMP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003368.htm ANA Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003535.htm Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm Chest X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Differential Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003657.htm EMG Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003929.htm Head CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003786.htm Lumbar puncture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003428.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm MRI of head Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003791.htm Protein C Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003659.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm

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Nutrition for Amyotrophic Lateral Sclerosis Nursing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002450.htm

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Surgery and Procedures for Amyotrophic Lateral Sclerosis Tracheostomy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002955.htm

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Background Topics for Amyotrophic Lateral Sclerosis ALS - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002189.htm Aspiration Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002216.htm Choking Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000047.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Lateral Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002244.htm Noninvasive Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002269.htm Proximal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002287.htm Respiratory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002290.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

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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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AMYOTROPHIC LATERAL SCLEROSIS 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] Ablation: The removal of an organ by surgery. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] 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] Acidemia: Increased acidity of blood. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Actin: Essential component of the cell skeleton. [NIH] Action Potentials: The electric response of a nerve or muscle to its stimulation. [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]

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Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenoleukodystrophy: A chromosome X-linked disease. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] 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] 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] 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] Allogeneic: Taken from different individuals of the same species. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH]

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Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Ambulatory Care: Health care services provided to patients on an ambulatory basis, rather than by admission to a hospital or other health care facility. The services may be a part of a hospital, augmenting its inpatient services, or may be provided at a free-standing facility. [NIH]

Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino 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] Aminolevulinic Acid: A compound produced from succinyl-CoA and glycine as an intermediate in heme synthesis. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgenic: Producing masculine characteristics. [EU]

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Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] 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] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anterograde: Moving or extending forward; called also antegrade. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-infective: An agent that so acts. [EU]

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Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] 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] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [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] Approximate: Approximal [EU] Apraxia: Loss of ability to perform purposeful movements, in the absence of paralysis or sensory disturbance, caused by lesions in the cortex. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articulation: The relationship of two bodies by means of a moveable joint. [NIH] Artificial Organs: Devices intended to replace non-functioning organs. They may be temporary or permanent. Since they are intended always to function as the natural organs they are replacing, they should be differentiated from prostheses and implants and specific types of prostheses which, though also replacements for body parts, are frequently cosmetic (artificial eye) as well as functional (artificial limbs). [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

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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] 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] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [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] Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [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] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Axotomy: Transection or severing of an axon. This type of denervation is used often in experimental studies on neuronal physiology and neuronal death or survival, toward an understanding of nervous system disease. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [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]

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Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Beta Rays: A stream of positive or negative electrons ejected with high energy from a disintegrating atomic nucleus; most biomedically used isotopes emit negative particles (electrons or negatrons, rather than positrons). Cathode rays are low-energy negative electrons produced in cathode ray tubes, also called television tubes or oscilloscopes. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassays: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] 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] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and

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protein structure function analysis and prediction. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blinking: Brief closing of the eyelids by involuntary normal periodic closing, as a protective measure, or by voluntary action. [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 Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood urea: A waste product in the blood that comes from the breakdown of food protein. The kidneys filter blood to remove urea. As kidney function decreases, the BUN level increases. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body 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] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Diseases: Pathologic conditions affecting the brain, which is composed of the intracranial components of the central nervous system. This includes (but is not limited to) the cerebral cortex; intracranial white matter; basal ganglia; thalamus; hypothalamus; brain stem; and cerebellum. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Bromine: A halogen with the atomic symbol Br, atomic number 36, and atomic weight 79.904. It is a volatile reddish-brown liquid that gives off suffocating vapors, is corrosive to the skin, and may cause severe gastroenteritis if ingested. [NIH]

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Bronchial: Pertaining to one or more bronchi. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bulbar: Pertaining to a bulb; pertaining to or involving the medulla oblongata, as bulbar paralysis. [EU] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [NIH] Calcitonin Gene-Related Peptide: Calcitonin gene-related peptide. A 37-amino acid peptide derived from the calcitonin gene. It occurs as a result of alternative processing of mRNA from the calcitonin gene. The neuropeptide is widely distributed in neural tissue of the brain, gut, perivascular nerves, and other tissue. The peptide produces multiple biological effects and has both circulatory and neurotransmitter modes of action. In particular, it is a potent endogenous vasodilator. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Cannabis: The hemp plant Cannabis sativa. Products prepared from the dried flowering tops of the plant include marijuana, hashish, bhang, and ganja. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [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] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH]

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Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Castration: Surgical removal or artificial destruction of gonads. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Ceftriaxone: Broad-spectrum cephalosporin antibiotic with a very long half-life and high penetrability to usually inaccessible infections, including those involving the meninges, eyes, inner ears, and urinary tract. [NIH] Celecoxib: A drug that reduces pain. Celecoxib belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is being studied for cancer prevention. [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 Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and

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adaptability. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Diseases: Diseases of any component of the brain (including the cerebral hemispheres, diencephalon, brain stem, and cerebellum) or the spinal cord. [NIH] Centrioles: Self-replicating, short, fibrous, rod-shaped organelles. Each centriole is a short cylinder containing nine pairs of peripheral microtubules, arranged so as to form the wall of the cylinder. [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] Centrosome: The cell center, consisting of a pair of centrioles surrounded by a cloud of amorphous material called the pericentriolar region. During interphase, the centrosome nucleates microtubule outgrowth. The centrosome duplicates and, during mitosis, separates to form the two poles of the mitotic spindle (mitotic spindle apparatus). [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [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] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or

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immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [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] Chlorine: A greenish-yellow, diatomic gas that is a member of the halogen family of elements. It has the atomic symbol Cl, atomic number 17, and atomic weight 70.906. It is a powerful irritant that can cause fatal pulmonary edema. Chlorine is used in manufacturing, as a reagent in synthetic chemistry, for water purification, and in the production of chlorinated lime, which is used in fabric bleaching. [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] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chondrodysplasia Punctata: A heterogeneous group of bone dysplasias, the common character of which is stippling of the epiphyses in infancy. The group includes a severe autosomal recessive form (Chondrodysplasia punctata, rhizomelic), an autosomal dominant form (Conradi-Hunermann syndrome), and a milder X-linked form. Metabolic defects associated with impaired peroxisomes are present only in the rhizomelic form. [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 the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chromosome Segregation: The orderly segregation of chromosomes during meiosis or mitosis. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary Neurotrophic Factor: A neurotrophic factor that promotes the survival of various neuronal cell types and may play an important role in the injury response in the nervous system. [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

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certain fractures. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] 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] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] 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

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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] Compulsions: 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 for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] 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

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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] Coreceptors: Invariant receptor of the helper T-cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] 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] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Cranial Nerves: Twelve pairs of nerves that carry general afferent, visceral afferent, special afferent, somatic efferent, and autonomic efferent fibers. [NIH] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]

Creatine Kinase: A transferase that catalyzes formation of phosphocreatine from ATP + creatine. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic isoenzymes have been identified in human tissues: MM from skeletal muscle, MB from myocardial tissue, and BB from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins. EC 2.7.3.2. [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] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [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

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contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [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] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [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

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cell membrane potential to become positive with respect to the potential outside the cell. [EU] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] 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] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] 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

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its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [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] Doxycycline: A synthetic tetracycline derivative with a range of antimicrobial activity and mode of action similar to that of tetracycline, but more effective against many species. Animal studies suggest that it may cause less tooth staining than other tetracyclines. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dynein: A transport protein that normally binds proteins to the microtubule. [NIH] Dysarthria: Imperfect articulation of speech due to disturbances of muscular control which result from damage to the central or peripheral nervous system. [EU] Dyskinesias: Abnormal involuntary movements which primarily affect the extremities, trunk, or jaw that occur as a manifestation of an underlying disease process. Conditions which feature recurrent or persistent episodes of dyskinesia as a primary manifestation of disease may be referred to as dyskinesia syndromes (movement disorders). Dyskinesias are also a relatively common manifestation of basal ganglia diseases. [NIH] Dysphagia: Difficulty in swallowing. [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] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service

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produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electromyography: Recording of the changes in electric potential of muscle by means of surface or needle electrodes. [NIH] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

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] Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium,

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vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [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] Eukaryote: An organism (or a cell) that carries its genetic material physically constrained within a nuclear membrane, separate from the cytoplasm. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH]

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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] 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] Expiratory: The volume of air which leaves the breathing organs in each expiration. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

External radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external-beam radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [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] Eye Movements: Voluntary or reflex-controlled movements of the eye. [NIH] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH]

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

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

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Flatus: Gas passed through the rectum. [NIH] Flexion: In gynaecology, a displacement of the uterus in which the organ is bent so far forward or backward that an acute angle forms between the fundus and the cervix. [EU] Flexor: Muscles which flex a joint. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] 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]

Fundus: The larger part of a hollow organ that is farthest away from the organ's opening.

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The bladder, gallbladder, stomach, uterus, eye, and cavity of the middle ear all have a fundus. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors,

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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] Generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used in a radiopharmaceutical. [NIH] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] 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]

Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

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Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonads: The gamete-producing glands, ovary or testis. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] 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] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Hair Color: Color of hair or fur. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Health Promotion: Encouraging consumer behaviors most likely to optimize health potentials (physical and psychosocial) through health information, preventive programs, and access to medical care. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated

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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] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [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] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to

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remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] 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] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hyperreflexia: Exaggeration of reflexes. [EU] 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] Hypochlorous Acid: HClO. An oxyacid of chlorine containing monovalent chlorine that acts as an oxidizing or reducing agent. [NIH] Hypokinesia: Slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other

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conditions. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

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

effects

of

foreign

Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]

Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU]

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In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [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] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH]

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Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of any of a number of different proteins and form a ring around the cell nucleus. [NIH] Interneurons: Most generally any neurons which are not motor or sensory. Interneurons may also refer to neurons whose axons remain within a particular brain region as contrasted with projection neurons which have axons projecting to other brain regions. [NIH] Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH]

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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] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isometric Contraction: Muscular contractions characterized by increase in tension without change in length. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Language Disorders: Conditions characterized by deficiencies of comprehension or expression of written and spoken forms of language. These include acquired and

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developmental disorders. [NIH] Laryngeal: Having to do with the larynx. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lip: Either of the two fleshy, full-blooded margins of the mouth. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Liposomes: Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes

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and membrane proteins. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Loading dose: A quantity higher than the average or maintenance dose, used at the initiation of therapy to rapidly establish a desired level of the drug [EU] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Potentiation: A persistent increase in synaptic efficacy, usually induced by appropriate activation of the same synapses. The phenomenological properties of long-term potentiation suggest that it may be a cellular mechanism of learning and memory. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macroglia: A type of neuroglia composed of astrocytes. [NIH]

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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] Malformation: A morphologic developmental process. [EU]

defect

resulting

from

an

intrinsically

abnormal

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] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Mechanical ventilation: Use of a machine called a ventilator or respirator to improve the exchange of air between the lungs and the atmosphere. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into

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immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metabotropic: A glutamate receptor which triggers an increase in production of 2 intracellular messengers: diacylglycerol and inositol 1, 4, 5-triphosphate. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] 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] Microfilaments: The smallest of the cytoskeletal filaments. They are composed chiefly of actin. [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] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubule-Associated Proteins: High molecular weight proteins found in the microtubules of the cytoskeletal system. Under certain conditions they are required for

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tubulin assembly into the microtubules and stabilize the assembled microtubules. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [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] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitotic Spindle Apparatus: An organelle consisting of three components: (1) the astral microtubules, which form around each centrosome and extend to the periphery; (2) the polar microtubules which extend from one spindle pole to the equator; and (3) the kinetochore microtubules, which connect the centromeres of the various chromosomes to either centrosome. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular mass: The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16). [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH]

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Mononuclear: A cell with one nucleus. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] Motor Cortex: Area of the frontal lobe concerned with primary motor control. It lies anterior to the central sulcus. [NIH] Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [NIH]

Motor Neurons: Neurons which activate muscle cells. [NIH] Movement Disorders: Syndromes which feature dyskinesias as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle 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 Fatigue: A state arrived at through prolonged and strong contraction of a muscle. Studies in athletes during prolonged submaximal exercise have shown that muscle fatigue increases in almost direct proportion to the rate of muscle glycogen depletion. Muscle fatigue in short-term maximal exercise is associated with oxygen lack and an increased level of blood and muscle lactic acid, and an accompanying increase in hydrogen-ion concentration in the exercised muscle. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscle Hypertonia: Abnormal increase in skeletal or smooth muscle tone. Skeletal muscle hypertonicity may be associated with pyramidal tract lesions or basal ganglia diseases. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Diseases: Acquired, familial, and congenital disorders of skeletal muscle and smooth muscle. [NIH] Musculature: The muscular apparatus of the body, or of any part of it. [EU] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH]

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Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [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] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [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] Nervous System Diseases: Diseases of the central and peripheral nervous system. This includes disorders of the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscle. [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]

Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized

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by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) ubiquitin. As one of the hallmarks of Alzheimer disease, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease. [NIH] Neurofilaments: Bundle of neuronal fibers. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurologist: A doctor who specializes in the diagnosis and treatment of disorders of the nervous system. [NIH] 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 Diseases: A general term encompassing lower motor neuron disease; peripheral nervous system diseases; and certain muscular diseases. Manifestations include muscle weakness; fasciculation; muscle atrophy; spasm; myokymia; muscle hypertonia, myalgias, and musclehypotonia. [NIH] 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 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] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [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]

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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] Neurotrophins: A nerve growth factor. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nucleates: Bacteria-inducing ice nucleation at warm temperatures (between zero and minus ten degrees C.). [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides

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form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [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] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] 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] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Orderly: A male hospital attendant. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] 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] 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]

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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] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Paraparesis: Mild to moderate loss of bilateral lower extremity motor function, which may be a manifestation of spinal cord diseases; peripheral nervous system diseases; muscular diseases; intracranial hypertension; parasagittal brain lesions; and other conditions. [NIH] Paraplegia: Severe or complete loss of motor function in the lower extremities and lower portions of the trunk. This condition is most often associated with spinal cord diseases, although brain diseases; peripheral nervous system diseases; neuromuscular diseases; and muscular diseases may also cause bilateral leg weakness. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] 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]

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Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pentoxifylline: A methylxanthine derivative that inhibits phosphodiesterase and affects blood rheology. It improves blood flow by increasing erythrocyte and leukocyte flexibility. It also inhibits platelet aggregation. Pentoxifylline modulates immunologic activity by stimulating cytokine production. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perineal: Pertaining to the perineum. [EU] Perineum: The area between the anus and the sex organs. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Nervous System Diseases: Diseases of the peripheral nerves external to the brain and spinal cord, which includes diseases of the nerve roots, ganglia, plexi, autonomic nerves, sensory nerves, and motor nerves. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Perivascular: Situated around a vessel. [EU] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Peroxisomal Disorders: A heterogeneous group of inherited metabolic disorders marked by absent or dysfunctional peroxisomes. Peroxisomal enzymatic abnormalities may be single or multiple. Biosynthetic peroxisomal pathways are compromised, including the ability to synthesize ether lipids and to oxidize long-chain fatty acid precursors. Diseases in this category include Zellweger syndrome; infantile Refsum disease; rhizomelic

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chondrodysplasia (chondrodysplasia punctata, rhizomelic); hyperpipecolic acidemia; neonatal adrenoleukodystrophy; and adrenoleukodystrophy (X-linked). Neurologic dysfunction is a prominent feature of most peroxisomal disorders. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylbutyrate: An anticancer drug that belongs to the family of drugs called differentiating agents. [NIH] 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] 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] Phosphotyrosine: An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis. [NIH] Photoallergy: Sensitization of the skin to light usually due to the action of certain substances or drugs, may occur shortly after exposure to a substance or after a latent period of from days to months. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] 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.

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[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] Pitch: The subjective awareness of the frequency or spectral distribution of a sound. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] 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] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [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] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] 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]

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Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] Porphyria, Hepatic: Porphyria in which the liver is the site where excess formation of porphyrin or its precursors is found. Acute intermittent porphyria and porphyria cutanea tarda are types of hepatic porphyria. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Presynaptic Terminals: The distal terminations of axons which are specialized for the release of neurotransmitters. Also included are varicosities along the course of axons which have similar specializations and also release transmitters. Presynaptic terminals in both the central and peripheral nervous systems are included. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prion: Small proteinaceous infectious particles that resist inactivation by procedures

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modifying nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH]

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Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostaglandins F: (9 alpha,11 alpha,13E,15S)-9,11,15-Trihydroxyprost-13-en-1-oic acid (PGF(1 alpha)); (5Z,9 alpha,11,alpha,13E,15S)-9,11,15-trihydroxyprosta-5,13-dien-1-oic acid (PGF(2 alpha)); (5Z,9 alpha,11 alpha,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1oic acid (PGF(3 alpha)). A family of prostaglandins that includes three of the six naturally occurring prostaglandins. All naturally occurring PGF have an alpha configuration at the 9carbon position. They stimulate uterine and bronchial smooth muscle and are often used as oxytocics. [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] Prosthesis: An artificial replacement of a part of the body. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein 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] Protein Transport: The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport. [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] 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] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH]

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Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] 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 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] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH]

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Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [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] Reaction Time: The time from the onset of a stimulus until the organism responds. [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, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [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 blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] 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] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Rehabilitative: Instruction of incapacitated individuals or of those affected with some mental disorder, so that some or all of their lost ability may be regained. [NIH]

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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] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rheology: The study of the deformation and flow of matter, usually liquids or fluids, and of the plastic flow of solids. The concept covers consistency, dilatancy, liquefaction, resistance to flow, shearing, thixotrophy, and viscosity. [NIH] 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] Ribonucleoproteins: Proteins conjugated with ribonucleic acids (RNA) or specific RNA. Many viruses are ribonucleoproteins. [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] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Robotics: The application of electronic, computerized control systems to mechanical devices designed to perform human functions. Formerly restricted to industry, but nowadays applied to artificial organs controlled by bionic (bioelectronic) devices, like automated insulin pumps and other prostheses. [NIH]

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Rod: A reception for vision, located in the retina. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] 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 structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Seminal vesicles: Glands that help produce semen. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH]

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Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [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] 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]

Sialorrhea: Increased salivary flow. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] 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] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH]

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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] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrometer: An apparatus for determining spectra; measures quantities such as wavelengths and relative amplitudes of components. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU]

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Speech Disorders: Acquired or developmental conditions marked by an impaired ability to comprehend or generate spoken forms of language. [NIH] Speech Intelligibility: Ability to make speech sounds that are recognizable. [NIH] Sperm: The fecundating fluid of the male. [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] Spinal Cord Diseases: Pathologic conditions which feature spinal cord damage or dysfunction, including disorders involving the meninges and perimeningeal spaces surrounding the spinal cord. Traumatic injuries, vascular diseases, infections, and inflammatory/autoimmune processes may affect the spinal cord. [NIH] Spinal Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [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] Stenosis: Narrowing or stricture of a duct or canal. [EU] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Stereotaxis: Use of a computer and scanning devices to create three-dimensional pictures. This method can be used to direct a biopsy, external radiation, or the insertion of radiation implants. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other

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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] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] 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] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [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

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nervous system. Called also adrenergic. [EU] 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] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synchrotron: An accelerator in which the particles are guided by an increasing magnetic field while they are accelerated several times in an approximately circular path by electric fields produced by a high-frequency generator. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] 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] 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] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetani: Causal agent of tetanus. [NIH] Tetanic: Having the characteristics of, or relating to tetanus. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by Clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the

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generalized form. [NIH] Tetanus Toxin: The toxin elaborated by Clostridium tetani. It is a protein with a molecular weight of about 150,000, probably consisting of two fragments, tetanolysin being the hemolytic and tetanospasmin the neurotoxic principle. The toxin causes disruption of the inhibitory mechanisms of the CNS, thus permitting uncontrolled nervous activity, leading to fatal convulsions. [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] Thanatology: The study of the theory, philosophy, and doctrine of death. [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] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] 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]

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Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] 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] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Tracheotomy: Surgical incision of the trachea. [NIH] Traction: The act of pulling. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

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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] Translocate: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]

Trophic: Of or pertaining to nutrition. [EU] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH]

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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] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Umbilical cord blood: Blood from the placenta (afterbirth) that contains high concentrations of stem cells needed to produce new blood cells. [NIH] 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] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urogenital System: All the organs involved in reproduction and the formation and release of urine. It includes the kidneys, ureters, bladder, urethra, and the organs of reproduction ovaries, uterus, fallopian tubes, vagina, and clitoris in women and the testes, seminal vesicles, prostate, seminal ducts, and penis in men. [NIH] Uroporphyrinogen Decarboxylase: One of the enzymes active in heme biosynthesis. It catalyzes the decarboxylation of uroporphyrinogen III to coproporphyrinogen III by the conversion of four acetic acid groups to four methyl groups. EC 4.1.1.37. [NIH] URR: A blood test that compares the amount of blood urea nitrogen before and after dialysis to measure the effectiveness of the dialysis dose. [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]

Dictionary 269

Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] VE: The total volume of gas either inspired or expired in one minute. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] 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]

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Vital Capacity: The volume of air that is exhaled by a maximal expiration following a maximal inspiration. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vocal cord: The vocal folds of the larynx. [NIH] 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]

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] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

271

INDEX 3 3-dimensional, 156, 187, 208 A Abdomen, 208, 215, 240, 249, 263, 269 Aberrant, 24, 36, 39, 48, 70, 208 Ablation, 64, 208 Acceptor, 39, 208, 239, 248, 266 Acetylcholine, 208, 247 Acidemia, 208, 251 Acoustic, 26, 208 Actin, 157, 208, 242, 244, 245, 246 Action Potentials, 34, 48, 208 Adaptability, 208, 217, 218 Adaptation, 34, 208, 252 Adenine, 150, 208, 256 Adenosine, 76, 151, 208, 251 Adenosine Triphosphate, 151, 208, 251 Adenovirus, 183, 208 Adjustment, 208, 209 Adolescence, 4, 46, 209 Adrenal Medulla, 209, 217, 227, 247 Adrenoleukodystrophy, 47, 209, 251 Adverse Effect, 209, 260 Aerobic, 209, 243 Affinity, 27, 43, 62, 209, 213, 261 Age of Onset, 141, 209 Agonist, 38, 209, 225 Algorithms, 58, 209, 214 Alkaline, 209, 216, 249 Alleles, 67, 152, 169, 209, 233, 234 Allergen, 209, 224 Allogeneic, 50, 209 Alpha-1, 165, 169, 209 Alternative medicine, 209 Aluminum, 209 Alveoli, 210, 269 Ambulatory Care, 210 Ameliorated, 56, 210 Amino Acid Sequence, 210, 211, 228, 231 Amino Acid Substitution, 68, 210 Aminolevulinic Acid, 141, 142, 210 Amnion, 210 Amniotic Fluid, 178, 180, 210 Ampulla, 210, 226 Amyloid, 41, 51, 57, 83, 92, 210 Anaesthesia, 210, 236 Anal, 64, 210, 240 Analogous, 74, 210, 266 Anaphylatoxins, 210, 221

Anatomical, 75, 82, 210, 219, 235, 242, 259 Androgenic, 26, 45, 210 Androgens, 26, 45, 211 Anemia, 164, 165, 168, 169, 174, 211 Aneuploidy, 162, 163, 211 Animal model, 31, 35, 36, 46, 48, 50, 57, 61, 63, 72, 76, 101, 116, 211 Anions, 211, 238, 263 Anomalies, 57, 211 Anterograde, 28, 211 Antibacterial, 211, 261 Antibiotic, 29, 199, 211, 217, 243, 250, 261, 265 Antibodies, 46, 65, 86, 142, 157, 211, 232, 235, 243, 252 Antibody, 143, 157, 209, 211, 220, 232, 234, 235, 236, 241, 243, 256, 261 Anticoagulant, 211, 255 Anticonvulsant, 211, 258 Antifungal, 29, 211 Antigen, 209, 211, 220, 234, 235, 236, 241, 242 Antigen-Antibody Complex, 211, 220 Anti-infective, 211, 234 Anti-inflammatory, 63, 212, 217 Anti-Inflammatory Agents, 63, 212, 217 Antimicrobial, 212, 225 Antioxidant, 31, 32, 66, 73, 81, 91, 212, 249 Anuria, 212, 238 Anus, 210, 212, 220, 237, 250 Anxiety, 212, 248 Aponeurosis, 212, 230 Apoptosis, 27, 29, 30, 40, 45, 50, 54, 59, 62, 90, 105, 108, 151, 160, 212, 217, 222 Approximate, 44, 212 Apraxia, 12, 69, 212 Aqueous, 212, 214, 223, 234 Arachidonic Acid, 35, 212, 239, 254 Arginine, 13, 64, 210, 212, 233, 247 Arterial, 212, 234, 255 Arteries, 212, 215, 222, 238, 265, 268 Arterioles, 212, 215, 216 Artery, 36, 212, 238, 256, 268 Articulation, 212, 225 Artificial Organs, 212, 258 Aspartate, 30, 43, 46, 212 Assay, 38, 58, 74, 212, 235 Astrocytes, 27, 49, 93, 108, 212, 240, 242 Ataxia, 12, 69, 74, 213, 265

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Atmospheric Pressure, 213, 234 Atrophy, 4, 26, 37, 54, 103, 123, 205, 213, 246 Attenuated, 213 Attenuation, 53, 213 Atypical, 173, 213 Auditory, 213 Autoimmune disease, 29, 213, 244 Autonomic Nervous System, 213, 245, 250, 263 Axons, 18, 21, 28, 65, 90, 213, 223, 237, 245, 250, 253 Axotomy, 53, 213 B Bacteria, 29, 65, 149, 157, 161, 211, 213, 228, 240, 242, 247, 257, 261, 262, 266, 268 Bacterial Physiology, 208, 213 Basal Ganglia, 213, 215, 225, 230, 234, 244 Basal Ganglia Diseases, 213, 225, 234, 244 Base Sequence, 161, 214, 229, 231 Basophils, 214, 232 Benign, 214, 230 Beta Rays, 214, 226 Beta-pleated, 210, 214 Bewilderment, 214, 221 Bilateral, 35, 101, 214, 249 Bile, 214, 234, 240, 262 Binding Sites, 71, 214 Bioassays, 67, 214 Bioavailability, 60, 214 Biological Transport, 214, 224 Biomarkers, 45, 84, 87, 113, 141, 214 Biophysics, 23, 28, 55, 58, 62, 65, 93, 214 Biopsy, 206, 214, 262 Biosynthesis, 29, 212, 214, 259, 268 Biotechnology, 5, 79, 145, 156, 183, 185, 190, 214 Bladder, 205, 215, 230, 244, 246, 255, 268 Blastocyst, 215, 221, 252 Blinking, 73, 215 Blood Coagulation, 215, 216, 265 Blood Glucose, 215, 233, 237 Blood Platelets, 215, 260 Blood pressure, 168, 215, 216, 234, 243, 261 Blood urea, 215, 238, 268 Blood vessel, 172, 215, 216, 218, 219, 226, 233, 238, 242, 250, 260, 261, 263, 265, 269 Blot, 61, 215 Body Fluids, 214, 215, 216, 225, 248, 261, 267 Bone Marrow, 111, 184, 215, 231, 240, 243 Bowel, 210, 215, 263

Bradykinin, 215, 247 Brain Diseases, 215, 249 Brain Stem, 215, 218, 246 Bromine, 78, 215 Bronchial, 216, 255 Buccal, 178, 180, 216 Bulbar, 9, 26, 53, 84, 85, 86, 88, 95, 111, 115, 216 Bypass, 66, 216 C Calcitonin, 26, 216 Calcitonin Gene-Related Peptide, 26, 216 Calcium, 34, 48, 85, 143, 216, 220, 241, 260 Callus, 216, 226 Cannabis, 216 Capillary, 71, 215, 216, 269 Carbohydrate, 216, 232 Carcinogenesis, 216, 251 Carcinogenic, 216, 236, 248, 254, 262 Cardiac, 216, 227, 228, 262 Cardiovascular, 31, 45, 187, 216, 239, 260 Cardiovascular disease, 31, 187, 216 Carnitine, 107, 216 Case report, 106, 116, 217 Case series, 217 Caspase, 30, 54, 63, 217 Castration, 45, 217 Catecholamine, 217, 224, 251 Cathode, 214, 217, 226 Cations, 217, 238 Causal, 46, 81, 217, 264 Cause of Death, 74, 217, 223 Ceftriaxone, 199, 217 Celecoxib, 119, 217 Cell Cycle, 159, 160, 217, 222 Cell Death, 30, 36, 40, 48, 54, 55, 63, 70, 105, 160, 212, 217, 245 Cell Differentiation, 217, 260 Cell Division, 152, 159, 160, 172, 173, 213, 217, 218, 232, 237, 241, 243, 252, 254, 259 Cell membrane, 8, 143, 214, 217, 223, 230, 270 Cell proliferation, 54, 217, 260 Cell Respiration, 217, 243, 258 Cell Survival, 41, 70, 74, 217, 232 Central Nervous System Diseases, 60, 218 Centrioles, 218, 254 Centromere, 152, 155, 218 Centrosome, 10, 218, 243 Ceramide, 29, 218 Cerebellar, 38, 56, 213, 218, 257, 267 Cerebellum, 215, 218, 257

Index 273

Cerebral, 36, 58, 75, 77, 85, 89, 213, 215, 218, 221, 227, 229, 245, 249, 261, 264 Cerebral Cortex, 58, 213, 215, 218, 227, 245 Cerebral hemispheres, 213, 215, 218, 264 Cerebral Palsy, 75, 218, 261 Cerebrospinal, 84, 100, 112, 113, 119, 143, 218 Cerebrospinal fluid, 84, 100, 112, 113, 119, 143, 218 Cerebrovascular, 213, 216, 218, 265 Cerebrum, 218, 264 Cervical, 218 Cervix, 218, 229 Character, 218, 219, 223 Chelation, 31, 218 Chemotactic Factors, 218, 221 Chin, 219, 242 Chlorine, 219, 234 Cholesterol, 151, 214, 219, 222, 262 Chondrocytes, 219, 229 Chondrodysplasia Punctata, 219, 251 Chromatin, 212, 219, 227, 240 Chromosomal, 57, 160, 162, 163, 173, 174, 175, 177, 211, 219, 233, 244 Chromosome, 3, 9, 11, 13, 15, 16, 17, 19, 21, 22, 46, 72, 95, 110, 152, 153, 154, 155, 156, 159, 160, 162, 163, 169, 170, 173, 174, 179, 182, 209, 211, 218, 219, 233, 238, 239, 244, 259, 267 Chromosome Fragility, 219, 267 Chromosome Segregation, 72, 219 Chronic, 24, 30, 35, 46, 48, 78, 219, 224, 236, 238, 239, 263 Chronic Disease, 219, 239 Ciliary, 56, 219 Ciliary Neurotrophic Factor, 56, 219 Cirrhosis, 219, 232 CIS, 219, 230, 231 Clamp, 38, 55, 219 Clear cell carcinoma, 220, 224 Clinical Medicine, 186, 220, 253 Cloning, 30, 46, 214, 220 Codon, 157, 220, 231 Cofactor, 32, 68, 70, 220, 255, 265 Collagen, 220, 228, 241, 252, 254 Colloidal, 220, 226 Colon, 166, 220 Colonoscopy, 168, 220 Complement, 71, 87, 210, 220, 221, 231, 238 Complementary medicine, 125, 221 Compulsions, 221, 248

Computational Biology, 190, 221 Concentric, 221, 247 Conception, 159, 221, 229, 261, 262 Concomitant, 77, 221 Conduction, 16, 198, 221 Confusion, 166, 221, 224, 268 Conjugated, 31, 221, 223, 258 Connective Tissue, 215, 220, 221, 229, 230, 240, 242, 250, 264 Consciousness, 221, 223, 224, 255 Constriction, 152, 155, 221, 238 Consultation, 174, 175, 178, 179, 221 Contamination, 79, 221 Contraindications, ii, 221 Controlled study, 63, 221 Convulsions, 211, 221, 265 Coordination, 27, 33, 39, 218, 222, 244 Coreceptors, 39, 222 Coronary, 36, 216, 222 Coronary heart disease, 216, 222 Cortex, 34, 73, 212, 222, 227, 254 Cortical, 39, 54, 116, 123, 143, 222, 228, 265 Cranial, 56, 218, 222, 237, 245, 250 Cranial Nerves, 222, 245 Creatine, 35, 198, 222 Creatine Kinase, 198, 222 Creatinine, 222, 238 Crossing-over, 222, 257 Curative, 222, 247, 265 Cutaneous, 142, 222, 251 Cyclic, 65, 222, 232, 247, 251, 254 Cyclin, 51, 222 Cysteine, 36, 222 Cysteinyl, 86, 222 Cystine, 222 Cytochrome, 70, 222, 248 Cytokine, 35, 56, 223, 250 Cytoplasm, 24, 65, 149, 150, 151, 157, 212, 214, 217, 223, 227, 240, 243, 246, 247, 258, 264 Cytosine, 150, 223, 256 Cytoskeleton, 8, 24, 223, 243 Cytotoxic, 64, 120, 142, 143, 223, 235, 260 Cytotoxicity, 143, 223 D De novo, 160, 223 Death Certificates, 168, 223 Degenerative, 26, 34, 44, 54, 66, 76, 198, 223, 244 Deletion, 18, 55, 106, 162, 212, 223 Dementia, 25, 30, 41, 59, 83, 87, 94, 95, 110, 116, 117, 119, 142, 145, 146, 163, 223, 246

274

Amyotrophic Lateral Sclerosis

Dendrites, 18, 21, 45, 223, 246 Dendritic, 24, 41, 223 Dentate Gyrus, 223, 233 Deoxyribonucleic, 150, 223, 258 Deoxyribonucleic acid, 150, 223, 258 Deoxyribonucleotides, 223 Depolarization, 223, 260 Deprivation, 62, 224 DES, 31, 210, 224 Desensitization, 38, 224, 235 Deuterium, 224, 234 Diabetes Mellitus, 224, 233 Diagnostic procedure, 140, 224 Diffusion, 48, 62, 89, 90, 113, 115, 214, 224 Digestion, 214, 215, 224, 240, 263, 268 Diploid, 211, 224, 244, 252, 267 Discrimination, 180, 181, 186, 224 Disease Progression, 4, 27, 29, 35, 42, 54, 61, 63, 79, 113, 118, 121, 224 Disorientation, 221, 224 Dissociation, 39, 45, 209, 224 Dissociative Disorders, 224 Distal, 28, 90, 224, 250, 253, 255 Dopamine, 91, 224, 247, 251 Dorsum, 225, 230 Double-blind, 32, 35, 47, 63, 225 Doxycycline, 30, 225 Drug Resistance, 29, 225 Drug Tolerance, 225, 266 Duct, 210, 225, 240, 259, 262 Duodenum, 214, 225, 226, 263 Dura mater, 225, 242, 249 Dyes, 23, 210, 214, 225 Dynein, 65, 72, 225 Dysarthria, 26, 225 Dyskinesias, 213, 225, 244 Dysphagia, 107, 111, 138, 225 Dystonia, 57, 225 Dystrophic, 53, 225 Dystrophy, 6, 53, 57, 59, 198, 199, 225 E Eating Disorders, 72, 225 Effector, 208, 220, 225, 251 Efferent, 222, 225, 244 Efficacy, 31, 32, 33, 35, 36, 43, 51, 61, 63, 72, 76, 77, 146, 225, 240 Electrolyte, 226, 238, 248, 261 Electromyography, 118, 198, 226 Electrons, 62, 212, 214, 217, 226, 238, 241, 248, 256 Electrophoresis, 71, 226 Elementary Particles, 226, 241, 255

Embryo, 159, 160, 161, 169, 210, 215, 217, 226, 236, 242, 268 Embryogenesis, 66, 226 Encephalitis, 141, 226 Encephalitis, Viral, 226 Endemic, 226, 262 Endogenous, 30, 31, 34, 49, 62, 216, 224, 226, 227, 228, 251, 266 Endorphins, 226, 247 Endoscope, 226 Endoscopic, 220, 226 Endothelial cell, 226, 229, 265 Endothelium, 226, 227, 247 Endothelium-derived, 227, 247 Endotoxins, 220, 227 Enhancer, 30, 40, 227 Enkephalins, 227, 247 Entorhinal Cortex, 227, 233 Environmental Health, 41, 189, 190, 227 Enzymatic, 65, 68, 216, 220, 227, 250 Enzyme Inhibitors, 63, 227 Eosinophils, 227, 232 Epidemic, 227, 262 Epidemiological, 86, 227 Epinephrine, 224, 227, 247, 267 Epithelial, 214, 227, 233 Epithelial Cells, 227, 233 Erythrocytes, 211, 215, 227, 257 Ether, 227, 250 Ethnic Groups, 174, 177, 227 Eukaryote, 65, 227 Eukaryotic Cells, 227, 236, 248, 268 Evoke, 76, 227, 262 Excitability, 48, 85, 90, 228 Excitation, 30, 34, 39, 228, 247 Excitatory, 34, 38, 43, 48, 55, 228, 231 Excitatory Amino Acids, 43, 228 Excitotoxicity, 34, 48, 59, 63, 76, 93, 120, 228 Excrete, 212, 228, 238 Exogenous, 226, 228, 230 Exon, 19, 22, 228 Expiration, 228, 258, 270 Expiratory, 104, 228 Extensor, 92, 228 External radiation, 228, 262 Extracellular, 39, 43, 55, 103, 210, 213, 221, 228, 241, 255, 261 Extracellular Matrix, 221, 228, 241 Extracellular Matrix Proteins, 228, 241 Extremity, 228, 249 Eye Color, 161, 228

Index 275

Eye Infections, 208, 228 Eye Movements, 59, 73, 228 F Fallopian tube, 228, 268 Family Planning, 190, 229 Fasciculation, 229, 246 Fat, 212, 215, 218, 222, 229, 239, 244, 261 Fathers, 169, 229 Fatigue, 32, 109, 114, 229, 244 Fatty acids, 120, 229, 254, 265 Fetus, 177, 178, 180, 184, 229, 252, 253, 262, 268 Fibroblast Growth Factor, 82, 229 Fibrosis, 161, 164, 168, 169, 229, 259 Flatus, 229, 230 Flexion, 35, 229 Flexor, 228, 229 Fluorescence, 28, 29, 39, 71, 104, 229 Fold, 38, 53, 229 Forearm, 215, 229 Frameshift, 162, 229 Frameshift Mutation, 162, 229 Free Radicals, 59, 212, 224, 229 Frontal Lobe, 229, 244 Functional magnetic resonance imaging, 123, 229 Fundus, 229 G Ganglia, 208, 213, 230, 245, 250, 263 Ganglion, 91, 230 Gap Junctions, 230, 264 Gas, 78, 219, 224, 229, 230, 234, 247, 256, 258, 269 Gas exchange, 230, 258, 269 Gastric, 216, 230 Gastrin, 230, 234 Gastroenteritis, 215, 230 Gastrointestinal, 98, 215, 227, 230, 239, 260, 263, 267 Gastrointestinal tract, 230, 239, 260, 267 Gastrostomy, 96, 230 Gene Expression, 33, 52, 54, 76, 77, 157, 158, 230 Gene Products, rev, 230, 231 Gene Targeting, 47, 230 Gene Therapy, 80, 98, 112, 182, 183, 184, 208, 230 Generator, 231, 264 Genes, env, 168, 231 Genetic Code, 231, 247 Genetic Engineering, 214, 220, 231

Genetic testing, 20, 22, 171, 175, 176, 177, 178, 179, 180, 181, 186, 231 Genital, 220, 231, 268 Genitourinary, 231, 268 Genomics, 187, 231 Genotype, 42, 96, 231, 251 Germ Cells, 160, 184, 231, 241, 248, 261, 264 Germline mutation, 160, 231, 233 Gland, 209, 231, 240, 249, 252, 255, 259, 262, 265 Glucose, 77, 215, 224, 231, 232, 233, 236, 237, 259 Glutamic Acid, 139, 231, 247, 254 Glutathione Peroxidase, 231, 259 Glycine, 64, 100, 210, 232, 247, 259 Glycogen, 232, 244 Glycosylation, 111, 232 Gonadal, 232, 262 Gonads, 217, 232 Governing Board, 232, 253 Grade, 93, 232 Granule, 38, 223, 232, 258 Granulocyte, 105, 232 Growth factors, 232, 242 Guanine, 10, 150, 232, 256 Guanylate Cyclase, 232, 247 H Habitat, 232, 247 Hair Color, 161, 232 Half-Life, 217, 232 Haptens, 209, 232 Health Promotion, 31, 232 Health Services, 44, 232 Heart attack, 216, 232 Hemochromatosis, 177, 232 Hemodialysis, 232, 238 Hemoglobin, 151, 211, 227, 232, 233 Hemoglobinopathies, 231, 233 Hemolytic, 233, 265 Hemophilia, 169, 233 Hemorrhage, 233, 263 Hemostasis, 233, 260 Hepatic, 141, 142, 233, 253 Hepatocytes, 101, 233 Hepatotoxicity, 67, 233 Hereditary, 8, 9, 40, 141, 149, 150, 160, 169, 175, 231, 233, 244, 245, 250, 258 Hereditary mutation, 160, 231, 233 Heredity, 152, 230, 231, 233 Heterogeneity, 122, 209, 233 Heterozygote, 57, 233

276

Amyotrophic Lateral Sclerosis

Hippocampus, 25, 39, 43, 223, 233, 246, 263 Histology, 51, 101, 233, 246 Histones, 152, 219, 233 Homeostasis, 70, 71, 74, 233 Homogeneous, 9, 234 Homologous, 46, 67, 209, 222, 230, 231, 233, 234, 259, 264, 267 Homozygote, 57, 234 Hormonal, 213, 234 Hormone, 157, 214, 216, 224, 227, 230, 234, 237, 241, 254, 260, 265 Humoral, 143, 234 Humour, 234 Hybrid, 39, 45, 58, 234 Hydrogen, 74, 208, 214, 216, 224, 228, 231, 234, 239, 243, 244, 248, 251, 255, 263 Hydrogen Bonding, 234, 248 Hydrogen Peroxide, 74, 231, 234, 239, 263 Hydrolysis, 65, 72, 234, 251, 252, 255 Hyperbaric, 234 Hyperbaric oxygen, 234 Hyperreflexia, 114, 234, 264 Hypersensitivity, 209, 224, 234, 239 Hypertension, 216, 234, 237 Hypochlorous Acid, 64, 234 Hypokinesia, 234, 249 Hypoxia, 36, 235, 265 Hypoxic, 30, 235 I Imaging procedures, 235, 266 Immune response, 50, 143, 211, 213, 232, 235, 263, 269 Immune system, 49, 92, 142, 235, 239, 241, 244, 268, 270 Immunity, 50, 235 Immunoassay, 61, 235 Immunodeficiency, 141, 235 Immunodeficiency syndrome, 141, 235 Immunoglobulins, 142, 235 Immunohistochemistry, 52, 235 Immunologic, 219, 235, 250 Immunology, 209, 235 Immunosuppression, 49, 235, 240 Immunosuppressive, 50, 235 Immunosuppressive Agents, 235 Immunotherapy, 224, 235 Impairment, 104, 145, 205, 213, 214, 228, 235, 242 Implantation, 221, 235 In situ, 52, 71, 235 In Situ Hybridization, 52, 236

In vitro, 30, 31, 40, 43, 44, 48, 50, 54, 57, 61, 68, 70, 76, 113, 231, 236, 265 In vivo, 24, 25, 27, 30, 35, 36, 43, 44, 48, 51, 54, 61, 68, 70, 74, 75, 76, 77, 231, 236, 240, 265 Incision, 236, 237, 266 Incubation, 236, 239 Incubation period, 236, 239 Induction, 43, 50, 66, 77, 104, 211, 236 Infancy, 187, 219, 236 Infantile, 8, 9, 236, 250 Infection, 63, 219, 226, 228, 230, 232, 235, 236, 239, 240, 246, 250, 263, 270 Infertility, 65, 236 Inflammation, 41, 69, 183, 212, 219, 226, 228, 229, 230, 236, 239, 242, 249, 252, 255 Informed Consent, 178, 181, 186, 236 Infusion, 236, 266 Initiation, 61, 236, 240, 266 Inner ear, 217, 236 Inositol, 236, 242 Insight, 27, 40, 41, 48, 55, 60, 66, 71, 236 Insulator, 236, 244 Insulin, 60, 96, 237, 258 Insulin-dependent diabetes mellitus, 237 Insulin-like, 60, 96, 237 Interleukin-1, 54, 237 Interleukin-2, 237 Intermediate Filaments, 17, 237, 246 Interneurons, 49, 237 Interphase, 218, 237 Intestinal, 39, 237 Intestines, 230, 237, 259 Intoxication, 237, 270 Intracellular, 41, 52, 55, 60, 72, 76, 105, 236, 237, 241, 242, 247, 254, 257, 259, 260 Intracranial Hypertension, 237, 249 Intramuscular, 61, 237 Intrathecal, 83, 103, 105, 237 Intravenous, 142, 236, 237 Intrinsic, 48, 209, 237 Invasive, 35, 91, 110, 143, 235, 237, 241 Involuntary, 213, 215, 225, 237, 257, 261 Ion Channels, 213, 237, 264 Ions, 45, 70, 71, 214, 224, 226, 234, 238 Iris, 228, 238 Ischemia, 30, 36, 39, 49, 54, 213, 238 Ischemic stroke, 30, 238 Isoenzyme, 222, 238 Isometric Contraction, 35, 47, 238 K Karyotype, 154, 238

Index 277

Kb, 11, 238 Kidney Failure, 163, 238 Kidney Failure, Acute, 238 Kidney Failure, Chronic, 238 Kidney stone, 238, 268 L Labile, 220, 238 Laceration, 238, 264 Language Disorders, 59, 238 Laryngeal, 117, 239 Larynx, 107, 239, 266, 270 Lentivirus, 40, 239 Lesion, 48, 97, 239, 240 Lethal, 50, 142, 239 Leucocyte, 209, 239 Leukaemia, 93, 239 Leukemia, 82, 231, 239 Leukotrienes, 212, 239 Libido, 211, 239 Life Expectancy, 67, 239 Ligaments, 222, 239 Ligands, 39, 239 Linkage, 11, 96, 110, 239 Lip, 96, 142, 239 Lipid, 29, 48, 237, 239, 244, 249 Lipid Peroxidation, 239, 249 Liposomes, 62, 239 Liver, 146, 158, 212, 214, 216, 219, 232, 233, 240, 253 Loading dose, 35, 240 Localization, 39, 45, 75, 235, 240, 245 Localized, 236, 240, 252, 264 Longitudinal study, 44, 86, 87, 113, 240 Long-Term Potentiation, 41, 240 Luciferase, 49, 240 Lumbar, 83, 91, 206, 240 Lymph, 218, 226, 227, 234, 240 Lymph node, 218, 240 Lymphatic, 227, 236, 240, 242 Lymphocyte Depletion, 235, 240 Lymphocytes, 50, 143, 211, 237, 239, 240, 270 Lymphoid, 50, 211, 239, 240 Lysine, 233, 240 M Macroglia, 240, 242 Macrophage, 160, 237, 241 Magnetic Resonance Imaging, 241 Magnetic Resonance Spectroscopy, 48, 89, 241 Malformation, 85, 241 Malnutrition, 213, 241, 244

Mammography, 168, 241 Manifest, 46, 241 Matrix metalloproteinase, 119, 241 Mechanical ventilation, 101, 241 Mediate, 38, 51, 60, 77, 224, 241 Mediator, 54, 237, 241, 260 Medical Records, 168, 181, 241 MEDLINE, 190, 241 Meiosis, 159, 219, 241, 264 Melanin, 238, 241, 251, 267 Melanoma, 241, 268 Membrane Proteins, 240, 241 Memory, 24, 38, 43, 56, 223, 240, 241 Meninges, 217, 218, 225, 242, 262 Meningitis, 141, 242 Mental Health, iv, 23, 94, 189, 191, 242, 255 Mental Processes, 224, 242, 255 Mental Retardation, 59, 173, 175, 177, 242 Mesenchymal, 82, 242 Mesoderm, 66, 242 Metabolic disorder, 242, 250 Metabolite, 242, 256 Metabotropic, 52, 99, 108, 113, 242 Metastasis, 241, 242 Microbe, 242, 266 Microbiology, 208, 213, 242 Microfilaments, 237, 242 Microglia, 53, 213, 242 Micronutrients, 31, 242 Microorganism, 220, 242, 270 Microscopy, 23, 57, 72, 104, 242 Microtubule-Associated Proteins, 242, 246 Microtubules, 65, 218, 237, 242, 243, 246 Migration, 35, 40, 52, 65, 243 Minocycline, 53, 63, 243 Miscarriage, 180, 243 Mitochondria, 23, 29, 36, 41, 59, 70, 87, 108, 112, 120, 150, 151, 163, 169, 170, 243, 248 Mitosis, 159, 212, 218, 219, 243 Mitotic, 52, 65, 218, 243 Mitotic Spindle Apparatus, 218, 243 Modification, 20, 22, 231, 243, 256 Modulator, 71, 243 Molecular mass, 65, 243 Monitor, 39, 222, 243, 247 Monoclonal, 89, 142, 243, 256 Monoclonal antibodies, 89, 142, 243 Monocytes, 50, 237, 243, 245 Mononuclear, 35, 91, 243, 244 Monosomy, 163, 211, 244

278

Amyotrophic Lateral Sclerosis

Morphological, 226, 244 Morphology, 24, 244 Mosaicism, 160, 244 Motility, 72, 244, 260 Motor Cortex, 85, 244, 257 Motor nerve, 23, 63, 85, 229, 244, 250 Movement Disorders, 72, 225, 244, 265 Mucinous, 230, 244 Multiple sclerosis, 29, 59, 69, 78, 88, 141, 244 Muscle Contraction, 57, 244 Muscle Fatigue, 85, 244 Muscle Fibers, 26, 122, 244, 245 Muscle Hypertonia, 244, 246 Muscular Atrophy, 15, 18, 19, 20, 21, 22, 23, 26, 53, 88, 90, 198, 200, 244 Muscular Diseases, 244, 246, 249 Musculature, 143, 234, 244 Mutagenesis, 65, 244 Mutagens, 229, 244, 245 Myelin, 48, 59, 244, 245 Myeloid Cells, 50, 245 Myosin, 244, 245 Myotonic Dystrophy, 172, 245, 267 N NCI, 1, 188, 219, 245, 249 Necrosis, 212, 245 Neocortex, 245, 246 Neonatal, 245, 251 Neoplasia, 39, 245 Nerve Degeneration, 245 Nerve Growth Factor, 27, 245, 247 Nervous System Diseases, 60, 245 Networks, 39, 245 Neural, 39, 54, 57, 58, 66, 72, 74, 101, 130, 210, 216, 234, 242, 245 Neural Pathways, 245 Neuroblastoma, 29, 104, 245 Neurodegenerative Diseases, 25, 28, 33, 36, 37, 44, 45, 48, 51, 52, 55, 67, 76, 121, 141, 213, 245 Neurofibrillary Tangles, 25, 83, 99, 246 Neurofilaments, 16, 17, 28, 246 Neurogenic, 26, 116, 147, 246 Neurologic, 24, 30, 52, 74, 80, 136, 198, 246, 251 Neurologist, 24, 44, 51, 132, 246 Neuromuscular, 26, 45, 53, 55, 59, 75, 107, 123, 198, 208, 245, 246, 249 Neuromuscular Diseases, 59, 246, 249 Neuromuscular Junction, 46, 208, 245, 246 Neuronal Plasticity, 57, 246

Neuropathy, 12, 141, 169, 246, 250 Neuropeptide, 216, 246 Neurophysiology, 73, 82, 84, 86, 90, 92, 94, 114, 126, 127, 132, 134, 138, 223, 245, 246 Neurosurgery, 69, 72, 83, 85, 87, 91, 112, 120, 246 Neurotoxic, 43, 142, 246, 265 Neurotoxicity, 25, 54, 68, 103, 141, 142, 246 Neurotoxin, 43, 77, 246 Neurotransmitter, 41, 48, 52, 55, 120, 208, 215, 216, 224, 228, 231, 232, 237, 247, 260, 263, 264 Neurotrophins, 41, 247 Niacin, 247, 267 Niche, 247 Nitric Oxide, 27, 50, 62, 64, 84, 99, 247 Nitrogen, 31, 39, 211, 228, 238, 243, 247, 267, 268 Norepinephrine, 48, 224, 247 Nuclear, 42, 48, 65, 69, 150, 213, 226, 227, 230, 245, 247 Nuclear Envelope, 150, 247 Nuclear Pore, 247 Nucleates, 218, 247 Nuclei, 226, 231, 233, 241, 243, 247, 255 Nucleic acid, 46, 214, 223, 231, 236, 245, 247, 254, 256, 258 Nucleic Acid Hybridization, 46, 247 Nurse Practitioners, 178, 248 Nutritional Support, 230, 248 O Obsessive-Compulsive Disorder, 59, 248 Ocular, 12, 69, 248 Oliguria, 238, 248 Oncogenic, 239, 248 Oocytes, 55, 248 Open Reading Frames, 239, 248 Orderly, 219, 248 Organ Culture, 248, 265 Organelles, 149, 150, 218, 223, 243, 248, 252 Osteoclasts, 216, 248 Outpatient, 248 Ovaries, 177, 248, 260, 268 Overexpress, 26, 248 Oxidation, 29, 208, 212, 222, 231, 239, 248, 249 Oxidative Phosphorylation, 77, 151, 248 Oxidative Stress, 27, 32, 36, 62, 77, 84, 104, 249 Oxides, 57, 249

Index 279

P Pachymeningitis, 242, 249 Palliative, 114, 128, 145, 146, 249, 265 Pancreas, 214, 232, 237, 249, 267 Pancreatic, 216, 249 Paralysis, 8, 9, 50, 67, 73, 101, 143, 205, 212, 216, 249, 261 Paraparesis, 102, 249 Paraplegia, 9, 249 Parietal, 58, 249 Parietal Lobe, 249 Parkinsonism, 51, 83, 87, 94, 117, 127, 145, 146, 249 Particle, 249, 261, 266 Patch, 38, 55, 103, 249 Paternity, 177, 249 Pathologic, 37, 58, 76, 77, 102, 212, 214, 215, 222, 234, 249, 262 Pathologic Processes, 212, 249 Pathophysiology, 32, 57, 63, 249 PDQ, 188, 249 Pelvis, 208, 238, 240, 248, 249, 268 Penicillin, 250, 269 Penis, 250, 268 Pentoxifylline, 105, 250 Peptide, 36, 58, 216, 229, 250, 252, 255 Perception, 250, 259 Perfusion, 235, 250 Perineal, 45, 250 Perineum, 250 Peripheral blood, 91, 103, 143, 250 Peripheral Nerves, 245, 250, 262 Peripheral Nervous System, 37, 141, 142, 225, 227, 245, 246, 247, 249, 250, 253, 263 Peripheral Nervous System Diseases, 246, 249, 250 Peripheral Neuropathy, 59, 250 Perivascular, 216, 242, 250 Peroxidase, 36, 239, 250 Peroxide, 250 Peroxisomal Disorders, 48, 250 PH, 39, 79, 251 Phagocytosis, 242, 251 Pharmacodynamics, 76, 251 Pharmacologic, 112, 232, 251, 266 Pharmacotherapy, 80, 251 Phenotype, 9, 20, 22, 25, 26, 49, 50, 51, 57, 62, 87, 102, 251 Phenylalanine, 157, 251, 267 Phenylbutyrate, 251 Phosphodiesterase, 250, 251 Phospholipases, 251, 260

Phosphorus, 216, 251 Phosphorylation, 28, 45, 151, 251 Phosphotyrosine, 40, 251 Photoallergy, 251 Photosensitivity, 142, 251, 253 Physical Examination, 175, 251 Physiologic, 209, 214, 232, 234, 242, 251, 254, 257, 267 Physiology, 23, 41, 48, 55, 62, 91, 213, 246, 252 Pilot study, 109, 252 Pitch, 119, 252 Pituitary Gland, 229, 252 Placenta, 252, 254, 268 Plants, 231, 244, 247, 252, 259, 266, 267 Plasma, 37, 83, 150, 211, 216, 217, 233, 238, 252 Plasma cells, 211, 252 Plasticity, 24, 34, 41, 43, 52, 56, 59, 252 Plastids, 248, 252 Platelet Activation, 252, 260 Platelet Aggregation, 210, 247, 250, 252, 265 Platelets, 247, 252 Pneumonia, 221, 252 Point Mutation, 68, 95, 252 Polymers, 28, 252, 255 Polymorphic, 50, 219, 223, 252 Polymorphism, 67, 99, 112, 121, 179, 252 Polypeptide, 16, 65, 210, 220, 252, 270 Porphyria, 142, 253 Porphyria Cutanea Tarda, 142, 253 Porphyria, Hepatic, 253 Posterior, 210, 213, 218, 225, 238, 249, 253 Postnatal, 57, 253, 262 Postsynaptic, 24, 253, 260, 264 Post-synaptic, 39, 253 Post-translational, 45, 253 Post-traumatic, 244, 253 Potentiates, 237, 253 Potentiation, 85, 240, 253, 260 Practice Guidelines, 191, 253 Preclinical, 61, 253 Precursor, 27, 30, 41, 51, 58, 92, 212, 224, 225, 226, 227, 247, 251, 253, 267, 269 Prenatal, 177, 180, 226, 253 Presynaptic, 34, 39, 247, 253, 264 Presynaptic Terminals, 34, 253, 264 Prevalence, 25, 143, 165, 253 Prion, 25, 59, 253 Progeny, 68, 254 Progesterone, 254, 262

280

Amyotrophic Lateral Sclerosis

Progression, 27, 47, 54, 63, 68, 81, 107, 110, 116, 211, 254 Progressive disease, 3, 200, 254 Projection, 237, 247, 254, 257 Proline, 14, 15, 220, 254 Promoter, 49, 52, 122, 254 Prone, 163, 172, 254 Prophase, 248, 254, 264 Prospective study, 113, 240, 254 Prostaglandin, 64, 254, 265 Prostate, 214, 255, 267, 268 Prosthesis, 58, 255 Protein Transport, 28, 255 Proteolytic, 52, 209, 220, 255 Protocol, 89, 183, 255 Protons, 234, 241, 255, 256 Proximal, 207, 224, 253, 255 Psychiatry, 34, 59, 85, 87, 91, 112, 120, 124, 145, 255, 269 Psychic, 239, 242, 255 Psychoactive, 255, 270 Psychology, 26, 45, 75, 221, 224, 255 Public Health, 52, 65, 78, 79, 146, 191, 255 Public Policy, 190, 256 Pulmonary, 35, 114, 215, 219, 238, 239, 256, 258, 269 Pulmonary Artery, 215, 256, 269 Pulmonary Edema, 219, 238, 256 Pulmonary Ventilation, 256, 258 Pulse, 243, 256 Purines, 214, 256, 259 Pyrimidines, 214, 256, 259 Q Quality of Life, 35, 74, 91, 100, 256, 263 Quinolinic, 104, 256 Quinolinic Acid, 104, 256 R Race, 238, 243, 256 Radiation, 115, 208, 226, 228, 229, 234, 235, 256, 262, 268, 270 Radiation therapy, 208, 228, 234, 256 Radioactive, 232, 234, 235, 243, 247, 248, 256 Radioisotope, 256, 266 Radiological, 25, 256 Radiology, 90, 109, 256 Random Allocation, 257 Randomization, 32, 33, 47, 63, 257 Randomized, 32, 63, 226, 257 Reaction Time, 115, 257 Reactive Oxygen Species, 29, 257 Reagent, 219, 240, 257

Receptor, 24, 27, 30, 36, 38, 39, 41, 46, 50, 53, 59, 79, 80, 96, 99, 108, 113, 142, 166, 208, 211, 222, 224, 242, 257, 260 Receptors, Serotonin, 257, 260 Recombinant, 38, 55, 61, 72, 77, 183, 257, 269 Recombination, 67, 77, 230, 231, 257 Rectum, 212, 220, 229, 230, 255, 257 Red blood cells, 227, 233, 253, 257, 259 Red Nucleus, 213, 257 Refer, 1, 155, 159, 161, 166, 184, 216, 220, 226, 237, 240, 257, 266 Reflex, 72, 114, 228, 257 Refraction, 257, 261 Regeneration, 41, 53, 229, 257 Regimen, 225, 251, 257 Rehabilitative, 89, 257 Reliability, 34, 44, 258 Reproductive cells, 162, 173, 174, 231, 233, 258 Respiration, 243, 258 Respirator, 241, 258 Respiratory failure, 4, 111, 258 Respiratory Physiology, 258, 269 Respiratory System, 4, 258 Retinoblastoma, 165, 258 Retinoid, 66, 258 Retrograde, 65, 258 Retroviral vector, 230, 258 Rheology, 250, 258 Ribonucleic acid, 157, 258 Ribonucleoproteins, 20, 258 Ribose, 208, 258 Ribosome, 157, 258, 267 Rigidity, 249, 252, 258 Riluzole, 47, 67, 81, 108, 145, 146, 258 Risk factor, 25, 42, 66, 107, 254, 258 Robotics, 58, 258 Rod, 218, 219, 259 S Salivary, 259, 260 Saponins, 259, 262 Scatter, 259, 268 Schizoid, 259, 270 Schizophrenia, 59, 170, 259, 270 Schizotypal Personality Disorder, 259, 270 Screening, 38, 66, 117, 168, 177, 178, 180, 220, 249, 259 Secretion, 27, 86, 103, 234, 237, 242, 259, 268 Secretory, 70, 259, 264 Segmental, 27, 259

Index 281

Segmentation, 259 Segregation, 219, 257, 259 Selenium, 259 Seminal vesicles, 259, 268 Semisynthetic, 243, 259 Sensor, 39, 259 Sequencing, 45, 67, 185, 259 Serine, 14, 15, 76, 259 Serologic, 235, 260 Serotonin, 48, 247, 251, 257, 260, 267 Serum, 32, 74, 84, 119, 143, 210, 220, 222, 238, 240, 260 Sex Characteristics, 209, 211, 260 Shock, 260, 267 Sialorrhea, 84, 260 Side effect, 67, 184, 187, 209, 260, 263, 266 Signal Transduction, 36, 56, 60, 236, 251, 260 Signs and Symptoms, 4, 5, 11, 171, 172, 177, 260 Skeletal, 26, 37, 103, 116, 120, 122, 211, 219, 222, 244, 260, 261 Skeleton, 39, 208, 254, 260 Skull, 260, 264 Small intestine, 225, 234, 237, 260 Smooth muscle, 210, 244, 255, 260, 261, 263 Social Environment, 256, 260 Social Work, 174, 261 Sodium, 48, 261 Soft tissue, 215, 260, 261 Soma, 46, 261 Somatic, 160, 163, 174, 209, 222, 226, 234, 241, 243, 250, 261 Somatic cells, 160, 163, 174, 241, 243, 261 Somatic mutations, 163, 261 Sound wave, 221, 261 Spasm, 246, 261 Spastic, 8, 9, 102, 261 Spasticity, 72, 97, 205, 261 Specialist, 178, 202, 261 Specificity, 20, 37, 72, 209, 261 Spectrometer, 45, 261 Spectroscopic, 48, 116, 241, 261 Spectrum, 20, 34, 217, 242, 261 Speech Disorders, 26, 262 Speech Intelligibility, 26, 262 Sperm, 65, 159, 160, 162, 163, 172, 173, 174, 177, 184, 211, 219, 231, 233, 258, 261, 262, 267 Spinal Cord Diseases, 249, 262 Spinal Nerves, 250, 262

Stabilization, 118, 262 Staphylococcus, 230, 243, 262 Steel, 219, 262 Stem Cells, 30, 35, 82, 103, 262, 268 Stenosis, 204, 262, 263 Stereotactic, 73, 262 Stereotaxis, 72, 262 Sterility, 236, 262 Steroid, 45, 259, 262 Stillbirth, 175, 262 Stimulant, 262, 269 Stimulus, 34, 228, 237, 257, 262, 265 Stomach, 230, 234, 237, 260, 263 Stool, 220, 263 Strand, 150, 263 Stress, 31, 32, 36, 63, 107, 112, 213, 217, 230, 249, 263 Stricture, 262, 263 Stroke, 5, 7, 24, 30, 34, 36, 38, 55, 56, 59, 74, 75, 141, 168, 189, 198, 199, 216, 238, 263 Subacute, 236, 263 Subclinical, 236, 263 Subiculum, 233, 263 Subspecies, 261, 263 Substrate, 227, 263 Superoxide Dismutase, 12, 13, 14, 28, 37, 41, 46, 49, 50, 62, 64, 67, 68, 70, 71, 74, 77, 80, 85, 86, 87, 88, 89, 90, 93, 94, 95, 96, 100, 101, 102, 103, 104, 105, 106, 109, 112, 116, 118, 120, 121, 263 Supplementation, 29, 263 Support group, 207, 263 Supportive care, 67, 249, 263 Suppression, 77, 263 Sympathetic Nervous System, 213, 246, 263 Sympathomimetic, 225, 227, 247, 263 Synapse, 96, 246, 253, 264, 267 Synapsis, 264 Synaptic, 24, 34, 38, 39, 41, 43, 48, 52, 56, 60, 71, 72, 85, 240, 247, 260, 264 Synaptic Transmission, 24, 38, 43, 71, 264 Synaptic Vesicles, 264 Synchrotron, 57, 264 Synergistic, 54, 264 Systemic, 49, 92, 101, 215, 227, 236, 237, 246, 256, 264 T Telencephalon, 213, 218, 264 Temporal, 39, 57, 233, 264 Tendon, 230, 261, 264 Terminator, 220, 264

282

Amyotrophic Lateral Sclerosis

Testis, 50, 232, 264 Tetani, 264, 265 Tetanic, 264 Tetanus, 60, 264, 265 Tetanus Toxin, 60, 265 Tetracycline, 30, 225, 243, 265 Thalamic, 213, 265 Thalamic Diseases, 213, 265 Thanatology, 145, 265 Therapeutics, 34, 40, 48, 67, 146, 265 Thermal, 74, 115, 224, 265 Threonine, 259, 265 Threshold, 228, 234, 265 Thrombin, 252, 255, 265 Thrombomodulin, 255, 265 Thrombosis, 255, 263, 265 Thromboxanes, 212, 265 Thyroid, 177, 216, 265, 267 Thyroid Gland, 177, 265 Thyroid Hormones, 265, 267 Tissue Culture, 47, 265 Tolerance, 50, 208, 266 Tone, 244, 261, 266 Tonicity, 225, 266 Tooth Preparation, 208, 266 Topical, 234, 266 Toxic, iv, 14, 15, 25, 33, 36, 37, 50, 53, 68, 70, 74, 76, 77, 79, 149, 223, 225, 235, 246, 259, 266 Toxicity, 24, 28, 33, 36, 43, 49, 50, 54, 61, 62, 63, 68, 70, 76, 77, 93, 109, 113, 124, 143, 183, 266 Toxicology, 50, 61, 130, 190, 266 Toxin, 84, 264, 265, 266 Trace element, 78, 266 Tracer, 78, 266 Trachea, 239, 265, 266 Tracheotomy, 47, 112, 266 Traction, 219, 266 Transcription Factors, 30, 52, 158, 266 Transduction, 56, 260, 266 Transfection, 29, 30, 214, 231, 266 Transferases, 232, 266 Transfusion, 84, 266 Transgenes, 30, 40, 266 Translation, 61, 69, 157, 158, 230, 267 Translational, 45, 48, 57, 75, 267 Translocate, 41, 65, 267 Translocation, 24, 55, 70, 219, 255, 267 Transmitter, 208, 213, 224, 228, 237, 241, 247, 264, 267 Transplantation, 35, 50, 103, 238, 240, 267

Trauma, 30, 43, 54, 213, 245, 265, 267 Tremor, 249, 267 Trinucleotide Repeat Expansion, 172, 267 Trinucleotide Repeats, 267 Trisomy, 163, 211, 267 Trophic, 62, 245, 267 Tropism, 72, 267 Tryptophan, 29, 220, 256, 260, 267 Tubulin, 243, 267 Tumor marker, 214, 267 Tumour, 230, 267 Tyrosine, 31, 39, 41, 51, 62, 224, 251, 267 U Ubiquitin, 91, 93, 246, 268 Ultraviolet radiation, 160, 268 Umbilical Arteries, 268 Umbilical Cord, 35, 103, 268 Umbilical cord blood, 35, 103, 268 Uremia, 238, 268 Ureters, 238, 268 Urethra, 250, 255, 268 Uric, 31, 256, 268 Urinary, 206, 217, 231, 248, 268 Urinary tract, 217, 268 Urine, 212, 215, 222, 238, 248, 268 Urogenital, 39, 231, 268 Urogenital System, 39, 268 Uroporphyrinogen Decarboxylase, 253, 268 URR, 19, 268 Uterus, 177, 218, 229, 230, 248, 254, 268, 269 V Vaccine, 255, 268 Vacuoles, 248, 268 Vagina, 218, 224, 268, 269 Valine, 13, 269 Vascular, 36, 94, 117, 121, 227, 236, 247, 252, 262, 265, 269 Vascular endothelial growth factor, 94, 117, 121, 269 Vasodilator, 215, 216, 225, 269 Vasomotor, 82, 269 VE, 42, 92, 101, 269 Vector, 72, 182, 183, 266, 269 Vein, 237, 247, 268, 269 Venous, 255, 269 Ventilation, 78, 91, 102, 107, 110, 121, 269 Ventricle, 233, 256, 269 Venules, 215, 216, 269 Vertebrae, 262, 269 Vesicular, 255, 269

Index 283

Veterinary Medicine, 190, 269 Viral, 51, 68, 72, 182, 226, 230, 231, 248, 266, 269 Viral vector, 51, 72, 269 Virulence, 213, 266, 269 Virus, 72, 122, 182, 227, 231, 258, 266, 269 Viscera, 261, 269 Vital Capacity, 32, 35, 63, 270 Vitro, 30, 44, 54, 177, 270 Vivo, 30, 43, 44, 54, 68, 77, 240, 270 Vocal cord, 101, 270 Voltage-gated, 48, 270 W White blood cell, 160, 211, 232, 240, 241, 252, 270

Windpipe, 265, 270 Withdrawal, 62, 74, 270 Womb, 268, 270 Wound Healing, 229, 241, 270 X Xenograft, 211, 270 X-ray, 26, 57, 71, 104, 206, 217, 229, 247, 256, 262, 270 Y Yeasts, 251, 270 Z Zygote, 221, 244, 270 Zymogen, 255, 270